Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([OH:24])(=[O:23])[CH2:18][CH2:19][C:20]([CH3:22])=O.Cl>C(OC(C)C)(C)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][C:20]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)([CH3:22])[CH2:19][CH2:18][C:17]([OH:24])=[O:23])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CCC(=O)O
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CC(C)OC(C)C
Product: CC(CCC(=O)O)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 16.3 %

Procedure:
To a solution of 2,6-di-t-butyl-4-mercaptophenol (4.77 g, 20.0 mmol) in isopropyl ether (50 mL) was added levulinic acid (1.16 g, 10.0 mmol) and a catalytic amount of concentrated hydrochloric acid. The mixture was heated under reflux over 10 days. The solvent was distilled off from the reaction mixture, and the resulting residue was purified by a flash column chromatography (filler: manufactured by Kanto Kagaku, K.K., 60Nmesh40-100, developing solvent:n-hexane/ethyl acetate (volume ratio)=5/1 to 2/1) to give 4,4-bis(3,5-di-t-butyl-4-hydroxyphenylthio)pentanoic acid (yield 935 mg and 16%).
Reaction SMILES: CC1(C)[O:6][C@H:5]2[C:7](=[O:51])[O:8][C@H:9]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][C:21]5[C:27](=[O:28])[NH:26][C:25]6[CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]7[CH:41]=[CH:40][C:39]([N:42]8[CH2:47][CH2:46][O:45][CH2:44][CH2:43]8)=[CH:38][CH:37]=7)[CH:31]=[CH:32][C:24]=6[NH:23][C:22]=5[CH:48]=4)=[CH:14][C:13]=3[O:49][CH3:50])[C@H:4]2[O:3]1.FC(F)(F)C(O)=O>ClCCl>[OH:3][C@H:4]1[C@@H:5]([OH:6])[C:7](=[O:51])[O:8][C@@H:9]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:27](=[O:28])[NH:26][C:25]4[CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]5[CH:41]=[CH:40][C:39]([N:42]6[CH2:43][CH2:44][O:45][CH2:46][CH2:47]6)=[CH:38][CH:37]=5)[CH:31]=[CH:32][C:24]=4[NH:23][C:22]=3[CH:48]=2)=[CH:14][C:13]=1[O:49][CH3:50]
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OC[C@H]1OC(=O)[C@@H]2OC(C)(C)O[C@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OC[C@H]1OC(=O)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A mixture of Example 642B (11.2 mg, 0.016 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (50 μL, 0.65 mmol) and stirred at room temperature. The reaction mixture was then concentrated and purified by preparative HPLC. MS (ESI) m/e 668 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 9.74 (s, 1H), 7.84 (s, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.25 (d, J=1.5 Hz, 1H), 7.22 (d, J=1.8 Hz, 1H), 7.15-1.19 (m, 2H), 7.07 (d, J=8.3 Hz, 1H), 6.85-6.96 (m, 7H), 4.73 (d, J=5.5 Hz, 1H), 4.59 (t, J=3.4 Hz, 1H), 4.25-4.29 (m, 3H), 4.05 (t, J=6.8 Hz, 2H), 3.86 (s, 3H), 3.75-3.85 (m, 2H), 3.73-3.75 (m, 4H), 3.03-3.05 (m, 4H), 2.87 (t, J=6.6 Hz, 2H).
Reaction SMILES: Br[C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH2:25]([NH2:27])[CH3:26]>CN1C(=O)CCC1.O>[CH2:25]([NH:27][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1)[CH3:26]
Reactant: O=Cc1ccc(-c2nc3nc(Br)nn3cc2-c2ccccc2)cc1
Reactant: CCN
Solvent: O
Solvent: CN1CCCC1=O
Product: CCNc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Temperature: 100 °C

Procedure:
To 90 mg 4-(2-bromo-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described above) in 2 mL NMP were added 0.71 mL ethylamine. The mixture was heated under microwave irradiation to 100° C. for 80 min and then overnight at 100° C. under conventional heating. On cooling the reaction was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated in vacuo to give the crude title compound as an orange oil which was used in the next step without further purification.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:11]1.Cl>CCOCC.O1CCCC1>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:11]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(O)CC1CCCC(=O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CC1CCCC(O)(c2ccccc2)C1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 80 mmol of phenyl magnesium bromide (from 24.2 ml of a 3.3 M solution of phenyl magnesium bromide in ether) in 100 ml of tetrahydrofuran at 10° C. was slowly added 5.0 g (32.1 mmol) of 3-oxocyclohexane-1-acetic acid (prepared by the method of Bartlett and Woods, J.A.C.S. 62, 2933 (1960)) in 25 ml of tetrahydrofuran. The reaction was stirred 1 hr. longer at 25° and then added to 250 ml 1 N hydrochloric acid and 250 ml ether. The organic extract was extracted with 150 ml of 1 N sodium hydroxide. The base extract was reacidified with 200 ml of 1 N hydrochloric acid and extracted with 300 ml of ether. This ether extract was dried over magnesium sulfate and evaporated to an oil. Crystallization from ether gave 3.25 g (43%) of the title compound, MP, 152°, as a pure diastereomer. The mother liquor (4.0 g, 53%) was pure by PMR analysis and contained the other diastereomer. Crystallization of the mother liquor in cyclohexane followed by several recrystallizations gave the other diastereomer of the title compound, MP, 114°-115°.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9]([O-:12])(=[S:11])[CH3:10].[K+].C(OCC)C>CN(C=O)C>[O:6]1[CH2:7][CH2:8][CH:3]([CH2:2][S:11][C:9](=[O:12])[CH3:10])[CH2:4][CH2:5]1
Reactant: BrCC1CCOCC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)SCC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a solution of 0.97 g (5.4 mmol) of 4-bromomethyl tetrahydropyran in DMF (9.7 mL) were added 1.27 g (11.2 mmol) of potassium thioacetate. The reaction was stirred at room temperature for 3 h. Diethyl ether (100 mL) was added and the reaction mixture was washed with saturated aqueous NaHCO3 solution (2×25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, eluent: heptanes, 10% ethyl acetate) to afford 0.81 g of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl)ester.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.[N-:26]=[N+:27]=[N-:28].[Na+].C(OCC)C>CS(C)=O>[N:26]([CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CN=[N+]=[N-])ccc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 93.5 %

Procedure:
To a solution of 600 mg of tert-butyl 5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-24-b in 4 ml dimethyl sulfoxide was added 162 mg of sodium azide, and the mixture was stirred at room temperature for 50 minutes. To the reaction mixture was added 25 ml of diethyl ether. The mixture was sequentially washed with water (×3) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 571 mg of the title compound as pale yellow crystals.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([C:9]1[N:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=O)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:7][CH3:8].C(=O)(O)[O-].[Na+]>>[CH2:6]([C:9]1[N:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH2:5])=[O:29])[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:7][CH3:8]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(N)=O
Temperature: 25 °C
Yield: 45.2 %

Procedure:
Ammonium acetate (20 g) and ethyl 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (4.11 g, 11.6 mmol) were heated overnight at 140° C. in a sealed vessel. The reaction was allowed to cool to ambient temperature, and saturated aqueous sodium bicarbonate was added. The mixture was extracted with chloroform (3×), and the extracts were combined and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) to provide 1.7 g of 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:6][NH:5][N:4]=1.CC(C)([O-])C.[K+].Cl[CH2:21][C:22]1[NH:23][C:24](=[O:32])[C:25]2[CH:30]=[C:29]([CH3:31])[S:28][C:26]=2[N:27]=1>C1COCC1>[OH:11][C:8]([C:7]1[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4][N:5]([CH2:21][C:22]2[NH:23][C:24](=[O:32])[C:25]3[CH:30]=[C:29]([CH3:31])[S:28][C:26]=3[N:27]=2)[CH:6]=1)([CH3:9])[CH3:10]
Reactant: CC(C)(O)c1c[nH]nc1C(F)(F)F
Reactant: Cc1cc2c(=O)[nH]c(CCl)nc2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc2c(=O)[nH]c(Cn3cc(C(C)(C)O)c(C(F)(F)F)n3)nc2s1
Reaction time: 0.03 h
Yield: 3.7 %

Procedure:
A mixture of 2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)propan-2-ol (73 mg, 0.376 mmol) and potassium tert-butoxide (127 mg, 1.13 mmol) in THF (2 mL) was stirred for ˜2 min. To this was added 2-(chloromethyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (81 mg, 0.376 mmol) and the resultant mixture was stirred for 18 h. The reaction mixture was quenched with saturated NH4Cl solution and concentrated in vacuo. The residue was partitioned between DCM and water and the organic layer was separated. The aqueous layer was extracted with further DCM and the combined organics were washed with saturated brine, dried over MgSO4, filtered and concentrated in vacuo to give a light yellow gum. The gum was purified by preparative LCMS to give the product as a white solid (5 mg, 0.014 mmol, 4%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.[N:14](OCCC(C)C)=[O:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[OH:15][N:14]=[C:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3][N:2]([CH3:1])[C:8]1=[O:9]
Reactant: CC(C)CCON=O
Reactant: CN1CCc2ccccc2CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCc2ccccc2C(=NO)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
In a 22 L flask, under nitrogen, was 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (606 g, 3.46 mol) and isoamyl nitrite (543 g, 4.5 mol) in THF (7.88 L). The mixture was cooled to about 0° C. before LiHMDS (1 N THF solution, 4.5 L, 04.5 mol) was added at a rate such that the temperature remained below about 7° C. After addition, the reaction was allowed to stir at room temperature for about 2 h while monitoring for the reaction progress by HPLC. Upon completion of the reaction, the mixture was cooled to about 0° C., and the pH adjusted from 12 to about 2-1 using aqueous HCl (2N). The resulting precipitate was stirred for about 6 h before isolation by filtration and drying to provide 1-hydroxyimino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one 604.7 g (85.6%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([NH2:9])[CH3:8].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[O:24]=[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[N:26]1[CH2:35][CH2:36][CH2:37][CH:38]=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH:9][CH2:38][CH2:37][CH2:36][CH2:35][N:26]1[C:27](=[O:34])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]1=[O:24])[CH3:8]
Reactant: C[C@@H](N)c1ccccn1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1

Procedure:
Using General Procedure B, reaction of (R)-1-pyridin-2-yl-ethylamine (Shin, C-G et al, Bull. Chem. Soc. Jpn. 2002, 75, 1583-1596) in CH2Cl2 and 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde with NaBH(OAc)3 gave 2-[4-(1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dione as a yellow oil. 1H NMR (CDCl3) δ 1.37 (d, 3H, J=6.0 Hz), 1.51-1.54 (m, 1H), 1.66-1.71 (m, 2H), 2.02-2.03 (m, 2H), 2.41-2.45 (m, 1H), 2.52-2.57 (m, 1H), 3.66 (t, 2H, J=7.5 Hz), 3.81-3.88 (m, 1H), 7.12-7.14 (m, 1H), 7.28-7.30 (m, 1H), 7.63-7.64 (m, 1H), 7.68-7.71 (m, 2H), 7.81-7.84 (m, 2H), 8.53-8.54 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]=[CH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.Cl.[CH2:13]([NH:16][OH:17])[CH2:14][CH3:15]>CO>[OH:17][N:16]([CH2:13][CH2:14][CH3:15])[CH:8]1[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]=2[CH2:10][CH2:9]1
Reactant: CCCNO
Reactant: Cc1ccnc2c1CCC=C2
Agent: Cl
Solvent: CO
Product: CCCN(O)C1CCc2c(C)ccnc2C1
Yield: 73.4 %

Procedure:
This compound was prepared from the product of Step 6 (4.5 g, 30 mmol), 1-propylhydroxylamine hydrochloride (6 g, 55 mmol), and methanol (20 ml) by the method outlined in Example 10. The crude material was recrystallised from cyclohexane to give the product (4.85 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.CN.[CH3:25][N:26](C=O)[CH3:27]>O>[CH3:25][N:26]([CH3:27])[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1cnc2c(c1)c(Br)cn2S(=O)(=O)c1ccccc1
Agent: CN
Solvent: O
Product: CN(C)c1c[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 150 °C
Yield: 51 %

Procedure:
3-Bromo-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.523 mmol) and methylamine (1.31 mL, 10.47 mmol, 40% solution in water) were combined with DMF (1 mL) in a microwave vessel and heated to 150° C. in a microwave reactor for one hour. The mixture was then diluted with water, extracted with EtOAc, extracts dried over sodium sulfate and concentrated under reduced pressure. Sep Pak purification (10 g cartridge, 1:1 ethyl acetate:hexanes to 100% ethyl acetate) afforded N,N-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-amine as a solid (55 mg, 51%). 1H NMR (400 MHz, d6-DMSO) δ 12.03 (br s, 1H), 8.70-8.72 (m, 1H), 8.20-8.23 (m, 1H), 5.46-5.47 (m, 1H), 2.98 (s, 6H); (APCI-pos) M+1=207.2.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:72]1[CH2:77][CH2:76][NH:75][CH2:74][C:73]1=[O:78].C(N(CC)CC)C>ClCCl>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:75]4[CH2:76][CH2:77][NH:72][C:73](=[O:78])[CH2:74]4)=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: O=C1CNCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCNC(=O)C2)CC1
Reaction time: 2 h
Yield: 23.1 %

Procedure:
{4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride salt (31.5 mg, 0.47 mmol, example 99), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 19.7 mg, 0.052 mmol, Advchemtech), piperazin-2-one (12 mg, ) and triethylamine (0.05 mL) was mixed in dichloromethane (2 ml) and stirred for 2 h. The mixture was diluted with dichloromethane (5 mL) and was washed with sodium hydroxide (0.1 N solution), saturated sodium chloride solution and water. Dichloromethane solution was dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by preparative HPLC (reversed phase, eluting with acetonitrile and water) gave the title compound (20.7 mg). HR-MS (ES, m/z) calculated for C39H48Cl2N7O4 [(M+H)+] 748.314, observed 748.3138.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH2:18][C:19]2[N:23]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]3=[N:21][C:20]=2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:12]=1>C1COCC1.C(OCC)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]2[N:23]([C:19]([CH2:18][NH:17][C:13]3[N:14]=[C:15]([O:7][C@@H:4]4[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]4)[CH:16]=[CH:11][N:12]=3)=[C:20]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[N:21]=2)[CH:24]=1
Reactant: CN1CC[C@@H](O)C1
Reactant: Fc1ccc(-c2nc3ccc(Cl)cn3c2CNc2nccc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CC[C@@H](Oc2ccnc(NCc3c(-c4ccc(F)cc4)nc4ccc(Cl)cn34)n2)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-1-methylpyrrolidin-3-ol (66 mg, 0.65 mmol) in THF (3 ml) was added NaH (25 mg, 65% in mineral oil). The mixture was stirred for 30 min and 4-chloro-N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine (50 mg, 0.13 mmol) was added. The mixture was heated from 65 to 95° C. until the reaction was completed. The mixture was diluted with ethyl acetate and the resulting mixture was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated by evaporation. The crude product was purified by silica gel chromatography (methanol/methylene chloride gradient) to obtain the desired product. 1H-NMR (CDCl3, 400 MHz, δ) 8.23 (s, 1H), 7.69 (m, 2H), 7.52 (d, J=9.5 Hz, 1H), 7.12 (m, 3H), 5.97 (s, 1H), 5.36 (s, 1H), 4.96 (d, J=4.7 Hz, 2H), 2.80 (m, 3H), 2.68 (m, 1H), 2.34 (s, 3H), 2.25 (m, 2H), 1.96 (m, 1H) ppm; m/e 453 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9][OH:10])[CH2:7][CH:6]=[CH:5][CH2:4]1.[H-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9][O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1
Reactant: ClCc1ccccc1
Reactant: OC[C@@H]1CC=CC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC[C@@H]1CC=CC[C@@H]1COCc1ccccc1
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
The diol (1) (16.2 g) in dimethylformamide (50 ml) is added dropwise to sodium hydride (3.1 g) in dimethylformamide (DMF) (50 ml). The mixture is stirred for 20 minutes and then benzyl chloride (16 g) is added and stirring is continued for a further 18 hours at 70° C. After removing the DMF in vacuo, water is added and the mixture is extracted with ether. The combined extracts are dried (MgSO4) and the solvent is evaporated to give a residue which is distilled under reduced pressure to give the title compound as an oil (16.5 g, ca. 60%), b.p. 140°-145° C./0.03 mm, λmax (film) 3440 and 1600 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=O)=[CH:5][CH:4]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[N:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])=[CH:5][CH:4]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: COc1ccc(-n2ccnc2C=O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(-n2ccnc2C=N[S@](=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-(4-methoxyphenyl)-1H-imidazole-2-carbaldehyde (200 mg, 1 mmol), (R)-2-methylpropane-2-sulfinamide (145 mg, 1.2 mmol), and CuSO4 (160 mg, 1 mmol) were combined in DCM (5 mL). The reaction was stirred at ambient temperature for 15 hr. The reaction was filtered, solvents removed in vacuo, and the residue purified by column chromatography on silica to provide the desired product: MS (m/z) 305.9 [M+H]+.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:52][CH3:53])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)C1C=CC=CC=1.C(O)=O>C(O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:52][CH3:53])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:39])[CH3:40])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)(OC)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)(OC)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a stirring solution of 80 mg (0.11 mmol) of 2-[3-(1-benzyl-1H-Indazol-3-ylmethyl)-3-methoxy-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 10 mL of a 10% solution of formic acid in absolute ethanol is added 70 mg of 10% palladium on carbon. The resulting black suspension is heated at reflux for 6 h, and then cooled to RT. The reaction mixture is filtered through Celite to remove the catalyst and the solvent removed in vacuo. Purification of the residue via silica gel MPLC using an Si60 column and hexane/EtOAc 1/1 as eluent followed by lyophilization afforded 41 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.83 (d, 1H, J=8.3), 7.38-6.94 (m, 16H), 6.59 (d, 1H, J=7.1), 4.76 (m, 1H), 4.19 (s, br, 2H), 3.85 (d, 1H), J=15.7), 3.73 (m, 4H), 2.88 (s, 3H), 0.93 (m, 6H); low resolution MS (FAB)m/e 618 (MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Br:12]>>[Br:12][CH2:11][C:10]1[CH:9]=[C:8]([O:7][C:6]([F:5])([F:16])[F:17])[CH:15]=[CH:14][C:13]=1[N+:1]([O-:4])=[O:2]
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1CBr
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Fuming nitric acid (5 mL) was cooled to 0° C. and 3-(trifluoromethoxy)benzyl bromide (1 mL, 6.16 mmol) was added. After 15 minutes, the reaction was poured into ice water (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water, saturated NaHCO3, and brine (75 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatograpy on silica gel (0 to 15% EtOAc/hexanes) afforded 2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene Rf=0.54 (15% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 8.14 (d, J=8.9 Hz, 1H), 7.43 (m, 1H), 7.31 (m, 1H), 4.82 (s, 2H).