Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH-].[K+].Cl[C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21]>CS(C)=O>[CH2:1]([O:3][C:7]1[C:8]([C:20]([F:21])([F:22])[F:23])=[CH:9][C:10]([N+:17]([O-:19])=[O:18])=[CH:11][C:12]=1[C:13]([F:14])([F:15])[F:16])[CH3:2]
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOc1c(C(F)(F)F)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Ethanol (20 mL, 343 mmol) was treated with potassium hydroxide (956 mg, 17.0 mmol) and the mixture was stirred at RT for 1 h. A solution of 2-chloro-5-nitro-1,3-bis(trifluoromethyl)benzene (1) (1.00 g, 3.41 mmol) in DMSO (10 mL) was added dropwise. The resultant mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc and water and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to afford 2-ethoxy-5-nitro-1,3-bis(trifluoromethyl)benzene (2) (1.00 g, 93%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.72 (2H, s), 4.21 (2H, q), 1.41 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[Br:22]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>[Br:22][CH2:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]([C:13]([F:16])([F:15])[F:14])[O:8]2)=[CH:3][C:2]=1[Cl:1]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C)cc2OC1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Temperature: 84 °C
Reaction time: 5 h
Yield: 78.1 %

Procedure:
To a mixture of the product of Example 157 Step 2 (4.0 g, 12.5 mmol), N-bromosuccinimide (2.3 g, 13.1 mmol), and 21 mL benzene, was added benzoyl peroxide (145 mg. 0.6 mmol). The reaction was heated to 84° C. After 5 h, the reaction was cooled to 25° C. and stored overnight. Solid was removed from the reaction by filtration, and washed with 4 mL benzene. To the filtrate, was added N-bromosuccinimide (1.0 g, 5.7 mmol) and benzoyl peroxide (145 mg, 0.6 mmol). The reaction was heated to 84° C. After 2.5 h, the reaction was cooled to 25° C. The solid was removed from the reaction by filtration and the filtrate was concentrated. The residue was purified by flash chromatography (toluene/EtOAc=9/1) to give 3.9 g a yellow solid of reasonably pure material, which was used without further purification.
Reaction SMILES: [C:1]([O-])(C)(C)C.[K+].CI.[CH2:9]([O:11][C:12](=[S:18])[CH2:13][C:14]([CH2:16][CH3:17])=[O:15])[CH3:10]>O1CCCC1>[CH2:9]([O:11][C:12](=[S:18])[CH:13]([CH3:1])[C:14]([CH2:16][CH3:17])=[O:15])[CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=S)CC(=O)CC
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=S)C(C)C(=O)CC
Temperature: 60 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
First 12.3 g (0.11 mol) of potassium tert.-butanolate and then 15.6 g (0.11 mol) of methyl iodide were added to a solution of 17.6 g (0.1 mol) of 4-methylthioacetoacetic acid ethyl ester in 100 ml of tetrahydrofuran, while cooling. The mixture was subsequently stirred at 60° C. for 12 hours, the solvent was then distilled off in vacuo, 200 ml of methylene chloride were added to the residue and the solution was extracted by shaking twice with 100 ml of water each time. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was distilled in vacuo. 14 g (74% of theory) of 2-methyl-4-methylthioacetoacetic acid ethyl ester with a boiling point of 95°-99° C./2 mm Hg were thus obtained. ##STR6##
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([Br:13])=[CH:7][C:8]=2[Br:12])[C:3]1=[O:14].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>CN(C)C=O>[N:15]1([CH:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][C:6]([Br:13])=[CH:7][C:8]=3[Br:12])[C:3]2=[O:14])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: O=C1c2cc(Br)cc(Br)c2CCC1Br
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)cc(Br)c2CCC1n1ccnc1
Yield: 62.1 %

Procedure:
A solution of 2,5,7-tribromo-3,4-dihydro-1(2H)-naphthalenone (1 g), imidazole (0.7 g), and N,N-dimethylformamide (15 ml) was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure and the residue, taken up with CH2Cl2 (20 ml), washed with H2O, was extracted with a solution of 8% HCl. The acid solution, neutralized with NaHCO3, extracted with CH2Cl2, dried and evaporated, gave 0.6 g of 2-(1-imidazolyl)-3,4-dihydro-5,7-dibromo-1(2H)-naphthalenone;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH3:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:17]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:11])[NH2:17])[CH2:13][O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: COC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
To a solution of (S)-2-tertbutoxycarbonylamino-3-methoxypropionic acid (1.13 g, 5.2 mmol) in anhydrous THF (20 mL) at −15° C. was added N-methylmorpholine (0.57 mL, 5.2 mmol) and isobutylchloroformate (0.67 mL, 5.2 mmol) under a nitrogen atmosphere. After 2 minutes, 33% aqueous ammonia (0.45 mL, 7.8 mmol) was added and the resulting mixture was stirred at −15° C. for 2 h. The reaction mixture was allowed to warm to RT and was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic fractions were washed with aqueous 5% NaHCO3, water, then dried (MgSO4) and concentrated in vacuo. The resulting pink oil was used without further purification (1.03 g, 91%). 1H NMR (CDCl3, 300 MHz): δ 6.42 (1H, br s), 5.48 (2H, br s), 4.25 (1H, br s), 3.83-3.74 (1H, m), 3.52-3.41 (1H, m), 3.40 (3H, s), 1.42 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].[Br:19][CH2:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCCOc1ccccc1O
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1OCCCBr
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a stirred solution of ethyl 4-(2-hydroxyphenoxy)butanoate (5.61 g, 25 mmol) in DMF (25 mL) at 0° C. was slowly added sodium hydride (0.6 g, 25 mmol) and then the solution was left stirring at 0° C. for 4 hours. To a stirred solution at 65-70° C. was added 1,3-dibromopropane (3.80 mL, 37.5 mmol). The resulting solution was continued to stir at 65-70° C. for 3 hours. Normal work-up and purification by silica gel column chromatography gave bromo-compound as a white solid in 60% yield (5.18 g, m.p. 31-32.6° C., CH2Cl2/hexane). 1H NMR (400 MHz, CDCl3): 1.25 (3H, t, J=7.1 Hz), 2.13 (2H, m), 2.34 (2H, m), 2.54 (2H, t, J=7.3 Hz), 3.64 (2H, t, J=6.4 Hz), 4.04 (2H, t, J=6.2 Hz), 4.10-4.15 (4H, m), 6.99-6.93 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[H-].[Na+].[C:32]12([C:42](Cl)=[O:43])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2.Cl>O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42]([C:32]45[CH2:41][CH:36]6[CH2:35][CH:34]([CH2:40][CH:38]([CH2:37]6)[CH2:39]4)[CH2:33]5)=[O:43])=[C:3]([N+:27]([O-:29])=[O:28])[CH:4]=3)(=[O:10])=[O:9])=[O:13])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(S(=O)(=O)NC(=O)c2ccc(-c3ccc(F)cc3)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)c1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of Example 380A (101 mg, 0.25 mmol) in TBF (3 mL) was treated with 60% sodium hydride in oil (40 mg, 1.0 mmol), stirred for 30 minutes, treated with 1-adamantanecarbonyl chloride (60 mg, 0.30 mmol), stirred for 30 minutes, adjusted to pH<7 with 4M HCl in dioxane (0.5 mL), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30-100% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 576 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.52 (d, 1H), 8.23 (dd, 1H), 8.19 (d, 1H), 7.95 (d, 2H, 7.75 (m, 4H), 7.31 (tt, 2H), 2.05 (3s, 3H), 1.90 (m, 6H), 1.70 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)([O-])=O.[H-].[Na+]>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Following the general procedure of J. Polym. Sci., Polym. Chem. Ed. (1980), 18(10), 3069-80, 4-hydroxybenzoic acid, 4-nitro-1-(trifluoromethyl)benzene, and sodium hydride in DMF were heated at 130° C. to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][NH:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:26]([CH3:25])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCC(C)C
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)CCN(C)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (82 mg, 0.22 mmol), methyl (3-methylbutyl)amine (45 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) in MeCN (4 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 57 mg (60% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.89 (d, J=6.64 Hz, 6 H), 1.39 (q, J=6.90 Hz, 2 H), 1.46-1.61 (m, 5 H), 1.64 (s, 9 H), 2.26-2.43 (m, 1 H), 2.70 (s, 3 H), 2.97-3.06 (m, 2 H), 3.29-3.38 (m, 2 H), 3.86-3.97 (m, 2 H), 4.48 (d, J=7.42 Hz, 2 H), 7.81 (dd, J=8.79, 1.76 Hz, 1 H), 7.96 (d, J=8.79 Hz, 1 H), 8.07 (d, J=1.37 Hz, 1 H); MS (ESI) (M+H)+=436.0; Anal. Calcd for C23H37N3O3S+0.70 TFA+0.30 EtOAc+0.5H2O (550.89): C, 55.82; H, 7.52; N, 7.63. Found: C, 55.90; H, 7.46; N, 7.63.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24]([S:27][CH2:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:26])[CH3:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]([C:30](=[O:31])[CH:29]([CH3:33])[CH2:28][S:27][C:24](=[O:26])[CH3:25])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1CCCCCC1
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCCCC1
Yield: 98.7 %

Procedure:
To a stirred and chilled (0°-5° C.) solution of N-cycloheptylglycine t-butyl ester (32.9 g, 0.12 mol) and triethyl amine (13.2 g, 0.13 mol) in methylene chloride (150 ml) was added dropwise 3-acetylthio-2-methylpropanoyl chloride (21.6 g, 0.12 mol) dissolved in 50 ml methylene chloride. The reaction mixture was stirred overnight. Filtration of the reaction mixture followed by washing the filtrate with saturated sodium bicarbonate (500 ml), brine (500 ml), 5% HCL (4×500 ml), brine (500 ml), saturated aqueous sodium bicarbonate (3×500 ml), brine (500 ml); drying the organic layer over Na2SO4 and MgSO4 ; filtration; and solvent evaporation afforded a nearly quantitative yield of the desired compound (44 g, crude).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]=[C:6]=[S:7].[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[S:7])[NH:15][NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NNc1ccccc1
Reactant: COCCN=C=S
Solvent: c1ccccc1
Product: COCCNC(=S)NNc1ccccc1

Procedure:
In benzene was dissolved 11.7 g of 2-methoxyethyl isothiocyanate with stirring and after adding thereto 11.9 g of phenylhydrazine at room temperature, the mixture was heat-refluxed. After performing the reaction for 6 hours, the reaction mixture was cooled and crystals thus formed were collected by filtration. The yield for the product was 66.7%. The product, 4-(2-methoxyethyl)-1-phenylthiosemicarbazide thus obtained could be used for the subsequent reaction without being purified.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C@H:15]([OH:21])[C:16](OCC)=[O:17])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.CO>[OH:21][C@H:15]([CH2:16][OH:17])[C@H:14]([NH:13][C:11](=[O:12])[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@@H](O)[C@H](NC(=O)OCc1ccccc1)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([C@@H](NC(=O)OCc2ccccc2)[C@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 (1.06 g, 28 mmol, 3.0 equiv) was added to a solution of 2.21.1a (3.5 g, 9.4 mmol, 1.0 equiv) in THF (10.0 mL) and MeOH (30 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour, after which, another 0.3 g of NaBH4 (300 mg, 7.8 mmol, 0.8 equiv) was added. After stirring at room temperature for 30 minutes, the solvent was removed under vacuum. The residue was dissolved in EtOAc and saturated aqueous NaHCO3 solution was added. The phases were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude material was used in the next step with no further purification. MS m/z (M+Na): 354
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:33])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[CH2:24][C:23]([CH3:32])([CH3:31])[CH2:22][N:21]3[CH:20]=1)=O>>[CH3:32][C:23]1([CH3:31])[CH2:24][C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:33])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]3[CH2:22]1)[CH:28]=[CH:27][CH:26]=2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(C)(C)C2
Product: CC1(C)Cc2cccc3c(C4=C(c5c[nH]c6ccccc56)C(=O)NC4=O)cn(c23)C1

Procedure:
Beginning with (indol-3-yl)acetamide and (5,5-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxo-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[K+].[Br-]>>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([CH2:28][CH:24]4[CH2:25][CH2:26][CH2:27][O:23]4)[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: C1COC(CN2CCNCC2)C1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)N1CCN(CC2CCCO2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(tetrahydrofuran-2-ylmethyl)-piperazine, yield 23%. White crystals, m.p. 98-100° C.; IR (KBr): ν 1731 (C═O) cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:34](OC(N1CCC2(CNC2)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:34][C:14]2([CH2:13][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[C:24]=4[N:25]=3)[CH2:11]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1nc3c(N4CCOCC4)nc(Cl)nc3s1)C2

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester hydrochloride in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (70 mg, 71%).
Reaction SMILES: C(OC([NH:8][C@@:9]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[CH3:24][C@:9]([NH2:8])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@](C)(C(=O)N1CCOCC1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](N)(C(=O)N1CCOCC1)c1ccccc1

Procedure:
A solution of 630 mg (1.884 mmol) of N-(tert-butoxycarbonyl)-(1S)-1-methyl-2-morpholin-4-yl-2-oxo-1-phenylethylamine in 20 mL of dioxane was treated with 2.5 mL of HCl 4N in dioxane overnight. The solvent was removed under vacuo and the solid was triturated with diethylether yielding 560 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:32])([CH3:31])[C:29]#[CH:30]>>[CH3:27][C:28]([CH3:32])([CH3:31])[C:29]#[C:30][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:7][CH2:6][C:5]=2[CH:17]=[CH:18][C:2]=1[F:1]
Reactant: C#CC(C)(C)C
Reactant: O=C(N1CCc2ccc(F)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(C)(C)C#Cc1c(F)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 85.4 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1 g, 2.4 mmol) with 3,3-dimethyl-1-butyne (0.599 mL, 4.9 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to give 6-(3,3-dimethyl-but-1-ynyl)-7-fluoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (700 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCCN1CCOCC1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCCN2CCOCC2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[3-(4-morpholinyl)propylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-aminopropylmorpholine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][NH2:17]>CO>[CH3:10][CH:9]([CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH3:16])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)=[O:12]
Reactant: CN
Reactant: CC(C)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CO
Product: CNc1ccc(C(=O)C(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a stirred solution of 30 parts of 1-(4-chloro-3-nitrophenyl)-2-methyl-1-propanone in 240 parts of methanol was added a solution of 20 parts of methanamine in 160 parts of methanol. After stirring for 12 hours at 60° C., the reaction mixture was evaporated to dry, yielding 30 parts (100%) of 2-methyl-1-[4-(methylamino)-3-nitrophenyl]-1-propanone as a residue (interm. 45).
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4([C:26]([O:28]CC)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Cl>O1CCOCC1.O>[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1

Procedure:
Sodium hydroxide (200 mg, 5 mmol) was added to a solution of ethyl 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylate (870 mg, 2.25 mmol) in dioxane (10 ml) and water (2 ml). The reaction mixture was heated to reflux for 16 hours under nitrogen. The reaction was not complete. More sodium hydroxide (190 mg, 4.75 mmol) in water (4 ml) was added and the reaction heated at reflux for 18 hours. 2N Hydrochloric acid (5 ml, 9.75 mmol) was added and the mixture concentrated in vacuo to a white powder (2.0 g) containing the title compound and sodium chloride. LRMS APCI+ m/z 360 [MH]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]2[O:15][CH2:16][O:17][C:5]=2[CH:4]=1.[C-:18]#[N:19].[Na+].O>CS(C)=O>[C:18]([CH2:2][C:3]1[C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]2[O:15][CH2:16][O:17][C:5]=2[CH:4]=1)#[N:19]
Reactant: CC(=O)NCCc1cc2c(cc1CCl)OCO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)NCCc1cc2c(cc1CC#N)OCO2

Procedure:
4.7 g of N-(6-chloromethyl-3,4-methylenedioxyphenethyl) acetamide was dissolved in 10 ml of DMSO and 1.32 g (0.028 mole) of sodium cyanide added to the stirred solution. Within a few minutes, the temperature rose from 25° to 32° C. After 1.5 hrs at ambient temperature the mixture was poured into ice and water. The suspension was extracted with three 50-ml portions of benzene. The benzene layers were washed with saturated brine six times, then with water, the solution dried, and the solvent distilled in the rotary evaporator leaving the above-named product as a crystalline solid, m.p. 153.3-155.5.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Li+].[F:20][C:21]([F:37])([F:36])[C:22]1[N:27]=[C:26]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33]([O-])=[O:34])[CH:25]=[CH:24][CH:23]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:37])([F:20])[F:36])[N:27]=3)=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C([O-])c1ncoc1-c1cccc(C(F)(F)F)n1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Agent: [Li+]
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C(F)(F)F)n3)n2)o1

Procedure:
Following general procedure Z3 followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(6-trifluoromethyl-pyridin-2-yl)-oxazole-4-carboxylic acid lithium salt. LC-MS-conditions 01: tR=0.90 min; [M+H]+=445.99.