Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10](O)[CH2:9]2)=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:24])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@@H:10]([F:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: O[C@H]1CC[C@@H](c2ccc(Br)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: F[C@@H]1CC[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of (1S,3R)-3-(4-bromophenyl)cyclopentanol (503 mg, 2.09 mmol) in 10 mL of CH2Cl2 at −78° C. was added (bis(2-methoxyethyl)amino)sulfur tri fluoride (Deoxo-Fluor, 462 μL, 2.50 mmol). The mixture was allowed to gradually warm up to rt overnight and then poured into sat'd NaHCO3 (20 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL). The organic layer was dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using hexanes as the eluant afforded 383 mg (76%) of the title compound: 1H NMR δ 1.53-1.78 (m, 2H), 1.95-2.39 (m, 4H), 3.35 (m, 1H), 5.19-5.32 (m, 1H), 7.09 (d, J 8.5, 2H), 7.40 (d, J=8.2, 2H).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[C:18](Br)=[C:17]([N+:20]([O-:22])=[O:21])[C:16]([Br:23])=[N:15]2)[N:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C(O)CC>[CH2:24]([NH:31][C:18]1[N:14]([CH2:13][CH2:12][CH2:11][N:4]2[C:5]([NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([Br:1])=[N:3]2)[N:15]=[C:16]([Br:23])[C:17]=1[N+:20]([O-:22])=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1c(Br)nn(CCCn2nc(Br)c([N+](=O)[O-])c2Br)c1Br
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCCO
Product: O=[N+]([O-])c1c(Br)nn(CCCn2nc(Br)c([N+](=O)[O-])c2NCc2ccccc2)c1NCc1ccccc1

Procedure:
11.6 g of 1,3-bis-(3,5-dibromo-4-nitropyrazol-1-yl)propane from step 5.1 are heated together with 6.5 g of benzylamine in 180 ml of n-propanol for 1 hour at 100° C. Subsequently the reaction mixture is cooled and poured into 1000 ml water. The precipitate is filtered with suction, washed with water and dried in vacuum at 60° C.
Reaction SMILES: [CH3:1][C@@H:2]([C:11]([O-])=[O:12])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1COCC1>CO>[OH:12][CH2:11][C@H:2]([CH3:1])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C[C@H](CC(=O)OC(C)(C)C)C(=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](CO)CC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Borane-dimethyl sulphide complex (10M, 10.3 ml) was added during 15 minutes to a stirred mixture of 1-tert-butyl (3R)-3-methylsuccinate (12.9 g) and THF (200 ml) which had been cooled to -10° C. and placed under an atmosphere of argon. The mixture was stirred at -10° C. for 30 minutes. The mixture was allowed to warm to room temperature and was stirred for 1 hour. The mixture was recooled to 5° C. and methanol (50 ml) was added portionwise. The mixture was allowed to warm to room temperature and was stirred for 30 minutes. The mixture was evaporated and the residue was partitioned between dichloromethane (100 ml) and water (100 ml). The organic phase was filtered through phase separating paper and evaporated to give tert-butyl (3R)-4-hydroxy-3-methylbutyrate as an oil (11 g); NMR(CDCl3) δ 3.55(2H,m), 2.1-2.4(3H,m), 1.46(9H,s), 0.98(3H,d).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([NH:32][CH3:33])[CH2:28][CH2:27]2)[CH2:24][CH2:23]1.C(N(CC)CC)C>C(#N)C>[CH:22]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH3:33])[C:18](=[O:20])[CH2:17][O:16][C:12]3[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:21])[N:11]=3)[CH2:28][CH2:27]2)[CH2:23][CH2:24]1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CNC1CCN(CC2CC2)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC3CC3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
Compound 9 (100 mg), 1-(cyclopropylmethyl)-N-methylpiperidine-4-amine (56.6 mg) and triethylamine (234 μL) were suspended in acetonitrile (2 mL). While the suspension was cooled with ice, a 50% propane phosphonic acid anhydride ethyl acetate solution (273 mg) was added portionwise. The equipment used to add the 50% propane phosphonic acid anhydride ethyl acetate solution was thoroughly washed with acetonitrile (0.5 mL) and was stirred at room temperature (20 to 30° C.) overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride: methanol=30:1) to give 79 mg (52% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH2:5])[CH2:2]1.C(N(CC)CC)C.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=1>C(O)(C)C>[O:1]1[CH2:4][CH:3]([NH:5][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=2)[CH2:2]1
Reactant: N#Cc1ccc(Br)nc1
Reactant: NC1COC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N#Cc1ccc(NC2COC2)nc1
Yield: 24.7 %

Procedure:
In a microwave vial, oxetan-3-amine (125 mg, 1.736 mmol), triethylamine (526 mg, 5.21 mmol) were added to a solution of 2-bromo-5-cyanopyridine (317 mg, 1.736 mmol) in isopropanol (3 mL). The vial was capped and irradiated in a microwave oven at 120° C. for 5 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography over silica gel (chloroform/MeOH, 0-5% EtOAc) to afford 75 mg (25%) of 6-(oxetan-3-ylamino)nicotinonitrile (I-25) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.58-7.61 (dd, J=1.9, 6.9 Hz, 1H), 6.39 (d, J=8.7 Hz, 2H), 5.37 (br. s, 1H), 4.91-5.06 (m, 3H), 4.54-4.57 (m, 2H); ESI-LC/MS (m/z): [M+H]+ 176.2, RT 1.65 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH:4]=[CH:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:35][C:36](O)=[O:37])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32].CCN(CC)CC.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([CH:5]3[CH2:6][CH:2]([NH:1][C:36](=[O:37])[CH2:35][C:27]4[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=4)[CH:3]=[CH:4]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1onc2c1c(=O)n(C1C=CC(N)C1)c1cccc(Cl)c21
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)NC2C=CC(n3c(=O)c4c(C)onc4c4c(Cl)cccc43)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.3 %

Procedure:
To a stirred solution of 5-(4-amino-cyclopent-2-enyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (47 mg, 0.15 mmol) in CH2Cl2 (2.5 mL) was added 3,4,5-trimethoxy phenyl acetic acid (45 mg, 0.20 mmol), Et3N (0.053 mL, 0.38 mmol) and EDCI (38 mg, 0.20 mmol) and stirred at r.t. for 18 hours. The mixture was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the title compound (23 mg, 29%). Mass Spectrum (FIA) (m/z) 522.2 (M−1). 1H NMR (CDCl3): δ 7.43 (d, 1H); 7.37 (m, 2H); 6.42 (s, 2H); 5.88 (m, 2H); 5.18 (m, 1H); 3.78 (s, 9H); 3.47 (s, 2H); 2.90 (m, 2H); 1.98 (m, 2H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[S:12][C:11]([S:13]([NH:16][CH:17]([CH:22]2[CH2:27][CH:26]3[CH:24]([C:25]3([F:29])[F:28])[CH2:23]2)[C:18](OC)=[O:19])(=[O:15])=[O:14])=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[S:12][C:11]([S:13]([NH:16][CH:17]([CH:22]2[CH2:27][CH:26]3[CH:24]([C:25]3([F:29])[F:28])[CH2:23]2)[CH2:18][OH:19])(=[O:14])=[O:15])=[CH:10][CH:9]=1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(Cl)s1)C1CC2C(C1)C2(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)C1CC2C(C1)C2(F)F)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a slurry of LAH (0.030 g, 0.78 mmol) in THF (5 mL) was added methyl {[(5-chlorothien-2-yl)sulfonyl]amino}(6,6-difluorobicyclo[3.1.0]hex-3-yl)acetate (0.154 g, 0.38 mmol) dropwise at 0° C. over 20 min. The slurry (gray) was allowed to warm to 25° C. over 19 h. The reaction slurry was cooled to 0° C. and the reaction was quenched with H2O (0.5 mL), 1N NaOH (1.5 mL) and H2O (0.5 mL). The reaction was stirred 4 h to obtain a white slurry. The slurry was filtered and the mother liquor was further dried over MgSO4, filtered, and concentrated in vacuo to obtain a crude yellow oil (0.162 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:4 EtOAc-hexanes, to afford 5-chloro-N-[1-(6,6-difluorobicyclo[3.1.0]hex-3-yl)-2-hydroxyethyl]thiophene-2-sulfonamide as a colorless oil (0.105 g, 77.77%). Mass Spectrum (−ESI): 356 (M−H)−.
Reaction SMILES: [CH2:1]([C@H:8]([NH:16][C:17]([C:19]1[NH:23][C:22]2[S:24][C:25]([C:27]#[C:28][Si](C)(C)C)=[CH:26][C:21]=2[CH:20]=1)=[O:18])[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([C@H:8]([NH:16][C:17]([C:19]1[NH:23][C:22]2[S:24][C:25]([C:27]#[CH:28])=[CH:26][C:21]=2[CH:20]=1)=[O:18])[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cc2cc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CC(O)C3)[nH]c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cc2cc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CC(O)C3)[nH]c2s1
Reaction time: 3 h
Yield: 89 %

Procedure:
Using a procedure analogous to that of G. M. Whitesides et al. (J. Org. Chem., 53: 2489-2496 (1988)), to a solution of 2-trimethylsilanylethynyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide (110 mg, 0.02 mmol) in methanol (0.5 ml) was added a 5% aqueous solution of potassium hydroxide (7 μL, 0.06 mmol). The reaction mixture was stirred for 3 h, concentrated to remove the methanol, diluted with water, and extracted with dichloromethane. The organic phase dried over MgSO4 and concentrated to give the title product (7 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:24])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)O)cc2)=C(C)C1=O
Reactant: CC(C)N
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 53.6 %

Procedure:
4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (50 mg, 0.14 mmol) obtained in Example 26 and isopropylamine (0.013 ml, 0.15 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (30 mg, 0.075 mmol, yield 54%).
Reaction SMILES: Br[C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].C([Li])(C)(C)C.CN(C)[CH:20]=[O:21].Cl>O1CCCC1.CCCCC>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2]([CH:20]=[O:21])[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4]1
Reactant: CN(C)C=O
Reactant: Cc1c(Br)c(C(F)(F)F)nn1C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)c(C(F)(F)F)nn1C
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
Dissolve 4-bromo-1,5-dimethyl-3-trifluoromethyl-1H-pyrazole (0.30 g, 1.23 mmol) in tetrahydrofuran (14.7 mL). Cool to −78° C. and add 1.7 M t-butyllithium in pentane (2.9 mL) dropwise. Stir for 3 min. at −78° C. and then add dimethylformamide (669 μL, 8.64 mmol). Stir for thirty min. at −78° C., then warm to 0° C. over 2 hr. Add 2 N hydrochloric acid (12.3 mL) and stir at room temperature for one hr. Separate layers and extract aqueous layer 2 times with DCM. Dry combined organic layers (magnesium sulfate), filter, concentrate and purify (silica gel chromatography eluting with 0:100 to 15:85 ethyl acetate:hexanes), to give the title preparation (79 mg, 33%). GC-MS: m/z=192 [M+].
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1)=[O:5].[Br:24][CH2:25][C:26](Br)=[O:27].C(=O)(O)[O-].[Na+]>CCOCC>[Br:24][CH2:25][C:26]([NH:1][C:2]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])=[CH:10][CH:11]=1)=[O:5])=[O:27]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a stirred mixture of 56 g (0.163 mole) of 2-amino-5-chloro-4'-(2,2,2-trifluoroacetamido)-benzophenone in 900 ml of ether was added 43 g (0.213 mole) of bromoacetyl bromide and a saturated aqueous solution of sodium bicarbonate in portions, keeping the solution slightly basis during the addition. The reaction was stirred for 90 min and filtered to give 66 g of product. The ether layer was dried and evaporated and the residual oil was crystallized from methanol to give an additional 10 g of the product for a total yield of 76 g (96%). Recrystallization from a mixture of dichloromethane, methanol and petroleum ether gave an analytical sample of off white rods, mp 198°-201° ir (KBr) 1750, 1663, 1640 cm-1 (3C=O).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH3:20])[CH:13]=2)[CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NCCc2ccc(OC)c(C)c2)nc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N(CCc2ccc(OC)c(C)c2)Cc2ccc(OC(F)(F)F)cc2)nc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A solution of 5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine (0.83 g; 3.07 mmol) and 4-trifluoromethoxy benzyl bromide (1.18 g; 4.61 mmol) in dry DMF (6 ml) was treated under nitrogen with NaH (95% dispersion in oil; 0.12 g; 4.61 mmol) and the mixture heated at 60C for 1 hr. Cooled to rt and quenched with a saturated solution of ammonium chloride. Diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated. Purification by flash chromatography on silica gel using dichloromethane-hexane mixture (4:1) afforded 5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine (1.26 g; 82% yield).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)([O-:5])=[O:4].I[CH3:16]>C1COCC1>[CH3:16][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
NaH (1.47 g, 36.8 mmol) was added to THF (40 mL) at 0° C. Separately, 5-nitroindazole (5.0 g, 30.6 mmol) was dissolved in THF (30 mL), and the mixed solution was slowly added to the prepared solution. Iodomethane (2.1 mL, 33.7 mmol) was added to the reaction solution at the same temperature, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and added with water and ethyl acetate. The reaction mixture was added with distilled water for quenching, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated compound (1-methyl added (Rf=0.3), 2-methyl added (Rf=0.1)) was purified using silica gel chromatography (ethyl acetate:hexane=1:1 (v/v)) to obtain the title compound (Rf=0.3, 2.29 g, 42%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:29][CH2:30][CH3:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:29][CH2:30][CH3:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:21]=2)=[O:19])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCCBr
Reactant: CCCC(CCCCCCC(=O)c1c[nH]c2ccccc12)c1ccc(CC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1

Procedure:
A mixture of 3-[8-(4-isobutylphenyl)undecanoyl]indole obtained in Pre. Ex. 8 (62 mg), ethyl 4-bromobutyrate (58 mg) and potassium carbonate (62 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 16 hours. After filtration, the solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on a silica gel column (hexane-ethyl acetate, 4: 1) to give ethyl 4-[3-[8-(4-isobutylphenyl)-undecanoyl]-1-indolyl]butyrate as an oil. (48 mg)
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]([NH2:18])=O)=[CH:12][N:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O>>[C:16]([C:13]1[CH:12]=[N:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[N:15][CH:14]=1)#[N:18]
Reactant: CCCc1ccc(-c2ncc(C(N)=O)cn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
8.3 G. of 2-(p-n-propylphenyl)-5-pyrimidinecarboxamide are boiled under reflux with 100 ml. of phosphorus oxychloride with the exclusion of moisture for 2 hours. Then, the excess phosphorus oxychloride is removed in vacuo and the mixture evaporated twice with toluene in vacuo. The residue is taken up in methylene chloride and chromatographed on 100 g. of silica gel in methylene chloride. Elution with methylene chloride and methylene chloride/2% acetone yields the 5-cyano-2-(4-n-propylphenyl)-pyrimidine, which is recrystallized from acetone/hexane up to a constant melting point and is sublimed at 120° C. in a high vacuum for purification. The pure, colorless 5-cyano-2-(4-n-propylphenyl)-pyrimidine has a melting point of 125.9-126.0° C. and on cooling is liquid crystalline (monotropic) at 106.4° C. The substance is identical with the compound obtained according to Example 6.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8](=[NH:10])[NH2:9].[CH:11]([NH2:14])([CH3:13])[CH3:12]>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:11]([NH:14][C:8]([NH2:10])=[NH:9])([CH3:13])[CH3:12]
Reactant: CC(C)N
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)NC(=N)N
Yield: 32.4 %

Procedure:
The solution of S-methylisothiourea sulfate (65.9 g, 250 mmol) in water (100 ml) was cooled with an ice/salt bath. To the solution was added isopropylamine (42.5 ml, 500 mmol) dropwise with stirring. The reaction mixture was allowed to stir at room temperature for 16 hours after the addition of amine was completed and was then refluxed for about 4 to about 5 hours. The solution was evaporated to dryness under the reduced pressure and the residue was crystallized from 95% EtOH, to give isopropylguanidine sulfate as colorless needles (16.12 g, 81.01 mmol, 32%). 1H NMR (300 MHz, D2O): δ 3.72 (m, 1H), 1.27 (d, J=6.4 Hz, 6H); 13C NMR: δ 158.45, 46.50, 24.11; IR: 1675, 1623, 1071 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].[C:29]([N:32]1[C@@H:36]([C:37](O)=[O:38])[CH2:35][S:34][CH2:33]1)(=[O:31])[CH3:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][C:37]([C@H:36]1[CH2:35][S:34][CH2:33][N:32]1[C:29](=[O:31])[CH3:30])=[O:38])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Reactant: CC(=O)N1CSC[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)[C@H]1CSCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of 331 mg (0.85 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 8.5 ml of dichloromethane, 149 mg (0.85 mmol) of (S)-3-acetylthiazolidin-4-carboxylic acid, 376 mg (0.85 mmol) of BOP reagent and 0.16 ml (0.95 mmol) of N,N-diisopropylethylamine were added, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, 10 ml of semi-saturated saline was added, and the resulting mixture was extracted with ethyl acetate. Organic phases were combined, washed with 0.5M hydrochloric acid, with saturated aqueous sodium hydrogen carbonate solution and with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to obtain 305 mg of 2-(((S)-3-acetylthiazolidin-4-carbonyl)amino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:12]1[C:24]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][C:13]=1[C:25](O)=[O:26]>>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:25]([C:13]3[CH:14]=[CH:15][C:16]4[C:17]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH2:23][C:24]=4[CH:12]=3)=[O:26])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Product: O=C(Nc1ccc2cccnc2c1)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (50 mg, 0.35 mmol) and 9H -fluorene-2-carboxylic acid (D71) (83 mg, 0.38 mmol) as an off-white solid. MS(ES): MH+ 337, M-H+ 335.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][C:14](OCC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[CH2:13][CH2:14][OH:15]
Reactant: CCOC(=O)CC1CCCc2c(OC)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2c1CCCC2CCO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 100.3 %

Procedure:
A suspension of ethyl (5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)acetate (1.02 g) and lithium aluminum hydride (0.20 g) in tetrahydrofuran (15 ml was stirred at 0° C. for 2.5 hours. The solution was poured into cold 1N-hydrochlorlc acid, then the resulting mixture was filtered through the celite, and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford 2-(5-methoxy-1,2,3,4-tetrahydro-1-naphthyl)ethanol as a colorless oil (0.85 g).