Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:21][C@H:19]1[NH:20][C:31](=[O:33])[N:17]([C:14]2[CH:15]=[N:16][C:11]([O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=3)=[CH:12][CH:13]=2)[C:18]1=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-D-alaninamide (Intermediate 26, 35 mg) was dissolved in dry dichloromethane (3 mL). The reaction mixture was cooled down in an ice bath. Triethylamine (98 μl, 0.701 mmol) was added. Then a solution of triphosgene in dry dichloromethane (13.88 mg, 0.047 mmol dissolved in 1 mL of dichloromethane) was added dropwise. The reaction mixture was stirred at 0° C., under argon, during 10 min. A saturated aqueous solution of NaHCO3 was added (4 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×5 mL). After drying over sodium sulphate, the solvents were removed under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, 2×4 g silica cartridges) with a gradient cyclohexane/ethylacetate from 100/0 to 50/50 during 10 min and 50/50 during 20 min. This afforded the title compound as a film (27 mg).
Reaction SMILES: IC.[CH2:3]([O:7][C:8]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][C:9]=1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=1)=[O:11])[CH:4]([CH3:6])[CH3:5].[C:37](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][C:9]=1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:16]([CH2:18][CH2:19][C:20]([O:22][CH3:37])=[O:21])[CH:17]=1)=[O:11])[CH:4]([CH3:6])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
At ambient temperature, 9.9 ml of iodomethane is dropwise added to a suspension of 50.0 g of 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]propanoic acid and 22.0 g of potassium carbonate in 150 ml of N,N-dimethylformamide. The mixture thus obtained is stirred at the same temperature as above for 30 minutes. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 51.0 g of methyl 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]propanoate as a light brown-colored solid product.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([CH:16]=[CH2:17])[CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H][H]>CO.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[CH2:16]([C:4]1[CH:3]=[CH:2][CH:15]=[CH:14][C:5]=1[O:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[CH3:17]
Reactant: [H][H]
Reactant: C=Cc1cc(Br)ccc1OCCN1CCCC1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: C1=CCCC=CCC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1ccccc1OCCN1CCCC1

Procedure:
A solution of 0.41 g (1.38 mmol) of 1-[2-(4-bromo-2-vinylphenoxy)ethyl]pyrrolidine and 0.41 mL (2.94 mmol) of triethylamine in 25 mL of MeOH was degassed with argon and then combined with 35.5 mg (0.072 mmol) of bis(1,5-cyclooctadiene)dirhodium (I) dichloride and 57.1 mg (0.138 mmol) of 1,3-bis(diphenylphosphino)propane. The mixture was hydrogenated at RT and 3 bar hydrogen pressure. The reaction mixture was evaporated down in vacuo, and the residue was stirred with EtOAc, filtered, and the filtrate was evaporated down in vacuo. Yield: 0.26 g (87% of theoretical); C14H21NO (M=219.330); calc.: molpeak (M+H)+: 220; found: molpeak (M+H)+: 220.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:16](=[O:17])[O:15][C:13](=O)[C:12]3=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]3[C:16](=[O:17])[N:20]([CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])[C:13](=[O:15])[C:12]3=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)c2cc(C#Cc3ccccc3)ccc21
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: C1CCOC1
Product: CCO[Si](CCCN1C(=O)c2ccc(C#Cc3ccccc3)cc2C1=O)(OCC)OCC
Reaction time: 0.08 h

Procedure:
4-phenylethynyl-N [3-triethoxysilylpropyl] phthalimide was synthesized as follows. 4-phenylethynyl phthalic anhydride (PEPA) was added to a round bottom flask containing sufficient tetrahydrafuran (THF) to dissolve the PEPA. An equimolar amount of 3-aminopropytriethoxy silane (3-APS) was added to the mixture at room temperature. The mixture was then heated over a steam bath until the THF mixture began to boil (T=65° C.). The heating continued for approximately 5 minutes. The solution was then removed from the steam bath and allowed to cool. The solvent was removed using a rotovaporator at 40° C. The resulting product is a thick, viscous, yellow (amber) liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][C:8]([O:15][CH3:16])=[C:7]([O:17][CH2:18][O:19][CH3:20])[C:4]=1[CH:5]=O.[CH3:21][C:22]1([CH3:30])[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])[O:23]1.C(N(CC)CC)C.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:21][C:22]1([CH3:30])[O:29][C:27](=[O:28])[C:26](=[CH:5][C:4]2[C:7]([O:17][CH2:18][O:19][CH3:20])=[C:8]([O:15][CH3:16])[CH:9]=[C:10]([O:11][CH2:12][O:13][CH3:14])[C:3]=2[O:2][CH3:1])[C:24](=[O:25])[O:23]1
Reactant: COCOc1cc(OC)c(OCOC)c(C=O)c1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCOc1cc(OC)c(OCOC)c(C=C2C(=O)OC(C)(C)OC2=O)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3 Grams (10.48 mM) of 2,5-dimethoxy-3,6-bis(methoxymethoxy)benzaldehyde was dissolved in 100 ml of benzene, next 1.82 g (1.2 times the equivalent) of Meldrum's acid and 3 ml of triethylamine were added thereto, and the reaction mixture was stirred at room temperature for 5 hours. 200 milliliters of ethyl acetate was added to the reaction mixture, and the organic layer was washed twice with 50 ml of water, then washed three times with a saturated sodium chloride aqueous solution. The organic layer was then dehydrated on anhydrous sodium sulfate and concentrated to yield 4.39 g of 1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]methane. Yellow powdery substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)(C)(C)C.[Br:29]Br.S([O-])([O-])=O.[Na+].[Na+]>CCOCC.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:13][C:14]=1[Br:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCCCCCC(C)(C)c1cccc(OCc2ccccc2)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)(C)N
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a -78° C. solution of 42.6 g. (0.134 mole) of 1-benzyloxy-3-(1,1-dimethylheptyl)benzene and 12.2 g. (0.200 mole) to t-butylamine in 300 ml. of dichloromethane is added a solution of 27.2 g. (0.151 mole), bromine in 100 ml. of dichloromethane. The reaction mixture is then allowed to warm to 25° C. and added to 500 ml. saturated sodium sulfite and 500 ml. ether. The organic extract is washed with two 500 ml. portions of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to an oil. The crude product is purified via column chromatography on 500 g. of silica gel eluted with 10% ether-hexane to give 41.9 g. (80%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2([CH2:23][CH2:22][C:21](=[CH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:20][CH2:19]2)[S:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([O:18][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:17])[C:10]2([CH2:19][CH2:20][C:21](=[CH:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:23]2)[S:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)(C)C)C(=O)N2CCC(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)(C)C)C(=O)N2CCC(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 25.1 %

Procedure:
In 10 ml of methylene chloride was dissolved 0.56 g of 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. At ambient temperature, 0.21 g of benzyl alcohol, 0.23 g of 1-hydroxybenzotriazole monohydrate and 0.31 g of dicyclohexyl carbodiimide were successively added. After stirring the resulting mixture for 24 hours at the same temperature as above, the insoluble matter was filtered off. The filtrate was washed successively with 2 mol/L hydrochloric acid, water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=6:1] gave 0.17 g of benzyl 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate as a light yellow oily product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][N:32]([S:38]([NH:41][C:42]1[S:43][C:44]([F:47])=[CH:45][N:46]=1)(=[O:40])=[O:39])[CH2:33]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[F:47][C:44]1[S:43][C:42]([NH:41][S:38]([N:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][CH:36]=[CH:37][C:28]=3[C:19]3[CH:20]=[C:21]([C:24]([F:26])([F:25])[F:27])[CH:22]=[CH:23][C:18]=3[C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)[CH2:33]2)(=[O:39])=[O:40])=[N:46][CH:45]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2cc(C(F)(F)F)ccc2Br)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN1CC=C(c2ccc(C(F)(F)F)cc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncc(F)s2)C3)CC1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.014 g, 0.019 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.054 g, 0.242 mmol), 5-(2-bromo-5-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.104 g, 0.194 mmol), and potassium phosphate (0.165 g, 0.776 mmol) in 2 mL dioxane and 1 mL water, was heated to 110° C. 2 hours. The reaction mixture was allowed to cool to room temperature, was diluted with EtOAc and washed with 1N citric acid. The organic layer was then concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 50 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave N-(5-fluorothiazol-2-yl)-5-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.011 g, 0.020 mmol). [M+H]+=553.0 1H NMR (400 mHz, Acetone-d6) δ ppm: 7.70-7.77 (m, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.05-7.14 (m, 2H), 6.93 (d, J=6.7 Hz, 1H), 6.62 (d, J=0.9 Hz, 1H), 5.87-5.93 (m, 1H), 4.48-4.56 (d, J=17.4 Hz, 1H), 4.19 (d, J=17.4 Hz, 1H), 3.70-3.84 (m, 2H), 3.32-3.43 (m, 1H), 3.12-3.32 (m, 3H), 2.87-2.98 (m, 1H), 2.76-2.82 (m, 1H), 2.57 (s, 3H), 1.98-2.04 (m, 2H)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: BrCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCCBr)cccc21

Procedure:
Potassium phthalimide (5.4 mmoles) was added to a solution of 1,6-dibromohexane (3.95 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. Reaction times and process as per Example 4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.Br[CH2:14][C@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOCC>[Si:18]([O:17][CH2:16][C@@H:15]([CH3:25])[CH2:14][N:7]1[C:6]2[CH:12]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: Cc1ccc2c(c1)NC(=O)CO2
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc2c(c1)N(C[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)CO2
Temperature: 50 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
A dry 50 mL r-flask was charged with 6-Methyl-4H-benzo[1,4]oxazin-3-one (0.59 g, 3.6 mmol), (R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (1.0 g, 3.6 mmol), Cs2CO3 (2.9 g, 8.9 mmol) and 10 mL of dry DMF. The mixture was stirred at 50° C. overnight (15 h) and dissolved in ether (50 mL) washed with water (20 mL) and the water phase was extracted with ether (20 mL). The combined organic phases were then washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and the resulting oil was purified by flash chromatography (SiO2; Heptane/EtOAc 85:15) to yield the title compound as an oil (1.1 g, 88%). 1H NMR (CDCl3) δ 6.87 (d, J=1.6 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.72 (dm, J=8.0 Hz, 1H), 4.5 (bars, 2H), 3.93 (dd, J=8.8, 14.0 Hz, 1H), 3.81 (dd, J=5.6, 14.0 Hz, 1H), 3.53 (dd, J=4.8, 10.2 Hz, 1H), 3.41 (dd J=7.2, 10.2 Hz, 1H), 2.25 (s, 3H), 2.18 (m, 1H), 0.87 (s, 9H), 0.83 (d, J=6.8 Hz, 3H), 0.01 (s, 6H); 13C NMR (CDCl3) δ 170.5, 148.9, 137.8, 129.6, 122.2, 121.6, 73.3, 71.6, 49.0, 39.7, 31.5, 26.6, 23.8, 20.1, 0.0.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]([OH:27])[CH2:14][CH2:15][CH2:16]C2C=CC(OC)=C(OC)C=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].CI.[CH2:30]1COCC1>O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]([O:27][CH3:30])[CH2:14][CH2:15][CH3:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(CCCC(O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCCC(OC)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 60% dispersion of NaH in mineral oil (32.7 g, 1.3625 mole) was added portionwise over 40 minutes to a mechanically stirred solution of 1,4-bis (3,4-dimethoxyphenyl)butane-1-ol (292 g, 0.843 mole), MeI (125.4 g, 0.883 mole, 55 cc), and dry THF (1.5 1) at 22°-33° C. maintained by intermittent cooling. Additional MeI (22.8 g, 0.16 mole, 10 cc) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with H2O (15 cc), stirred for 1 hour, and filtered. The filtrate was evaporated in vacuo to a syrup; the syrup was treated with CH2Cl2 (1 1) and H2O (500 cc) and the phases were separated. The aqueous phase was extracted with CH2Cl2 (1×500 cc). The combined organic phase was washed with H2O (3×400 cc), dried (Na ) and evaporated in vacuo to a yellow syrup; yield: 293 g (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.[N+:13]([C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:17]=1[CH:18]=O)([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:17]=1[CH:18]=[C:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:12])([O-:15])=[O:14]
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Product: COc1cc(C=C2C(=O)CCc3cc(Cl)ccc32)c([N+](=O)[O-])cc1OC

Procedure:
Prepared from 6-chloro-2-tetralone and 2-nitro-4,5-dimethoxybenzaldehyde; mp 56-58° C.; IR (Nujol): 2922, 1730, 1100; 1H NMR: δ2.68 (2H, t), 3.05 (2H t), 3.62 (3H, s), 3.98 (3H, s), 6.48 (1H, s), 6.82 (1H, d, J=8.4), 6.90-6.96 (1H, dd, J=8.4, 2.1), 7.26 (1H, d, J=2.1), 7.74 (1H, s), 8.01 (1H, s); 13C NMR: δ28.2, 37.4, 56.8, 56.9, 108.3, 112.2, 127.0, 127.2, 128.6, 130.9, 131.1, 133.3, 134.2, 134.5, 140.5, 141.5, 149.6, 153.7.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.C(N1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])(OCC)=O.C([O-])([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[OH:9][CH:6]1[CH2:7][CH2:8][CH:3]([N:2]2[C:19](=[O:20])[C:18]3[C:17](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]2=[O:25])[CH2:4][CH2:5]1
Reactant: NC1CCC(O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 15.6 h
Yield: 76.1 %

Procedure:
A solution of 4-aminocyclohexanol hydrochloride (2.52 g, 16.6 mmol) in water (20.0 mL) was treated with N-carbethoxyphthalimide (3.82 g, 17.4 mmol) and Na2CO3 (3.77 g, 35.6 mmol). The reaction was stirred at room temperature for 15.6 hours. The reaction was cooled to 0° C. and quenched with 10% HCl, filtered, and washed with water to give a white solid. The solid was dissolved in ethyl acetate washed with water, brine, dried over MgSO4 and concentrated in vacuo to give 3.10 g (76%) of 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione as a colorless solid: mp 176.9-177.0° C.; 1H NMR (400 MHz, Acetone-d6) δ 7.82 4.09, 3.74, 3.62, 2.28, 2.04, 1.76, 1.39; 13C NMR (100 MHz, acetone-d6) δ 168.7, 135.1, 133.0, 123.6, 69.5, 50.8, 35.7, 28.3; IR (mull) 3389, 3318, 2953, 2930, 2876, 2861, 1767, 1703, 1463, 1393, 1377, 1088, 1075, 1061, 720 cm−1; HRMS (FAB) calcd for C14H16NO3: 246.1130, found 246.1128; Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.39; H, 6.21; N, 5.70.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-])=O.Cl.O.O.[Sn](Cl)Cl.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[NH2:9]
Reactant: Cc1nccc(Br)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1nccc(Br)c1N
Temperature: 40 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
4-Bromo-2-methyl-3-nitropyridine (1.2 g, 5.53 mmol) was dissolved in HCl (2.189 ml, 26.3 mmol), tin(II)chloride dihydrate (4.99 g, 22.12 mmol) was added and stirred at 40° C. for 1 hour. The reaction mixture was made basic with 30% NaOH (18 mL), extracted with EtOAc, dried over sodium sulfate and concentrated under vacuum to give a yellow oil. The oil was further dried under high vacuum for 4 hours to give 4-bromo-2-methylpyridin-3-amine (1 g, 5.35 mmol, 97% yield) which was stored at −17° C. until use and was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26-2.42 (3H, m) 5.05-5.34 (2H, m) 7.17-7.32 (1H, m) 7.46-7.64 (1H, m). MS [M+H] found 187.0.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[NH:23]=[C:22]1[N:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]2=[N:1][CH:15]=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1nccc2ccccc12
Solvent: CCO
Product: CCOC(=O)c1cnc2c3ccccc3ccn2c1=N
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
A mixture of 1-aminoisoquinoline (14.4 g., 0.10 mole) and ethyl ethoxymethylenecyanoacetate (16.9 g., 0.10 mole) was plunged into an oil bath at 105°-110° and kept there for 10 minutes under a nitrogen atmosphere. During this time the mixture melted, evolved ethanol and set solid. The solid was crystallized from toluene to give bright yellow crystals (18 g., 67% yield) of ethyl 4-imino-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate, m.p. 197°-199°. Another recrystallization from toluene provided an analytical sample, m.p. 199°-201°.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:50])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][C:14]=2[NH:25][C:26]([C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[O:27])=[C:9]2[CH:51](CC)[N:52]([S:56]([C:59]3[CH:64]=[C:63]([F:65])[CH:62]=[C:61]([F:66])[CH:60]=3)(=[O:58])=[O:57])[C:53]([CH3:55])([CH3:54])[C:8]2=[N:7]1)=O)C>CO.ClCCl.N1CCCCC1>[F:66][C:61]1[CH:60]=[C:59]([S:56]([N:52]2[CH2:51][C:9]3[C:10]([NH:11][C:12]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[CH:15][C:14]=4[NH:25][C:26]([C@@H:28]4[CH2:32][CH2:31][CH2:30][NH:29]4)=[O:27])=[O:50])=[N:6][NH:7][C:8]=3[C:53]2([CH3:55])[CH3:54])(=[O:58])=[O:57])[CH:64]=[C:63]([F:65])[CH:62]=1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCOCC3)cc1NC(=O)[C@@H]1CCCN1C(=O)OCC1c3ccccc3-c3ccccc31)C(CC)N(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Solvent: C1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)c2[nH]nc(NC(=O)c3ccc(N4CCOCC4)cc3NC(=O)[C@@H]3CCCN3)c2CN1S(=O)(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
To a solution of ethyl 5-(3,5-difluoro-benzenesulfonyl)-3-(2-{[(S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-pyrrolidine-2-carbonyl]-amino}-4-morpholin-4-yl-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (0.3 g, 0.32 mmol) in MeOH (10 mL) and dichloromethane (3 mL), piperidine (1 mL) was added and the reaction mixture stirred at room temperature for 12 hours. After evaporation to dryness, the residue was washed with petroleum ether and purified by flash chromatography on silica gel, using a mixture dichloromethane-MeOH 95:5 as the eluant, affording the title compound as pale yellow powder (0.15 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([N+:19]([O-])=O)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]>C(O)C.C(O)(=O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([NH2:19])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2cc(C)c([N+](=O)[O-])cn2)c1C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2cc(C)c(N)cn2)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.5 %

Procedure:
To a solution of 5-methyl-1-(4-methyl-5-nitropyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (22.3 g) in ethanol (600 ml) and acetic acid (50 ml) was added palladium carbon (1.0 g), and stirred at room temperature for 6 hours under hydrogen atmosphere (1 atm). After completion of the reaction, the mixture was filtered through Celite, then the filtrate was concentrated, and the obtained residue was dissolved in chloroform. The organic layer was washed with saturated sodium bicarbonate water and water sequentially, dried over anhydrous sodium sulfate, and then the solvent was evaporated. To the obtained residue was added a small amount of diethyl ether and n-hexane, the precipitated solid was collected by filtration, and heat-dried in vacuo at 60° C. to give 1-(5-amino-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (18.3 g) as a pale yellow solid.