Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10](C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a solution of 3-(4-methanesulfonylbenzyl)-bicyclo[3.2.1]-1α,3,8-triaza-spiro[4.5]dodecan-2,4-dione hydrochloride (40 mg, 0.1 mmol) in 1.7 mL of anhydrous DCE were added successively 28 mg (0.1 mmol) of (3R,4S)-3-formyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 17 μL (0.12 mmol) of triethylamine. The reaction mixture was agitated at room temperature for 10 minutes before adding 26 mg (0.125 mmol) of sodium triacetoxyborohydride. After an overnight agitation, 2 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by bond elute (ethyl acetate to 5% methanol/DCM) to yield (3S,4S)-3-[3-(4-methanesulfonylbenzyl)-bicyclo[3.2.1]-2,4-dioxo-1α,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (20 mg, 32.1%).
Reaction SMILES: [C:1]1([C:7]2([C:13](O)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.C(OCC)(=O)C>[C:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-phenylcyclohexanecarboxylic acid (1.32 g) in tetrahydrofuran (30 mL) at 0° C. was slowly added 2 M LiAlH4 in tetrahydrofuran (6.46 mL). The resulting mixture was stirred at room temperature overnight and cooled to 0° C. Ice water was added to quench the reaction. The resulting mixture was diluted with ethyl acetate and washed with 1 N aqueous NaOH and water. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1.Cl.[CH2:12](O)[CH3:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH2:12][CH3:13])=[O:9])[N:3]=1
Reactant: CCO
Reactant: O=C(O)c1cccc(Cl)n1
Agent: Cl
Product: CCOC(=O)c1cccc(Cl)n1

Procedure:
14.1 g (0.0895 mole) of 2-chloro-6-hydroxycarbonylpyridine in 133 ml of a solution of HCl in ethanol is heated for 8 hours under reflux. The solvent is evaporated off, ethyl acetate added and the mixture washed with a solution of bicarbonate. The solvent is further evaporated and the reaction product purified by flash chromatography (cyclohexane/ethyl acetate=7/3). The required product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: C[Si](C)(C)C#Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was maintained with an inert atmosphere of nitrogen, was placed a solution of 1-bromo-4-iodobenzene (1.00 g, 3.53 mmol) in tetrahydrofuran/TEA (9:1) (30 mL). PdCl2(PPh3)2 (50 mg, 0.07 mmol), CuI (13.4 mg, 0.07 mmol), and ethynyltrimethylsilane (748 μL, 5.29 mmol) were added and the mixture was stirred for 18 h at room temperature, then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as the eluent to yield the title compound as a light yellow solid (0.83 g, 93%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1)[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:28]=2)[CH:29]=[CH:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(Cc2ccc(Cl)c(Cl)c2)c(Cl)c1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Cc2ccc(Cl)c(Cl)c2)c(Cl)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.00 g), 3-chloro-4-(3,4-dichlorobenzyl)benzonitrile (0.93 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (300 ml), washed with dilute hydrochrolic acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.64 g of desired compound (melting point: 179.0°-185.0° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])=[C:4]([O:34][CH3:35])[CH:3]=1.[O:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:41][C:38]4[CH:39]=[CH:40][O:36][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: Nc1ccon1
Reactant: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.070 g, 1.857 mmol), isoxazol-3-amine (0.158 ml, 2.135 mmol) and THF (12.38 ml) to give a clear solution. The flask was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (3.90 ml, 3.90 mmol) was added dropwise. After 10 min, the mixture was diluted with EtOAc and washed with 1N aq. HCl. The aq. layer was washed with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered; and concentrated. The residue was purified by chromatography (50-g SNAP Ultra column, 25-g silica gel loading column, 0-5% MeOH/DCM) to give 1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.867 g) as a tan foam that was ca. 90% pure. m/z (ESI) 476.1 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[Br-:11].[Br-].O1CCOCC1>CCOCC>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: [Br-]
Reactant: CC(C)c1ccccc1O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 2-isopropylphenol (12) (2.0 g, 14.6 mmol) in 15 ml of Et2O at 0° C. was added dioxane dibromide (3.62 g, 14.6 mmol, 1 eqv). The solution was allowed to stir for 30 min at rt. The reaction mixture was washed with sat. NaCl and 10% NaHCO3. The Et2O phase was concentrated in vacuo and then vacuum distilled (142-145° C., 20 mm Hg) to yield 2.07 g of a clear oil (66%) which solidified upon standing: 1H NMR (500 MHz, CDCl3) δ 1.23 (d, J=3.7 Hz, 6H), 3.16 (m, 1H), 4.84 (s, 1H), 6.61 (d, J=8.6 Hz, 1H), 7.15 (d, J=11.0 Hz, 1H), 7.28 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 22.33, 27.17, 113.24, 116.99, 129.34, 129.50, 136.91, 151.81; LRMS (EI) (M+, 214/216).
Reaction SMILES: CO.[C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)#[N:4].[BH4-].[Na+]>O1CCCC1>[C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)#[N:4]
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(c2ccccc2)CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
to an ice and methanol cooled solution of 4 g. (0.0205 M) of 4-cyano-4-phenylcyclohexanone (a) (prepared as in J. Chem. Soc. 1959, 1446) in 150 ml. of tetrahydrofuran, a suspension of 1 g. of sodium borohydride in 50 ml. of tetrahydrofuran is added in 5 ml. portions in in the course of about 10 minutes. The mixture is stirred for about 30 minutes and allowed to stand in the cold for about 18 hours. The bulk of the solvent is removed under vacuum and the residue treated with water. The precipitate is extracted with ether and the organic fraction washed successively with 2.5 N hydrochloric acid solution, saturated aqueous sodium bicarbonate, water and brine and then evaporated to dryness. The residue is recrystallized with benzene to give 1.81 g. (43.8% yield) of 4-cyano-4-phenylcyclohexanol (b) melting at 103° to 111° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.Cl>CC(O)(C)C.C1C=CC=CC=1>[CH2:15]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][C:7]2=[O:13])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: BrCCCCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: O=C1CCCCC12CCCC2
Temperature: 120 °C

Procedure:
In a flask containing potassium tert-butoxide (45.7 g, 407.6 mmol) in t-BuOH (200 mL) and Benzene (150 mL) was added cyclohexanone (20.0 g, 203.8 mmol) and 1,4-dibromobutane (44.0 g, 203.8 mmol). The solution was heated at 120° C. for 6 hrs. The mixture was cooled to room temperature and neutralized with HCl (1N). The solution was extracted with ether, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (1% EtOAc/hexanes) to afford the title compound: GCMS ES+=153.1.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][Cl:42]>C(#N)C>[Cl:42][CH2:41][CH2:40][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:32])[CH:14]=3)[C:19]2=[O:23])=[CH:30][CH:29]=1
Reactant: ClCCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(O)cc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCl)cc3)ccc2c1

Procedure:
A mixture of the product of step i) (0.33 g), potassium carbonate (1.07 g) and 1-bromo-2-chloroethane (1.12 g) in acetonitrile (10 mL) was heated at reflux for 38 hours. The reaction mixture was concentrated to dryness and the residue partitioned between dichloromethane and water. The organics were collected and purified (SiO2, 9:1 dichloromethane:methanol) to give the sub-title compound (0.31 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].[C:20](Cl)(=[O:22])[CH3:21]>ClCCl.O>[C:20]([C:10]1[CH:11]=[C:2]([Br:1])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14])(=[O:22])[CH3:21]
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
A stirred, cooled (−78° C.) solution of 6-bromo-2,2,4,4-tetramethyl chroman (1 g, 3.72 mmol) in anhydrous dichloromethane (10 mL) was treated with aluminum chloride (0.8 g, 6.8 mmol) followed by acetyl chloride (0.4 mL, 6.08 mmol). After 10 minutes, the reaction mixture was diluted with water and extracted with diethyl ether. The organic phase was washed with water, and dried over anhydrous sodium sulfate, filtered and evaporated to a residue that was subjected to flash column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as a solid (0.78 g, 67%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C@@:15]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[CH3:30][C:27]([CH3:28])([CH3:29])[CH2:26][CH2:25][C@:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 49G (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: CO.O=[C:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1.Cl.CN.[C:21]([BH3-])#[N:22].[Na+]>Cl.C(N(CC)CC)C>[CH3:21][NH:22][CH:4]([CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1
Reactant: COC(=O)Cc1ccc(CC(C)=O)cc1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(C)Cc1ccc(CC(=O)OC)cc1
Reaction time: 3 h

Procedure:
To 25 mL of methanol 0.59 g of methyl 4-(2-oxopropyl)phenylacetate, prepared above, was added and dissolved. Then with stirring the following were added: 2.0 g methylamine hydrochloride, 0.3 g sodium cyanoborohydride, and 0.3 mL of triethylamine. After approximately 12 hours an additional 0.1 g of sodium cyanoborohydride was added to the mixture. After 3 hours more, the reaction was diluted with 100 mL of 0.1M hydrochloric acid, washed with diethylether, and the resulting aqueous phase was basified to a pH of 12 by addition of 5 mL portions of 1N sodiumhydroxide solution. This was extracted three times with 100 mL portions of diethylether, combined extracts washed with brine and dried. The solvents were removed in vacuo to yield 0.44 g of a light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].N1C=CN=C1.[C:11]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[Si:15]([O:5][CH2:4][CH2:3][CH2:2][NH2:1])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCN
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-aminopropan-1-ol (2 g, 20 mmol) in DCM (10 mL), imidazole (79 mmol, 3 equiv.) was added and stirred at room temperature for 10 min. Reaction mixture was cooled to 0° C., t-butyl dimethyl silyl chloride (30 mmol, 1.2 equiv.) was added in portions and stirred the reaction mixture overnight at room temperature. Diluted the reaction mixture using DCM, the DCM layer was washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. ELSD method LC/MS: Retention time: 1.5 min; (ES-API), m/z 189.7 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([Cl:12])[CH:3]=1.[C:13](OCC)(=[O:15])C>>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]2[O:8][C:13](=[O:15])[NH:1][C:2]=2[CH:3]=1
Reactant: Nc1cc(Cl)cc([N+](=O)[O-])c1O
Reactant: CCOC(C)=O
Product: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
188.6 g (1 mole) of 6-amino-4-chloro-2-nitrophenol prepared according to Example 1c was suspended in 1000 ml of ethyl acetate under mild nitrogen purge and the optional present water was removed by azeotropic distillation of 250 ml of the solvent. The mixture was cooled to 20-25° C. and 224 g of carbonyldiimidazole was added as a slurry in 650 ml of ethyl acetate. An additional 100 ml of ethyl acetate was added and the mixture was vigorously stirred during two hours, without the application of cooling. 1000 ml of water was added and the mixture was stirred for 15 minutes. 1450-1500 ml of ethyl acetate was distilled off at about 200 mBar and about 50° C. The mixture was cooled to 0-5° C., 225 ml of 36% HCl was added and the mixture ws cooled again to 0-5° C. and stirred at this temperature for 15 minutes. The solid was filtered off, washed with 400 ml of 1N HCl, washed twice with 500 ml of cold water and once with 500 ml of cold water/ethanol (4/1), and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 99%.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N([O-])=O.[Na+]>>[C:5]1([S:8]([OH:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [Na+]
Product: O=S(=O)(O)c1ccccc1
Temperature: 70 °C

Procedure:
50 mg of graphene oxide was added into 0.06 M p-aminobenzene sulfonic acid solution, and the resulted solution was heated to 70° C. Then, 2 ml of 6×10−3 M NaNO2 solution was dropped slowly into the resulted solution while stirring, and the resulted solution was allowed to react at 70° C. for 12 hours. After the reaction was completed, the resulted solution was cooled, filtrated and washed with pure water until the powder was neutral, and thus graphite sulfonate (GO-Ph-SO3H) dispersion solution was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH3:12]>CO>[NH2:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N
Solvent: CO
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]

Procedure:
2,6-Dichloro-3-nitropyridine was suspended in MeOH, and the mixture was treated with ammonia at room temperature for 12 hours to yield 2-amino-3-nitro-6-chloropyridine. This was then treated with an ethanolic:aqueous solution of sodium hydroxide (10 M) at reflux to give 2-amino-3-nitro-6-(1H)-pyridinone. This was then treated with N-iodosuccinimide (1.05 equivalents) in dimethylformamide at room temperature to yield 2-amino-3-nitro-5-iodo-6-(1H)-pyridinone.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[NH:32][C:33]([C@@H:36]5[CH2:40][CH2:39][CH2:38][N:37]5[C:41](=[O:54])[C@H:42]([NH:49][C:50]([O:52][CH3:53])=[O:51])[C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[N:34][CH:35]=4)=[CH:27][CH:26]=3)=[N:23][CH:24]=2)=[CH:17][N:18]=1)=O)(C)(C)C.CO>CCOCC>[CH3:53][O:52][C:50](=[O:51])[NH:49][C@H:42]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:41](=[O:54])[N:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[C:33]1[NH:32][C:31]([C:28]2[CH:29]=[CH:30][C:25]([C:22]3[N:23]=[CH:24][C:19]([C:16]4[NH:15][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][NH:9]5)=[N:18][CH:17]=4)=[CH:20][N:21]=3)=[CH:26][CH:27]=2)=[CH:35][N:34]=1
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cn3)cc2)[nH]1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5)[nH]4)cn3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Cold (0° C.) 4 N HCl in dioxanes (4 mL) was added via syringe to (S)-2-{5-[2-(4-{2-[(S)-1-((R)-2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-pyrimidin-5-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (104.6 mg, 0.146 mmol) in a 100 mL pear-shaped flask followed by MeOH (0.5 mL). The homogeneous mixture was stirred at room temperature for 15 min before a precipitate was observed. After stirring further for 1.75 h, the suspension was diluted with ether and hexanes. Suction-filtration of a small portion of the suspension yielded the title compound as a yellow solid which was used for characterization purposes. The balance of the suspension was concentrated down to dryness and placed under high vacuum for 16 h. There was isolated the rest of the title compound also as a yellow solid (137.7 mg, 123%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][CH:7]=1.[C:29]([CH2:33][C:34](OC)=[O:35])(=O)[CH2:30][CH3:31].O>C1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Si:12]([O:11][CH2:10][CH2:9][O:8][C:5]1[N:6]=[C:7]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:29]([CH2:30][CH3:31])=[CH:33][C:34]2=[O:35])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](OCCOc1ccc(N)cn1)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CCc1cc(=O)c2nc(OCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2[nH]1
Temperature: 260 °C
Yield: 51.4 %

Procedure:
A solution of compound C (89.5 g), methyl propionylacetate (32.8 g) and p-toluenesulphonic acid (1.0 g) in cyclohexane (900 ml) was heated under reflux with azeotropic removal of water for 20 hours. Volatile material was then removed from the reaction mixture by evaporation and the residue was dissolved in ethyl acetate (1 l). The solution was washed with saturated sodium hydrogen carbonate solution (500 ml), water (500 ml), saturated sodium chloride solution (500 ml), and then dried (MgSO4). The solvent was removed by evaporation and the residue dissolved in a eutectic mixture of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (750 ml). The solution was heated to 260° C. and the temperature maintained for 30 minutes. The solution was cooled and diluted with hexane (1 l) to give 6-[2-(t-butyldiphenylsilyl)oxyethoxy]-2-ethyl-1,5-naphthyridin-4(1H)-one (D) (55.4 g), as a white solid, m.p. 209°-210° C.; NMR (d6 -DMSO): 1.1(s,9H), 1.35(t,3H), 2.8(q,2H), 4.15(t,2H), 4.65(t,2H), 6.3(br s,1H), 7.25(d,1H), 7.5-7.6(m,7H), 7.65-7.8(m,4H), 8.1(d,1H).