Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.CN(C)C=O.[H-].[Na+]>O>[C:30]([C:29]1[C:24]([O:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[CH3:1])=[CH:20][CH:19]=2)=[N:25][CH:26]=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.6 %

Procedure:
To a mixture of [4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (10.0 g), 2-chloro-3-cyanopyridine (4.27 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 1.48 g) under ice-cooling. The reaction mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (10.98 g, 90%) of 3-cyano-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]pyridine from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 119-120° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C@@H:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([O:13]CC2C=CC=CC=2)=[O:12])=[O:8])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C@@H:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([OH:13])=[O:12])=[O:8])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)OC(=O)N1CCOCC1
Yield: 97 %

Procedure:
A solution of benzyl 2(S)-morpholinocarbonyloxy-3-phenylpropionate (300 mg) in methanol (20 ml) was hydrogenated over 10% palladium on carbon (30 mg) at 3 atmospheric pressure of hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give 2(S)-morpholinocarbonyloxy-3-phenylpropionic acid (220 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:20]([OH:22])=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1)[NH2:24].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:20]([NH:24][NH:23][C:25]2[N:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][N:26]=2)=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1nccc(C(F)(F)F)n1
Reactant: O=CN(CC1(C(=O)O)CCCCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
To a mixture of 1-[(Benzyloxy-formyl-amino)-methyl]-cycloheptanecarboxylic acid (0.10 g, 0.33 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.07 g, 0.39 mmol), NMM (0.10 g, 1.0 mmol) and HOAt (0.053 g, 0.39 mmol) in DMF (1 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.075 g, 0.34 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.11 g, 72%). MH+466.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH2:11]([O:18][C:19]([C:21]1([C:52]([OH:54])=O)[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([C:39]4[CH:44]=[CH:43][C:42]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[C:41]([F:51])[CH:40]=4)[O:36][N:35]=3)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[CH2:11]([O:18][C:19]([C:21]1([C:52]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[O:54])[CH2:22][CH2:23][N:24]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[N:38]=[C:37]([C:39]4[CH:44]=[CH:43][C:42]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[C:41]([F:51])[CH:40]=4)[O:36][N:35]=3)=[CH:32][CH:33]=2)[CH2:25][CH2:26]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1COCCN1
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1(C(=O)N2CCOCC2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Hydroxybenzotriazole (0.183 g, 0.0012 mol) is added to a stirred solution of 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-piperidine-4,4-dicarboxylic acid benzyl ester (0.6 g, 0.0010 mol) in tetrahydrofuran (20 mL). Reaction mixture is stirred for 30 minutes at room temperature. Morpholine (0.13 mL, 0.0015 mol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.288 g, 0.0015 mol) are added to the reaction mixture and stirred for over night at room temperature. Demineralized water (10 mL) is added to the reaction mixture, tetrahydrofuran layer is separated and the aqueous layer is extracted with ethyl acetate (2×15 mL). Combined organic layer is dried over sodium sulphate and concentrated under reduced pressure to yield a crude viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate) to get 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(morpholine-4-carbonyl)-piperidine-4-carboxylic acid benzyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[N:11][N:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[NH2:21].N1C=CC=CC=1.[Cl:28][CH:29]([CH:33]1[CH2:36][CH2:35][CH2:34]1)[C:30](Cl)=[O:31]>CN(C)C=O>[Cl:28][CH:29]([CH:33]1[CH2:36][CH2:35][CH2:34]1)[C:30]([NH:21][C:9]1[N:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[N:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:31]
Reactant: Nc1c(-c2ccccc2F)nnn1CSc1ccccc1
Reactant: O=C(Cl)C(Cl)C1CCC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1c(-c2ccccc2F)nnn1CSc1ccccc1)C(Cl)C1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31359.2 %

Procedure:
To a cooled (0° C.), stirred solution of 5-(2-fluorophenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-ylamine (1 g, 3.33 mmol) in dimethylformamide (15 ml) was added pyridine (460μl, 4.33 mmol) followed by 2-chloro-2-cyclobutylacetyl chloride (810 mg, 3.83 mmol) and the reaction stirred at 0° C. for 1 hour. The reaction was quenched by partitioning between ethyl acetate (100 ml) and water (100 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (100 ml). The combined organic extracts were washed with citric acid (50 ml, 10% aqueous), sodium bicarbonate (50 ml, sat. aqueous), brine (50 ml). dried (Na2SO4) and the solvent removed in vacuo. The crude product was purified by flash chromatography (40% EtOAc/hexanes) to afford 2-chloro-2-cyclobutyl-N-[5-(2-fluorophenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-yl]acetamide (450 g, 31%; 52% based on recovered starting material) as a crystalline solid, m.p. 103-104° C.; δH (400 MHz, CDCl3) 1.79-2.18 (6H, m, CH(CH2)3), 2.83-2.93 (1H, m, CH(CH2)3), 4.28 (1H, d, J=8 Hz, CHCl), 5.58 (1H, d, J=14.3 Hz, PhSCH2A), 5.64 (1H, d, J=14.3 Hz, PhSCH2B), 7.10-7.16 (1H, m, ArH), 7.23-7.41 (7H, m, ArH), 7.79-7.85 (1H, m, ArH), 8.00-8.10 (1H, br m, NH); m/z (ES+) 431 (100%) (35ClM+H+), 433 (40%) (37 ClM+H+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[I:12][C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])I.[Cl-].[NH4+].C(Cl)Cl>CS(C)=O.[Cu]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]([F:18])([F:17])[C:14]([F:20])([F:19])[C:13]([F:22])([F:21])[I:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: FC(F)(I)C(F)(F)C(F)(F)I
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)Oc1ccc(C(F)(F)C(F)(F)C(F)(F)I)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
A solution of p-iodophenyl acetate (27.5 g, 105 mmol) and 1,3-diiodohexafluoropropane (52.0 g, 128.7 mmol) in 100 ml of anhydrous dimethyl sulfoxide was heated to 120° C. under nitrogen. Copper powder (13.5 g, 211 g atoms) was added to the vigorously stirred solution in five approximately equal amounts at 20 minute intervals. After the addition of copper was complete, the reaction mixture was stirred at 120° C. for an additional 1.5 hours. On cooling, saturated aqueous ammonium chloride together with methylene chloride was added to the reaction vessel. The excess copper and cuprous salts were filtered off, the organic layer was separated, and the aqueous layer was extracted with more methylene chloride. The organic extracts were combined, washed well with water, dried over anhydrous magnesium sulfate, and reduced in volume to a light yellow oil. The oil was refluxed in 25 ml of acetic anhydride for 45 minutes and the excess acetic anhydride and acetic acid were vacuum distilled. Distillation of the residual oil yielded 24.85 g of crude 4-(perfluoro3-iodopropyl)phenyl acetate, bp 126°-127° C./3.4 mm Hg, mp 75°-81° C. Recrystallization of this material from hexane gave 20.8 g (48% yield) of purer material, mp 84.5°-88° C. Repeated crystallization from hexane raised the melting point to 88.5°-89.5° C., which could not be improved upon by further recrystallization.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:33]=[CH:32][C:8]2[N:9]=[C:10]([C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:19]([CH3:31])[CH:18]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH3:29][C:26]([CH3:27])([CH3:28])[C:25](=[O:30])[CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]([C:10]2[O:11][C:7]3[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:33]=[CH:32][C:8]=3[N:9]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:31]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)OC)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-6-carboxylic acid methyl ester (1.50 g, 3.32 mmol) in MeOH (10 mL) and THF (10 mL) is treated with NaOH (2.0 M, 20.0 mL). The resulting mixture is stirred at RT for 16 h. The mixture is concentrated, acidified with HCl (5 N) until pH˜3, and extracted with EtOAc (100 mL, then 50 mL). The organic layer is dried over Na2SO4, filtered, and concentrated to afford the title compound (1.40 g, 97%). H-NMR (ppm, CDCl3) δ: 8.16 (1H, d, J=1.3 Hz), 8.11 (1H, dd, J=1.3, 8.4 Hz), 7.78 (1H, d, J=8.4 Hz), 7.02 (1H, d, J=1.8 Hz), 6.97 (1H, dd, J=2.2, 8.4 Hz), 6.54 (1H, d, J=8.4 Hz), 4.85 (2H, s), 2.40 (2H, q, J=7.5 Hz), 2.30 (2H, q, J=7.5 Hz), 2.26 (3H, s), 1.25 (9H, s), 0.77 (6H, t, J=7.5 Hz). MS (ES) m/e: 438.2 (M+1), 436.2 (M−1).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][NH:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:22]=[CH:23][CH:24]=[N:25][C:5]1=2.N1C=CC=CC=1.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33].[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][N:15]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:35]([NH:34][CH2:32][CH3:33])=[O:36])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:22]=[CH:23][CH:24]=[N:25][C:5]1=2
Reactant: CCN=C=O
Reactant: COCN1c2cc(CNc3cccnc3)ccc2Sc2nccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCNC(=O)N(Cc1ccc2c(c1)N(COC)c1nccnc1S2)c1cccnc1

Procedure:
341 mg of 10-methoxymethyl-8-[N-(pyridin-3-yl)aminomethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in 5 ml of toluene. After adding 3 ml of pyridine and 1.9 ml of ethyl isocyanate, the reaction mixture was heated under reflux for 3 days. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of sodium chloride and extracted repeatedly with ethyl acetate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with toluene/acetone) to thereby give 350 mg of the title compound as a yellow oily substance.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([C:8]1[CH:13]=[N:12][N:11]2[CH:14]=[C:15]([C:17]3[O:18][C:19](S(C)=O)=[N:20][N:21]=3)[CH:16]=[C:10]2[C:9]=1[NH:25][C@@H:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][C:27]1([CH3:40])[CH3:39])(=[O:7])[NH2:6]>>[CH:1]1([NH:4][C:19]2[O:18][C:17]([C:15]3[CH:16]=[C:10]4[C:9]([NH:25][C@@H:26]5[CH2:31][CH2:30][NH:29][CH2:28][C:27]5([CH3:40])[CH3:39])=[C:8]([C:5]([NH2:6])=[O:7])[CH:13]=[N:12][N:11]4[CH:14]=3)=[N:21][N:20]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CS(=O)c1nnc(-c2cc3c(N[C@@H]4CCN(C(=O)OC(C)(C)C)CC4(C)C)c(C(N)=O)cnn3c2)o1
Product: CC1(C)CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3nnc(NC4CC4)o3)cc12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Cyclopropanamine (0.067 mL, 0.966 mmol) was added to a crude solution of (4R)-tert-butyl 4-((3-carbamoyl-6-(5-(methylsulfinyl)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (⅙ of the total volume from Step 5, 0.097 mmol maximum). After 22 h at room temperature, the reaction was complete. The mixture was concentrated in vacuo. The crude material was dissolved in dichloromethane (0.5 mL) and treated with trifluoroacetic acid (0.100 mL). After stirring overnight at room temperature, the Boc-deprotection was approximately 50% complete. Additional trifluoroacetic acid (0.185 mL) was added. After 30 min at room temperature, the deprotection was complete. The mixture was concentrated and triturated with ether. The ether layer was decanted. The solid residue was used in the next reaction without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>CN(C)C=O>[CH2:26]([NH:29][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1)[CH2:27][CH3:28]
Reactant: CCCN
Reactant: O=C1c2ccccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2ccccc2-3)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A solution of 710 mg (2.0 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 10 ml of N,N-dimethylformamide was treated with 0.5 ml (6.0 mmol) of propylamine and stirred at room temperature under argon for 2 hrs. The solution was evaporated, the residue was triturated in 5 ml of water and the crystals were filtered off. Additional crude product was obtained by extracting the aqueous phase with methylene chloride. The combined crude products (0.65 g) were chromatographed on 25 g of silica gel (methylene chloride/methanol 2%, 5%, 10%). There were obtained 540 mg of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, which was dissolved in 5 ml of acetonitrile and thereupon converted with ethereal hydrochloric acid into the hydrochloride. By recrystallization from acetonitrile there were obtained 560 mg (62%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one hydrochloride (1:2) of m.p. 169°-173° (dec.).
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]([NH2:24])=[O:23])=[CH:13]1.C[O:26][C:27](=O)[C:28]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[N:37]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]=[CH:35]2)=O>CN(C=O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[C:22](=[O:23])[NH:24][C:27](=[O:26])[C:28]=2[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]3[C:38]=2[N:37]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]=[CH:35]3)=[CH:13]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cccc2ccn(COCC[Si](C)(C)C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cccc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
A 1.0 M solution of KOtBu in THF (8.1 mL, 8.1 mmol) was added to a solution of 2-(1H-indol-3-yl)-acetamide (417 mg, 2.4 mmol) and {1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-7-yl}-oxo-acetic acid methyl ester (774 mg, 2.32 mmol) in DMF (50 mL). The deep red-orange solution was stirred 16 h at room temperature and then 1 h at 65° C. The heating bath was removed and pH 7.0 buffer added. The mixture was poured into EtOAc, the layers separated and the EtOAc solution washed with 0.1 N HCl, water (3×), saturated aq NaHCO3 and brine (3×), dried (MgSO4), filtered and concentrated onto SiO2. Flash chromatography afforded 3-(1H-Indol-3-yl)-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-7-yl]-pyrrole-2,5-dione (141 mg, 13%) as a bright orange solid which was dried under vacuum overnight at 70° C., and 3-(1H-Indol-7-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione (165 mg, 22%) as a bright red solid which was dried under vacuum overnight at 70° C.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CCCCN(CC(=O)OCc1ccccc1)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide ( ) and benzyl bromoacetate according to the procedure of Intermediate 2 as a gum; 1H NMR (CDCl3) δ 0.85 (t, J=7.23 Hz, 3H), 1.19-1.32 (m, 2H), 1.43-1.53 (m, 2H), 2.56 (t, J=6.12 Hz, 4H), 3.19 (t, J=7.47 Hz, 2H), 3.72 (t, J=6.06 Hz, 4H), 4.09 (s, 2H), 5.10 (s, 2H), 6.84-6.89 (m, 2H), 7.29-7.40 (m, 5H), 7.69-7.74 (m, 2H); MS (ES) m/z 459.4 (MH+); HRMS for C25H30N2O6S: 459.1945 (MH+)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:22]=[C:21]3[C:16]([N:17]=[C:18]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[C:19]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)=[C:20]3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[C:21]3[C:16](=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:22]=3)[N:17]=[C:18]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[C:19]=2[C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc3c(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)nc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2nc3nn(C4CCNCC4)cc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
To a solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (0.62 g, 1.1 mmol, obtained in example 20) in CH2Cl2 (19 mL) under argon atmosphere and cooled to 0° C., trifluoroacetic acid (1.8 mL) was added. It was stirred at room temperature for 2.5 h. The solvent was evaporated. The residue was dissolved in CHCl3 and washed with 1 N NaOH and brine. The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 319 mg of the title compound (yield: 62%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([OH:22])=[O:21].[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>C1COCC1.CS(C)=O>[C:27]([CH2:26][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([OH:22])=[O:21])([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(CC(=O)O)c2cc(O)ccc2n1Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(=O)COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 590 mg (2.0 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (Example 2, Part C) in 30 mL of THF and 10 mL of DMSO was treated with 180 mg (4.5 mmol) of 60% NaH/mineral oil and after 10 minutes, 0.25 mL (2.25 mmol) of ethyl 2-bromoacetate was added. The mixture was stirred for 0.5 hour, acidified with 1N HCl and extracted with EtOAc. The EtOAc solution was washed with water, saturated NaCl solution, dried (Na2SO4) and concentrated at reduced pressure. After chromatography on silica (eluted with a gradient, CH2Cl2→3% MeOH/CH2C2) there was obtained 590 mg (77% yield) of 5-(carbethoxymethoxy)-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:30]([O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1)=[O:34])[CH3:31]>C(Cl)Cl>[CH2:30]([O:32][C:33](=[O:34])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([N:16]([C:12]2[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[CH:15]=[CH:14][N:13]=2)[CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:43])=[CH:37][CH:36]=1)[CH3:31]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: CC(C)c1ccc(-c2ccnc(NCc3cccs3)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)N(Cc2cccs2)c2nccc(-c3ccc(C(C)C)cc3)n2)cc1
Temperature: 100 °C
Yield: 13.7 %

Procedure:
To a solution of [4-(4-isopropyl-phenyl)-pyrimidin-2-yl]-thiophen-2-ylmethyl-amine (50 mg, 0.16 mmol) in DCM (2 mL) was added triethylamine (33 μL, 0.24 mmol) and 4-(ethoxycarbonyl)phenyl isocyanate (34 mg, 0.18 mmol). The resulting reaction mixture was heated in a CEM Exployer PLS™ microwave at 100° C. for 30 min. After cooling to room temperature the solvent was evaporated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 to give 11 mg of 4-{3-[4-(4-Isopropyl-phenyl)-pyrimidin-2-yl}-3-thiophen-2-ylmethyl-ureido}-benzoic acid ethyl ester. LCMS m/z: 502 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH2:16][CH2:17][O:18][CH2:19][CH3:20])[C:9]([O:11]C(C)(C)C)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([CH:8]([CH2:16][CH2:17][O:18][CH2:19][CH3:20])[C:9]([OH:11])=[O:10])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOCCC(C(=O)O)C(=O)OC(C)(C)C
Yield: 26.3 %

Procedure:
To a solution of the product from step (a) (5 g) in dioxane (25 ml) was added a solution of potassium hydroxide (1 g) in water (20 ml). The cloudy reaction mixture was heated to reflux for 5.5 hours and then evaporated to dryness. The residue was dissolved in water, washed with ether, and acidified to pH 4 with conc. HCl. The mixture was extracted thoroughly with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and evaporated to give 2-t-butoxycarbonyl-4-ethoxybutyric acid (1.06 g) as a yellow oil: NMR Spectrum (CDCl3) 1.19 (3H, t), 1.49 (9H, s), 2.19 (2H, m), 3.50 (5H, m); Mass Spectrum m/Z 233 (M+H)+.