Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:5])[CH:3]([OH:4])[CH2:2]1.N1[CH:10]=[CH:9]N=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>CN(C=O)C.[Cl-].[Na+].O>[C:14]([Si:11]([CH3:13])([CH3:12])[O:5][C@H:1]1[CH2:10][CH2:9][C@H:3]([OH:4])[CH2:2]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: c1c[nH]cn1
Reactant: OC1CC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.9 %

Procedure:
To a stirred solution of 1,3-cyclopropanediol (5 g, 49 mmol) and imidazole (5 g, 73.4 mmol) in DMF (20 mL) was added t-butyldimethylsilyl chloride (5.2 g, 34.5 mmol) and the mixture was stirred for 90 minutes at room temperature. The mixture was diluted with brine (200 mL) and extracted with ether three times (1×100 mL and 2×50 mL). Each extract was washed with a portion of brine. The organic phases were combined, dried over sodium sulfate and evaporated to dryness. The mixture of cis/trans isomers was purified by column chromatography using ether and hexanes to give the predominant trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol as a colorless liquid (4.1 g).
Reaction SMILES: N12CCC(CC1)[C@@H]([OH:9])C2.[C:10]([N:17]1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11]>ClCCl>[C:10](=[O:11])([O-:9])[NH2:17].[N-:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: ClCCl
Product: NC(=O)[O-]
Product: c1c[n-]cn1
Reaction time: 4 h

Procedure:
The reaction of (R)-3-Quinuclidinol with carbonyldiimidazole (CDI) in dichloromethane, at 0° C. during 4 h, afford the corresponding imidazolide carbamate (intermediate 2).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([NH:12][C:13](=[O:18])[CH2:14][C:15]([OH:17])=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:20][C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CC(C)N=C=NC(C)C>C1COCC1>[Cl:20][C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH:24]1[CH2:29][CH2:28][N:27]([C:15](=[O:17])[CH2:14][C:13]([NH:12][C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)=[O:18])[CH2:26][CH2:25]1
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1nc(-c2ccccc2)ns1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CC(=O)N1CCC(Oc2ccccc2Cl)CC1)Nc1nc(-c2ccccc2)ns1
Yield: 36.5 %

Procedure:
To a stirred solution of N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-malonamic acid (0.07 g, 0.00027 mole) in THF (3 mL) was added, 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.072 g, 0.00029 mol) followed by DIC (0.04 g, 0.00031 mole). The resulting mixture was heated to reflux for 4 hours then concentrated. The resulting residue was purified by column chromatography using neutral aluminium oxide (0.5% methanol in dichloromethane) to afford 0.045 g (37%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-propionamide. LC-MS purity: 457.1 (M+1)+, 84.85% 1H NMR (CDCl3): δ 8.2 (s, 2H), 7.5 (m, 4H), 7.2 (m, 1H), 7.0 (d, 2H), 4.7 (s, 1H), 4.2 (d, 1H), 3.8 (m, 1H), 3.6 (m, 5H), 2.0 (dd, 4H), 2.6 (bs, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[I:16]I>CN(C=O)C>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([I:16])=[N:10][NH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2cn[nH]c2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
To a solution of 6-tert-butyl-1H-indazole (1.02 g, 5.84 mmol) in DMF (20 ml) at room temperature was added potassium hydroxide (983 mg, 17.5 mmol) and iodine (2.22 g, 8.76 mmol). The maroon reaction mixture was stirred at room temperature for 1 h then quenched with 10% aqueous Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (2×). The combined organics were washed with water, sat LiCl, and sat NaCl, then dried over MgSO4 and concentrated to afford 1.92 g 6-tert-butyl-3-iodo-1H-indazole as a light brown solid.
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([O:3]C)=O.[NH3:30]>O1CCCC1.CO>[NH2:30][C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])=[O:3]
Reactant: N
Reactant: COC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 7) (5.6 mg) was dissolved in a mixture of tetrahydrofuran (2 mL) and 2 M ammonia in methanol solution (2 mL). After stirring for 16 h at room temperature, the solvent was evaporated under vacuum and the residue was coevaporated with toluene (5 mL twice) under vacuum. Purification by reverse phase preparative HPLC provided the title compound (3.4 mg). HPLC/MS [M+H]+, 397; HPLC/MS [M+H—NH3]+, 380.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8](=[NH:10])[NH2:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:8]([NH2:10])=[NH:9])[CH2:14][CH2:13]1
Reactant: CSC(=N)N
Reactant: CN1CCNCC1
Agent: O=S(=O)(O)O
Solvent: O
Product: CN1CCN(C(=N)N)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of S-methylisothiourea sulfate (2.78 g, 10.0 mmol) in distilled water (20 mL) was added 1-methylpiperazine (2.22 mL, 20 mmol). After stirring for 48 h at room temperature, the solution was concentrated to approximately 5 mL and treated with EtOH (10 mL). The resulting solid was collected by filtration, washed with EtOH, and dried to yield 4-methyl-piperazine-1-carboxamidine sulfate as a colorless solid. Further concentration of the mother liquor yielded a second crop or the material.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O[CH:18](OC(C)(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>C1(C)C=CC=CC=1>[C:3]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Br:12])[CH:9]=[C:10]([CH3:11])[C:2]=1[N:1]=[CH:18][N:19]([CH3:21])[CH3:20])([CH3:7])([CH3:4])[CH3:2]
Reactant: Cc1cc(Br)cc(C(=O)O)c1N
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(C(=O)OC(C)(C)C)c1N=CN(C)C
Yield: 97.5 %

Procedure:
A mixture of 5.0 g (21.7 mmol) of the product of Example 132 and 20.8 ml (86.9 mmol) of N,N-dimethylformamide di-t-butylacetal in 30 ml of toluene was heated to reflux for 2 hr. The reaction mixture was cooled to room tenperature, washed with water and brine, dried over MgSO4 and concentrated in vacuo to provide 3.61 g (49%) of the desired product as an yellow oil. Electrospray Mass Spec 341(M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[C:29]([CH2:31][NH2:32])[CH:28]=[CH:27][N:26]=1)(=[O:24])=[O:23].CN1CCOCC1.CCCP(=O)=O>O.CN1C(=O)CCC1>[CH3:21][S:22]([C:25]1[CH:30]=[C:29]([CH2:31][NH:32][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:19])[CH:28]=[CH:27][N:26]=1)(=[O:24])=[O:23]
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: CS(=O)(=O)c1cc(CN)ccn1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A 250 mL flask was charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (10.0 g, 33.9 mmol, 87.2 wt. %, 1.0 eq), (2-(methylsulfonyl)pyridin-4-yl)methanamine hydrochloride (8.54 g, 37.3 mmol, 97.3 wt. %, 1.10 eq), NMP (30 mL) and finally N-methylmorpholine (18.6 mL, 169.5 mmol, 5.0 eq). To the slurry was charged propylphosphonic anhydride (23.97 mL, 40.68 mmol, 50 wt. % solution in EtOAc, 1.2 eq). The batch was then heated to 60° C. and held at this temperature for 1 hour. Water (80 mL) was charged, and the batch was cooled to ambient temperature and held for 1 hour. The batch was filtered, the solid washed with water, and then oven dried under vacuum to afford the title compound as a light yellow solid, 12.7 g, >99.5 area % purity by HPLC, 88% yield.
Reaction SMILES: [CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([NH2:38])(=[O:37])=[O:36])=[CH:25][CH:24]=2)[C:8]2=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:39]1([CH:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46](Cl)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35]([NH:38][C:46](=[O:47])[CH:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)(=[O:37])=[O:36])=[CH:27][CH:28]=2)[C:8]2=[N:9][CH:10]=[C:11]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([CH3:13])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Nc1cnc2c(nc(CCCC)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCCC(=O)Nc1cnc2c(nc(CCCC)n2Cc2ccc(-c3ccccc3S(=O)(=O)NC(=O)C(c3ccccc3)c3ccccc3)cc2)c1C

Procedure:
The title compound was prepared from 2-butyl-3-[[2'-[(amino)sulfonyl][1,1'-biphenyl]-4-yl]methyl]-7-methyl-6-[(1-oxopentyl)amino]-3H-imidazo[4,5-b]pyridine and diphenylacetyl chloride as described in Example 1, Step 5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C(N(C(C)C)C(C)C)C.Cl[C:37](=[O:44])[CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:26][C:37](=[O:44])[CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: COC(=O)CCC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (140 mg, 0.387 mmol) was dissolved in THF (3.9 mL) and N-ethyl-N-isopropylpropan-2-amine (270 μl, 1.55 mmol) before methyl 4-chloro-4-oxobutanoate (189 μl, 1.55 mmol) was added at ambient temperature and the reaction mixture was stirred at ambient temperature for 30 min. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give methyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)-4-oxobutanoate after flash chromatography. MS (ESI) m/z: Calculated: 475.1; Observed: 476.4 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[NH:17][N:16]=2)[N:3]=1.[CH3:23][O:24][C@@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26]1>>[CH:20]1([C:18]2[NH:17][N:16]=[C:15]([NH:14][C:4]3[N:5]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:7]=[C:2]([N:28]4[CH2:29][C@@H:25]([O:24][CH3:23])[CH2:26][C@H:27]4[C:30]([OH:32])=[O:31])[N:3]=3)[CH:19]=2)[CH2:22][CH2:21]1
Reactant: CO[C@@H]1CN[C@H](C(=O)O)C1
Reactant: Clc1nc(Nc2cc(C3CC3)[nH]n2)nc(N2CCOCC2)n1
Product: CO[C@H]1C[C@@H](C(=O)O)N(c2nc(Nc3cc(C4CC4)[nH]n3)nc(N3CCOCC3)n2)C1

Procedure:
Compound 112B was prepared from 112A and (2S,4S)-4-methoxypyrrolidine-2-carboxylic acid as described for 1. LC/MS [M+H]+: 431; Ret time (Method F): 2.27 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH2:7]1)=[O:5])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(C=CC(=O)O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)N1CCC(CCC(=O)O)C1
Yield: 100 %

Procedure:
A mixture of 13 parts of 3-[1-(ethoxycarbonyl)-3-pyrrolidinyl]-2-propenoic acid and 100 parts of acetic acid was hydrogenated at normal pressure and at 20° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in methylbenzene and the latter was evaporated again, yielding 13 parts (100%) of 1-(ethoxycarbonyl) -3-pyrrolidinepropanoic acid as a residue (int. 28).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13]C(=O)OC(C)(C)C)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3].O1CCOCC1>Cl.C(Cl)Cl>[N:1]([CH2:4][C@@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.1 %

Procedure:
A solution of tert-butyl (S)-3-azido-1-phenylpropan-2-ylcarbamate (1.0045 g, 3.6 mmol) was dissolved in 4 M HCl in dioxane (20 mL, 80 mmol) and stirred at rt for 2 h. The solvent was stripped. The residue was taken up in CH2Cl2 (50 mL) and 1 N aq NaOH (10 mL), extracted with CH2Cl2 (3×10 mL), washed with brine (3×5 mL), dried (Na2SO4), decanted, and stripped to afford (S)-1-azido-3-phenylpropan-2-amine (812.9 mg, quant, 80% purity) as a clear oil. MS ESI +ve m/z 177 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:10]=3[C:8](=[O:9])[C:4]2=[C:5]([OH:7])[CH:6]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1>[OH:16][C:15]1[C:10]2[C:8](=[O:9])[C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[OH:7])[CH:17]([C:24](=[O:26])[CH3:25])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of 56.5 g (0.25 mol) of purified anthralin in 1750 cm3 of anhydrous toluene being stirred at room temperature, 27.3 cm3 (0.34 mol) of anhydrous pyridine was added first and then 21.4 cm3 (0.3 mol) of acetyl chloride was added dropwise by means of a dropping funnel. Slight heating occurred during addition then, after the end of addition, the mixture was heated to a temperature of around 90° C. for 1 hour. The mixture was cooled and 27.3 cm3 of pyridine and then, dropwise, 21.4 cm3 of acetyl chloride were again added at 30°-35° C. The mixture was then stirred for 1 hour at 85°-90° C. After a check to insure that the anthralin had been transformed to the 10-acetyl derivative, the reaction mixture was cooled to room temperature then washed 3 times with water (250 cm3). The toluene phase was decanted, dried over sodium sulfate and then concentrated to around 300 cm3. The solution was then deposited on a column of silica gel and eluted with toluene and a 1:1 mixture of toluene and methylene chloride. The first fractions were combined and then concentrated under vacuum. The solid obtained was then recrystallized from toluene to yield 21 g of bright-yellow crystals of 1,8-dihydroxy-10-acetylanthrone having a melting point of 146° C.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:14][CH3:15])=[N:7]2.[C:16]([Cu])#[N:17].O.C(N)CN>CN(C=O)C>[C:16]([C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:14][CH3:15])=[N:7]2)#[N:17]
Reactant: COc1ccc2nc(SC)ccc2c1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: NCCN
Solvent: CN(C)C=O
Product: COc1ccc2nc(SC)ccc2c1C#N
Temperature: 150 °C
Yield: 86.8 %

Procedure:
A mixture of 5-bromo-6-methoxy-2-methylthioquinoline (6.1 g, 21 mmol) and CuCN (3.7 g, 41 mmol) in DMF (80 mL) was heated at 150° C. for 14 hours. The mixture was cooled and treated sequentially with 2:1 H2O/ethylenediamine (15 mL). The mixture was extracted with 1:1 EtOAc/hexane. The organic layer was worked-up. HPLC (1:8 EtOAc/hexane) gave 4.2 g (87%) of 5-cyano-6-methoxy-2-methylthioquinoline as a light yellow solid, (M+) 230(100).
Reaction SMILES: [Li+].[OH-:2].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[C:45]([NH2:52])=[C:44]([Cl:53])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:34][CH2:33][CH:32](C(OCC)=O)[CH2:31][CH:30]4C)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:54]=[CH:55][CH:56]=[CH:57][C:6]=2[NH:5]1.[CH2:58]1[CH2:62][O:61]CC1>O>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:49])[F:50])[C:45]([NH2:52])=[C:44]([Cl:53])[CH:43]=3)[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:34][CH2:33][CH:32]([CH2:58][C:62]([OH:2])=[O:61])[CH2:31][CH2:30]4)[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:54]=[CH:55][CH:56]=[CH:57][C:6]=2[NH:5]1
Reactant: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)C(C)C1
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Li+]
Solvent: O
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(CC(=O)O)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 5.00 mg (0.21 mmol) LiOH in 3 mL water was added to 100 mg (0.13 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-ethoxycarbonyl-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 10 mL THF and the reaction mixture was stirred for 2 days at RT. The mixture was evaporated to dryness i. vac., the residue was taken up in 1 mL DMF and purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1]N(C)C=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[CH3:17][O:18][C:19](=[O:44])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:29])=[CH:22][CH:21]=1>O.C1(C)C=CC=CC=1>[CH3:17][O:18][C:19](=[O:44])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28](=[O:29])[C:30]3[C:31](=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[N:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH:1]=2)=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccn2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cc2cn(-c3ccccn3)c3cc(Cl)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 9.7 %

Procedure:
A solution of N,N-dimethylformamide (268 mg, 286 μL, 3.67 mmol) and tetrahydrofuran (2.94 mL) cooled to 0° C. was treated with oxalyl chloride (373 mg, 256 μL, 2.94 mmol). During the addition process, vigorous gas evolution occurred, the reaction became cloudy and a thick white precipitate formed. At this time, the ice bath was removed. The reaction mixture was stirred at 25° C. for 45 min and then was concentrated in vacuo. The resulting white paste was treated with toluene (11.8 mL) and 4-{3-[4-chloro-2-(pyridin-2-ylamino)-phenyl]-3-oxo-propyl}-benzoic acid methyl ester (290 mg, 734 μmol). This mixture was then heated to 115° C. for 5 h and then was stirred at 25° C. overnight. At this time, the reaction was diluted with water (30 mL) and extracted into methylene chloride (3×30 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (40 g column; 1-10% methanol/methylene chloride) afforded 4-(7-chloro-4-oxo-1-pyridin-2-yl-1,4-dihydro-quinolin-3-ylmethyl)-benzoic acid methyl ester (28.7 mg, 9.65%) as a brown solid. ES+-HRMS m/e calcd for C23H17ClN2O3 [M+H+] 405.1000. Found 405.0995; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.73 (d, J=4.7 Hz, 1H) 8.29 (s, 1H) 8.14-8.24 (m, 2H) 7.85 (d, J=8.2 Hz, 2H) 7.79 (d, J=7.9 Hz, 1H) 7.63-7.72 (m, 1H) 7.47 (d, J=8.2 Hz, 2H) 7.43 (m, 1H) 7.21 (d, J=1.7 Hz, 1H) 3.89 (s, 2H) 3.82 (s, 3H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C([C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])(C)C.[CH:18]1[CH:23]=CC=C[CH:19]=1>>[CH:18]([CH2:6][C:5]([NH:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:11]=1)=[O:7])([CH3:23])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccccc1
Reactant: CC(C)c1ccccc1N
Product: CC(C)CC(=O)Nc1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
86 g of acetic acid anhydride were added to a solution of 108 g of 2-isopropyl-aniline and 250 ml of benzene and another 86 g of acetic acid anhydride were added thereto. The mixture was stirred at 20° C. for 16 hours and was washed with water, with aqueous sodium bicarbonate, with water, dried and evaporated to dryness under reduced pressure. The residue was triturated with hexane, cooled and filtered. The product was washed with hexane and dried under reduced pressure to obtain 115 g of 2-isopropylacetanilide melting at 67°-68° C.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH:11]([O:19][CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=O)=O.Cl.[OH-].[Na+]>C(O)C.O>[CH3:20][O:19][CH:11]([C:9]1[N:8]=[CH:7][NH:6][CH:10]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(Cc1ccccc1)c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(Cc1ccccc1)c1c[nH]cn1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a stirred suspension of 2-(tert-butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole-1-sulfonic acid dimethylamide (105 mg) at r.t. in ethanol (3 ml) under an argon atmosphere was added 2 N HCl (3 ml). The mixture was heated to reflux for 3 hours. The mixture was cooled to r.t. and concentrated to leave a light yellow solid which was taken up in H2O and brought to pH 12 by the addition of 4 N NaOH. The product was extracted with CH2Cl2/MeOH 4:1. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 4-(1-methoxy-2-phenyl-ethyl)-1H-imidazole (38 mg) as white solid. MS (ISP): 203.4 ([M+H]+)