Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:29]([NH2:28])=[O:30])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)[C@@H](C)c2ccccn2)c(C)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: Cc1cnc(CN(CCCCNC(N)=O)[C@@H](C)c2ccccn2)c(C)c1
Yield: 41.5 %

Procedure:
To a solution of (S)-N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-butane-1,4-diamine (63 mg, 0.21 mmol) in 2-propanol (1 mL) was added trimethylsilyl-isocyanate (40 μL, 0.30 mmol). The resultant solution was stirred at room temperature for 6 hours then concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 31 mg (41%) of the free base of the title compound as a white foam. Using General Procedure D: Conversion to the HBr salt gave COMPOUND 148 (43 mg, 72%) as a white solid. 1H NMR (D2O) δ 1.29 (br s, 4H), 1.59 (d, 3H, J=6.6 Hz), 2.42 (s, 3H), 2.47 (s, 3H), 2.51-2.68 (m, 2H), 2.92 (br s, 2H), 4.24 (s, 2H), 4.57 (q, 1H, J=6.6 Hz), 7.97-8.02 (m, 1H), 8.11-8.18 (m, 2H), 8.41 (s, 1H), 8.56-8.62 (m, 1H), 8.77 (d, 1H, J=5.4 Hz); 13C NMR (D2O) δ 14.63, 16.78, 17.50, 24.06, 27.15, 39.52, 51.05, 52.94, 60.19, 126.67, 126.74, 136.16, 137.31, 137.65, 142.10, 147.93, 148.95, 149.33, 156.40, 161.76; ES-MS m/z 356 (M+H). Anal. Calcd. For C20H29N5O.3.3HBr.2.5H2O: C, 35.99; H, 5.63; N, 10.49; Br, 39.50. Found: C, 36.26; H, 5.38; N, 10.10; Br, 39.78.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:22][C:23](N(OC)C)=[O:24])=[CH:17][CH:16]=1.[NH4+].[Cl-]>C1COCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:22][C:23]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=2)=[O:24])=[CH:19][CH:20]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Temperature: -70 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of n-BuLi (12.9 mL 1.6 M in hexane) was added dropwise a solution of 4-bromo-2-methylpyridine (3.56 g) in THF (170 mL) at −70° C. over a period of 20 min. The reaction mixture was stirred at −70° C. for 5 min, before a solution of 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (2.5 g) in THF (100 mL) was added dropwise. After the addition was complete, the mixture was stirred at −70° C. for 3 hours. A saturated solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:1) to give the title compound as an yellow oil (1.49 g, 55%), MS (ESI+): m/z=394.0797 ([M+H]+, 1Br).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](Cl)=[O:9].C(OC(=O)C)C>O1CCOCC1.O.CCCCCC>[Cl:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([N:1]=[N+:2]=[N-:3])=[O:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(CCl)C(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(CCl)C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Sodium azide (4.64 g, 71.38 mmol) was added to a solution of 3-chloro-2,2-dimethyl-propionyl chloride (I-200a: 6 g, 35.71 mmol) in 1,4-dioxane (15 mL) and water (15 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (5% ethylacetate in hexane). The reaction mixture was extracted with diethyl ether and the organic layer was dried over Na2SO4 to afford 3.5 g of the product (61.40% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[CH:4][C:3]=1[NH2:19].CCO.C([O-])([O-])=O.[Na+].[Na+].[C:29]1(B(O)O)[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1>C1(C)C=CC=CC=1.CCOC(C)=O.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>[C:29]1([C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][S:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)(=[O:12])=[O:11])[CH:5]=[CH:4][C:3]=2[NH2:19])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: OB(O)C1=CCCCC1
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 80 °C
Yield: 98.9 %

Procedure:
A solution of 133 mg (0.381 mmol) of 2-bromo-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (as prepared in the previous step) in toluene (6 mL) and EtOH (3 mL) was treated with 1.52 mL (3.05 mmol) of 2.0 M aqueous Na2CO3 and 60.0 mg (0.476 mmol) of cyclohex-1-enylboronic acid. The mixture was degassed via sonication, placed under Ar, treated with 30.8 mg (0.027 mmol) of Pd(PPh3)4, and heated to 80° C. for 2.5 h. The mixture was cooled to RT, diluted with EtOAc (20 mL), and washed with saturated aqueous NaHCO3 (1×15 mL) and brine (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 132 mg (99%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C18H26N2O3S, 351.2 (M+H). found 351.1.
Reaction SMILES: C([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:11]=2[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][CH2:15][CH:9]([NH2:8])[CH2:10][C:11]=2[CH:19]=1
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc2c(c1)CC(N)CCC2
Yield: 76.7 %

Procedure:
A mixture of N-benzyl-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (68.7 g), ammonium formate (68.15 g), and 10% palladium on carbon (50% wet; 6.8 g) in ethanol (1.2 l) was refluxed for 1 hour. After cooling, the catalyst was filtered off and the solvent was removed in vacuo. To the residue, water and 28% ammonium hydroxide were added and the whole was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-amine (35.8 g) as an oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].Cl>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)N1CCc2cc([N+](=O)[O-])ccc21
Agent: Cl
Product: CCN1CCc2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Yield: 109.4 %

Procedure:
1-Acetyl-5-nitro-indoline (1.00 g, 4.85 mmol) was added to borane-THF complex (1 M, 10 mL, 10 mmol). The mixture was heated at reflux for 4 h. With ice-water bath cooling, the mixture was slowly treated with 6 N HCl (4 mL). Then the mixture was heated at 50° C. for 1 h. The organic solvent was evaporated off and the resulting suspension was filtered to give an orange solid (1.02 g) which was washed with water: mp 97-98° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2([CH2:9][C:10]([CH3:15])([CH3:14])[C:11]=1[CH2:12][OH:13])[O:8][CH2:7][CH2:6][O:5]2>C(Cl)Cl>[CH3:1][C:2]1[CH2:3][C:4]2([CH2:9][C:10]([CH3:15])([CH3:14])[C:11]=1[CH:12]=[O:13])[O:5][CH2:6][CH2:7][O:8]2
Reactant: CC1=C(CO)C(C)(C)CC2(C1)OCCO2
Solvent: ClCCl
Product: CC1=C(C=O)C(C)(C)CC2(C1)OCCO2

Procedure:
3 kg. of maganese dioxide was added in four portions over a period of 2 days to a solution of 150 g. of crystalline 7,9,9-trimethyl-1,4-dioxaspiro[4,5]dec-7-en-8-methanol in 3 l. of methylene chloride. After the mixture was stirred under nitrogen for an additional day, the oxidation was complete according to a determination by thin layer chromatography. Filtration and evaporation of the solvent yielded the crude product which was used for the next step without further purification. A small portion of this product was purified by vacuum distillation. This product was identified as 7,9,9-trimethyl-1,4-dioxaspiro[4,5]dec-7-en-8-carboxaldehyde.
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](C2C=CC=CC=2C([O-])=O)=[CH:12][C:11]=1[N+:25]([O-:27])=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH2:28].O.[OH-].[Li+].Cl>CO>[CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:28])=[CH:12][C:11]=1[N+:25]([O-:27])=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)Oc1ccc(-c2ccccc2C(=O)[O-])cc1[N+](=O)[O-]
Reactant: O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC[C@H](C)Oc1ccc(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
Compound 32a (380 mg, 1.02 mmol) was dissolved in 10 ml methanol, and water (approximately 3 ml) was added until the solution remained milky yellow with vigorous stirring. Lithium hydroxide monohydrate (258 mg, 6.1 mmol) was added, the reaction mixture was stirred for six hours at 25° C., and then was acidified with concentrated HCl. The reaction mixture was extracted with dichloromethane (30 ml). The organic layer was separated, washed with saturated sodium bicarbonate, followed by brine, and dried over magnesium sulfate. The solvent was evaporated and the crude product was purified via flash chromatography over silica gel (50/50, v/v, Hex/EtOAc) to yield 269 mg (98%) of an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19]([OH:21])=O.Cl.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28][CH2:27]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][CH:33]=[C:24]([F:23])[CH:25]=2)[CH2:30]1)=[O:21]
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12
Agent: Cl
Product: O=C(c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12)N1CCc2cc(F)ccc2C1
Yield: 26.7 %

Procedure:
Reaction of 6-fluoro-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 102 (26.7% yield). 1H NMR (400 MHz, CDCl3) δ 2.95 and 3.13 (2t, 2H), 3.64 and 4.20 (2t, 2H), 4.56 and 5.09 (2s, 2H), 6.82-7.28 (m, 4H), 7.50-7.54 (m, 1H), 7.70-7.77 (m, 2H), 8.17-8.21 (m, 1H), 8.28-8.35 (m 1H), 8.40-8.44 (m, 1H); 19F (376 MHz, DMSO-d6) δ −108.2, −112.8, −115.0, −115.6; MS (ESI) m/z 420 ([M+H]+).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:7]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])[CH2:6][CH2:5][O:4]1.CN1CCOCC1.[O:21]=[C:22]1[CH:26]([NH:27][C@H:28]([C:30](O)=O)C)[CH2:25][CH:24]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]CC)[O:23]1>>[CH2:24]([O:23][C:22](=[O:21])[C@@H:26]1[CH2:25][CH2:30][CH2:28][N:27]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][CH:7]1[CH2:6][CH2:5][O:4][C:3]1=[O:2])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C[C@H](NC1CCOC1=O)C(=O)O
Reactant: CCCCCCCCC1CC(N[C@@H](C)C(=O)O)C(=O)O1
Agent: Cl
Solvent: CN1CCOCC1
Product: C[C@H](NC1CCOC1=O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
Conducting a reaction and treatments in the same manner as in Step (3) of Example 1 except that N-(2-oxo-3-tetrahydrofuranyl)-L-alanine hydrochloride was used in a form neutralized with N-methylmorpholine in place of Isomer BCD of N-(2-oxo-5-octyl-3-tetrahydrofuranyl)-L-alanine, was obtained as a colorless syrupy substance N-(2-oxo-3-tetrahydrofuranyl)-L-alanyl-L-proline benzyl ester [in the formula (I), R1 =R2 =H, R3 =CH3, R4 and R5 =--(CH2)3 --, R6 =-CH2Ph (Compound 13)].
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31][C:32]1[CH:33]=[N:34][N:35]2[CH:40]=[CH:39][C:38]([NH:41][C@@H:42]([CH:45]([CH3:47])[CH3:46])[CH2:43]O)=[N:37][C:36]=12.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[Br:31][C:32]1[CH:33]=[N:34][N:35]2[CH:40]=[CH:39][C:38]([NH:41][C@@H:42]([CH:45]([CH3:47])[CH3:46])[CH2:43][N:2]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])=[N:37][C:36]=12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)[C@@H](CO)Nc1ccn2ncc(Br)c2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)[C@@H](CN1C(=O)c2ccccc2C1=O)Nc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Yield: 40.3 %

Procedure:
To a solution of isoindoline-1,3-dione (4.9 g, 34 mmol) in THF cooled to 0° C. was added triphenylphosphine (8.8 g, 34 mmol) and (S)-2-(3-bromopyrazolo[1,5-a]pyrimidin-5-ylamino)-3-methylbutan-1-ol (Example 15, Step 1; 6.7 g, 22 mmol) and the reaction stirred at ambient temperature until all reactants were dissolved. To the reaction was added (E)-diisopropyl diazene-1,2-dicarboxylate (8.2 g, 40 mmol) and the reaction was stirred for 2 hours at ambient temperature. The reaction was concentrated in vacuo and the material chromatographed using 20% EtOAc/dichloromethane as eluent to yield (S)-2-(2-(3-bromopyrazolo[1,5-a]pyrimidin-5-ylamino)-3-methylbutyl)isoindoline-1,3-dione (3.8 g, 40%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+].C(OCC)(=O)C>Cl.O1CCOCC1>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 159.6 %

Procedure:
N-tert-butyloxycarbonyl--N'-benzyloxycarbonyl-piperazine (1.8 g, 3.13 mmol) was dissolved in 10 mL of 4N-HCl/dioxane. It was stirred at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath, 1N-NaOH solution was carefully added to the mixture to adjust pH above 10. Ethyl acetate (50 mL×3) was used to extract the compound. The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate. After removal of the solvent, 1.1 g of N-benzyloxycarbonyl-piperazine was obtained in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][Si](C(C)(C)C)(C)C)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][CH:38]=[CH:37][C:27]=2[N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][CH:38]=[CH:37][C:27]=2[N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O[Si](C)(C)C(C)(C)C)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(tert-butyl-dimethyl-silanoxy)-indole-1-carboxylic acid tert-butyl ester (320 mg, 0.56 mmol, Example 5C) in tetrahydrofuran (5 mL) at 0° C. is added TBAF (1.0 M in tetrahydrofuran, 0.67 mL, 0.67 mmol). The solution is stirred at 0° C. for 30 minutes. The solvent is then removed and the residue is chromatographed through silica gel (dichloromethane-ethyl acetate, 95:05 to 90:10 as eluant) to produce 205 mg (80%) 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-hydroxy-indole-1-carboxylic acid tert-butyl ester as an orange foam. LC/MS: RT=3.74 minutes, 456.0 m/e.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:34][CH3:35])=[CH:11][C:12]2[C:13]3[CH:14]4[C:31](=[O:32])[NH:30][C:29](=[O:33])[CH:15]4[CH:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[CH2:17][C:18]=3[NH:19][C:20]=2[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:10]([O:34][CH3:35])=[CH:11][C:12]2[C:13]3[C:14]4[C:31](=[O:32])[NH:30][C:29](=[O:33])[C:15]=4[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])=[CH:17][C:18]=3[NH:19][C:20]=2[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c3c([nH]c2cc1OCc1ccccc1)CC(c1ccccc1Cl)C1C(=O)NC(=O)C31
Agent: [Mn+4]
Agent: [O-2]
Product: COc1cc2c(cc1OCc1ccccc1)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Yield: 93 %

Procedure:
Aromatisation of (161) prepared as described in example 261 with manganese dioxide using the procedure described in example 79 gave the carbazole (162) (93%) as an orange powder, mp 260–264° C. 1H NMR δ [(CD3)2SO] 11.86 (s, 1H), 11.01 (s, 1H), 8.43 (s, 1H), 7.58–7.34 (m, 10H), 7.26 (s, 1H), 5.26 (s, 2H), 3.91 (s, 3H). Found: C, 69.65; H, 3.84; N, 5.61. C28H19ClN2O4 requires C, 69.64; H, 3.97; N, 5.80.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=S)[CH2:15][C:16](=O)[CH3:17])=[O:4].[Cl:20][C:21]1[CH:26]=[C:25]([NH:27][NH2:28])[CH:24]=[CH:23][N:22]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([Cl:20])[CH:26]=2)[N:28]=[C:16]([CH3:17])[CH:15]=1)=[O:4]
Reactant: NNc1ccnc(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1-c1ccnc(Cl)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-methanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 448c) was reacted with (2-chloro-pyridin-4-yl)-hydrazine (CAS Reg. No. 700811-29-6) to give the title compound.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH:28]([OH:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:30][CH2:28][CH2:29][N:5]1[CH2:6][CH2:7][N:2]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[N:9]=2)[CH2:3][CH2:4]1
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: CC(O)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCN(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Yield: 44.6 %

Procedure:
A stirred mixture of 5.5 g of 3-(1-piperazinyl)-1-[4(trifluoromethyl)phenyl]-1H-indazole hydrochloride, 2.3 g of bromoethanol, 2.5 g of potassium carbonate and 60 ml of dimethylformamide was heated, under nitrogen, at 70°-75° for 16 hours. The reaction mixture was poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was chromatographed on silica gel utilizing a Water's Model 500 High Pressure Liquid Chromatograph and eluting with dichloromethane/methanol (6%). Evaporation of the appropriate fractions gave an oil which solidified upon standing. Recrystallization of the solid from hexane (2×) gave 2.5 g (40%) of 3-[4-(2-hydroxyethyl)-1piperazinyl-]-1-[4-(trifluoromethyl)phenyl]-1H-indazole, mp 82°-84°.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:14]([Br:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:4]=1[CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[ClH:1].[NH:2]([C:3]1[C:14]([Br:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:4]=1[CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[C:17]([CH3:18])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)Cc1cc(C)cc(Br)c1N
Agent: Cl
Product: CCN(CC)Cc1cc(C)cc(Br)c1NC(C)=O

Procedure:
1.53 gm of 2-amino-3-bromo-N,N-diethyl-5-methyl-benzylamine hydrochloride were dissolved in 50 ml of acetic acid anhydride at 75° C. The solution was evaporated to dryness in vacuo, and the residue was recrystallized from ethanol, yielding 2-acetamino-3-bromo-N,N-diethyl-5-methyl-benzylamine hydrochloride, m.p. 170-172° C.
Reaction SMILES: [N:1]#[N:2].C([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:31][C:32](=[O:51])[C@H:33]([CH2:47][C:48](=[O:50])[NH2:49])[NH:34][C:35]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[O:36])[C@H:16]([OH:30])[CH2:17][C@@:18]2([C:27]([NH2:29])=[O:28])[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:10][CH:9]=1)(C)(C)C.[ClH:52]>C(OCC)(=O)C>[N:1]#[N:2].[ClH:52].[OH:30][C@@H:16]([C@@H:15]([NH:31][C:32](=[O:51])[C@H:33]([CH2:47][C:48](=[O:50])[NH2:49])[NH:34][C:35]([C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)=[O:36])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([OH:7])=[CH:13][CH:12]=1)[CH2:17][C@@:18]1([C:27]([NH2:29])=[O:28])[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)c2ccc3ccccc3c2)[C@H](O)C[C@@]2(C(N)=O)CCCN2C(C)(C)C)cc1
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2c1)C(N)=O

Procedure:
A solution of 90 mg of N2 -[4-(4-tert.butoxyphenyl)-2(R)-hydroxy-3(S)-[[N-(2-naphthoyl)-L-asparaginyl]amino]butyl]-N1 -tert.butyl-L-prolinamide in 40 ml of 3.5M hydrogen chloride in ethyl acetate was stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue was triturated with diethyl ether and filtered to give 80 mg of N2 -[2(R)-hydroxy-4-(4-hydroxyphenyl)-3(S)-[[N-(2-naphthoyl)-L-asparaginyl]amino]butyl]-N1 -tert.butyl-L-prolinamide hydrochloride as a white solid of melting point 171°-174° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([CH2:20][CH3:21])[CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([CH2:20][CH3:21])[CH:19]=[C:13]4[N:12]([C:27](=[O:28])[C:26]4[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=4)[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCc1cc2[nH]c3c(cnc4c3cnn4CC)c(=O)n2n1
Product: CCc1cc2n(C(=O)c3ccc(Cl)cc3)c3c(cnc4c3cnn4CC)c(=O)n2n1

Procedure:
By treating the product of Example 25 with 4-chlorobenzoyl chloride according to the procedure of Example 2, 3,9-diethyl-3,11-dihydro-11-(4-chlorobenzoyl)-6H-pyrazolo-[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([O:19]CC)=O.[NH2:22][NH2:23]>>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH:22][NH2:23])=[O:19]
Reactant: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1C
Reactant: NN
Product: Cc1[nH]c(-c2cccc3ccccc23)nc1C(=O)NN

Procedure:
A mixture of 5.0 g of the above ester and 25 ml of hydrazine was refluxed overnight and then cooled. The solid was collected, stirred with water and cooled. The solid was collected, giving 4.5 g of 5-methyl-2-(1-naphthalenyl)-1H-imidazole-4-carboxylic acid, hydrazide.