Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:23][CH2:22][C@@:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH2:24][C:25]#[CH:26])[C:20]1=[O:35].N(CC)CC>C1COCC1.CCOC(C)=O.O.[Cu](I)I>[CH3:18][N:19]1[CH2:23][CH2:22][C@@:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])([CH2:24][C:25]#[C:26][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[C:20]1=[O:35]
Reactant: FC(F)(F)c1ccc(-c2ccnc(I)n2)cc1
Reactant: C#CC[C@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Agent: I[Cu]I
Solvent: CCNCC
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CC[C@](CC#Cc2nccc(-c3ccc(C(F)(F)F)cc3)n2)(NC(=O)OC(C)(C)C)C1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
Copper iodide (25.51 mg, 0.1300 mmol), followed by PdCl2(Ph3P)2 (47.01 mg, 0.0700 mmol) was added portionwise to a solution of 2-iodo-4-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 6) (703.46 mg, 2.01 mmol), tert-butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (which may be prepared as described in D4) (338 mg, 1.34 mmol) and Et2NH (0.69 mL, 6.7 mmol) in THF (10 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. The reaction was diluted with EtOAc and water was added. The phases were separated and the organic layer was dried (Na2SO4) and the solvent evaporated to afford a brown oil. This was purified by using a Biotage SP4, with a 25 g SNAP cartridge, eluting with 0 to 100% EtOAc in i-hexane to afford tert-butyl N-[(3S)-1-methyl-2-oxo-3-[3-[4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-3-yl]carbamate (D7) (555 mg, 1.17 mmol, 87.3% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.ClC1C=CC=C(C(OO)=[O:20])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-:20])[C:10]=2[CH:11]=1
Reactant: Brc1cnc2cccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.2 %

Procedure:
To 50 mL of chloroform, 5.00 g of 3-bromo-1,5-naphthyridin was dissolved, 6.40 g of m-chloroperbenzoic acid was added thereto, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, a 5% aqueous sodium thiosulfate solution and chloroform were added, and the organic layer was separated, washed sequentially with a 5% aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of ethyl acetate:hexane=1:1 to obtain 1.95 g of 3-bromo-1,5-naphthyridin-5-oxide as a light yellow solid.
Reaction SMILES: N[CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].N[C@H](CO)CC1N=CNC=1>O>[NH2:10][CH2:9][CH2:8][N:7]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: NCCNCCNCCN
Agent: N[C@H](CO)Cc1c[nH]cn1
Solvent: O
Product: NCCN1CCNCC1
Temperature: 150 °C

Procedure:
and 421 g triethylenetetraamine (equivalent weight 39.5; 10.7 equivalents) under a nitrogen atmosphere. The reactants were stirred by an agitator provided in the reactor and heated. As soon as water of condensation appeared in the reactor, the nitrogen gas supply was stopped and the temperature increased to bring the reaction mixture to reflux. The reaction was allowed to continue at a reflux temperature of between 190° C. and 250° C. at atmospheric pressure. The acid value of the reaction mixture was monitored and upon reaching an acid value of 2, the reactor was subjected to a mild vacuum. This was continued until the reaction pressure was reduced to 5 mm Hg. The reaction was continued at these thermodynamic conditions, 190° C. to 250° C. and 5 mm Hg, until the reaction mixture acid value dropped below 1.0.. At that time the reactor was cooled to 150° C., atmospheric pressure was reinstituted, by the addition of nitrogen gas, and Hisol (Ashland Oil Co., highly aromatic solvent) was added to acceptable handling viscosity. The addition of the Hisol permitted cooling of the reaction mixture to ambient temperature. The product of this reaction was a liquid weighing 9,520 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.C1C=CC(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([N:35]=[N+:36]=[N-:37])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cccc(/C=C/C(=O)N=[N+]=[N-])c1
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To a solution of (E)-3-(3-methoxyphenyl)acrylic acid (20 g, 112 mmol) in benzene (200 ml) was added triethylamine (22.72 g, 224 mmol) followed by DPPA (30.9 g, 112 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. Combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desire compound as white solid (18 g, 79%). 1H NMR (400 MHz, CDCl3): δ ppm 7.73-7.69 (d, J=16 Hz, 1H), 7.33-7.29 (t, J=8 Hz, 1H), 7.26 (s, 1H), 7.14-7.12 (d, J=8 Hz, 1H), 7.05 (s, 1H) 6.98-6.96 (d, J=4 Hz, 1H), 6.43-6.39 (d, J=16 Hz, 1H), 3.86 (s, 3H);
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([C:17](OCC)=[O:18])=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16]3)[NH:11][N:10]=2)[C:5]([CH2:17][OH:18])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 11.6 %

Procedure:
To a solution of ethyl 2-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-5-carboxylate (3.5 g, 11.4 mmol, 1.0 eq) in anhydrous THF (50 mL), LiAlH4 (1.3 g, 34.2 mmol, 3.0 eq) was added portionwise under 0° C. (ice bath). The mixture was stirred at 0° C. for 1 h and 20° C. for 16 h. Ice-water (50 mL) was added and the resulting mixture was extracted by EtOAc (4×50 mL). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (CH2Cl2/MeOH 500:1 to 15:1 as eluent) to afford (2-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-5-yl)methanol (350 mg, 12%) as white solid. LC-MS (m/z)=266.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O.C(OCC)(=O)C.C(#N)C.C(N(CC)CC)C>[N:17]1([CH2:16][CH2:15][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 4-hydroxybenzoate (8.31 g), 1-(2-chloroethyl)piperidine monohydrochloride (10.13 g), potassium carbonate (16.59 g), and methyl ethyl ketone (60 mL) was heated to 80° C. After one hour, the mixture was cooled to about 55° C. and treated with additional 1-(2-chloroethyl)piperidine monohydrochloride (0.92 g). The resulting mixture was heated to 80° C. The reaction was monitored by thin layer chromatography (TLC), using silica-gel plates and ethyl acetate/acetonitrile/triethylamine (10:6:1, v/v). Additional portions of 1-(2-chloroethyl)piperidine hydrochloride were added until the starting 4-hydroxybenzoate ester was consumed. Upon complete reaction, the reaction mixture was treated with water (60 mL) and allowed to cool to room temperature. The aqueous layer was discarded and the organic layer concentrated in vacuo at 40° C. and 40 mm Hg. The resulting oil was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([O:14][C@@H:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:17]12[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18]1)[C@@H:15]([O:14][C:11]1[N:12]=[N:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:36]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=1)[CH2:16]2
Reactant: Brc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(C(=Nc2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
The product of Example 29D (360 mg, 1 mmol) was coupled with benzhydrylideneamine (Aldrich, 270 mg, 1.5 mmol) under the catalysis of Pd2(dba)3 (Aldrich, 18.3 mg, 0.02 mmol) and Xantphos (Strem Chemicals, 36 mg, 0.06 mmol) with t-BuONa (Aldrich, 150 mg, 1.5 mmol) in toluene (anhydrous, Aldrich, 10 mL) at 100° C. for 2 h. The mixture was then cooled down to ambient temperature and diluted with EtOAc (50 mL), washed with water (2×5 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.4) as a solid (360 mg, yield, 78%). 1H NMR (300 MHz, CD3OD) δ 1.45-1.63 (m, 1H), 1.64-1.94 (m, 2H), 1.94-2.13 (m, 1H), 2.23-2.41 (m, 1H), 2.71-3.06 (m, 5H), 3.39-3.55 (m, 1H), 5.10-5.37 (m, 1H), 6.82-6.93 (m, 2H), 7.12-7.23 (m, 3H), 7.25-7.35 (m, 3H), 7.39-7.57 (m, 3H), 7.67-7.74 (m, 2H), 7.74-7.83 (m, 2H), 7.96 (d, J=9.2 Hz, 1H) ppm. MS (DCl/NH3): 461 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([CH3:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[S:13]([O-:17])(=[O:16])(=[O:15])[CH3:14]>>[S:13]([OH:17])(=[O:16])(=[O:15])[CH3:14].[NH2:1][C:2]1([CH3:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1
Reactant: CS(=O)(=O)[O-]
Agent: CC1(C)CC(C)(C)CC(C)(N)C1
Product: CS(=O)(=O)O

Procedure:
In one embodiment, crude 1-amino-1,3,3,5,5-pentamethylcyclohexane comprising 1-amino-1,3,3-trans-5-tetramethylcyclohexane is subjected to mesylate formation according to the process of the invention, wherein 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate is formed comprising 1-amino-1,3,3-trans-5-tetramethylcyclohexane mesylate.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=1)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][C:8]=1[S:13]([CH3:16])(=[O:14])=[O:15]
Reactant: CC(N=[N+]=[N-])c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 4-(1-azidoethyl)-1chloro-2-(methylsulfonyl)benzene (2.1 g, 7.7 mmol), THF (20 mL), triphenylphosphine (2.4 g, 8.5 mmol) and water (0.6 mL, 34.2 mmol) at 0° C. and the reaction was stirred at room temperature over night. The solvents were removed and the residue was dissolved in MTBE and 20% HCl in dioxane was added dropwise at 0° C. The resulting salt was collected and washed with EtOAc. The salt was then neutralized with 6N NaOH and extracted with CH2Cl2. The combined organic layers were concentrated under reduced pressure to get the title compound as a very thick oil. 1H NMR (400 MHz, CDCl3): 8.14 (d, 1H, J=2.0 Hz), 7.63 (dd, 1H, J=8.4, 2.4 Hz), 7.52 (d, 1H, J=8.0 Hz), 4.24 (q, 1H, J=6.4 Hz), 3.28 (s, 3H), 1.40 (d, 3H, J=6.4 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[F:22])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([N+:16]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.Cl.O.[Cl-].[Na+]>C(O)C.[Fe]>[NH2:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[C:7]([C:6]1[CH:19]=[CH:20][C:21]([F:22])=[C:4]([NH2:1])[CH:5]=1)=[O:8]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)c2ccc(F)c(N)c2)ccc1F
Temperature: 75 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a glass reaction vessel equipped with a stirrer, reflux condenser and a thermometer, 124 g (0.4 mole) of 3,3'-dinitro-4,4'-difluorobenzophenone, 1100 ml of a 80% aqueous ethanol solution and 280 g (5.0 mole) of iron powder were charged and the internal temperature was raised to 75° C. Successively, a solution containing 10.5 g of 36% hydrochloric acid in 124 ml of 80% ethanol was added dropwise and the reaction was further continued for 3 hours with stirring. After finishing the reaction, the reaction mixture was filtered at the same temperature and the filtrate was poured into 2 l of water. The precipitated crystal was filtered, washed with water and dried to obtain 90.5 g of crude crystals of 3,3'-diamino-4,4'-difluorobenzophenone. The crude crystal was mixed with 180 ml of water, 36% hydrochloric acid and activated carbon, and dissolved by heating. The solution was hot filtered. To the filtrate, 18 g of sodium chloride was added and dissolved. The solution thus obtained was gradually cooled to precipitate 3,3'-diamino-4,4'-difluorobenzophenone hydrochloride. The hydrochloride was filtered and neutralized in water with a 28% aqueous ammonia solution to obtain 82.3 g (83.0% yield) of 3,3'-diamino-4,4'-difluorobenzophenone. The purified product had purity of 99.1% by high performance liquid chromatography and a melting point of 130.8°-131.6° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O.O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>O>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 60 °C

Procedure:
This example describes the application of the immobilized glucose isomerase produced from DSM 3253. 11.7 g of the dried granulate produced in Example 6 was soaked in 200 ml 45% w/w glucose syrup, pH 7.5 for two hours. The enzyme particles were then transferred to a water jacketed column and a 45% w/w glucose syrup with 0.4 g MgSO4, 7H2O/l and 2 mM NaHCO3 at pH 7.5 was continuously pumped through the column at room temperature. After 1 hour the column temperature was raised to 60° C. and the flow adjusted to obtain a 41-44.5% conversion to fructose. The activity increased during the first 137 hours of isomerization. The syrup flow after 137 hours was 0.88 g syrup dry substance per g enzyme per hour and the degree of conversion in the outlet syrup was 44.3%. The experiment was terminated after 328 hours, the final syrup flow being 1.03 g syrup dry substance per g enzyme per hour with a degree of conversion in the outlet syrup of 42.0%.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@@H:8]([NH:18][C:19]1[C:24]([N+:25]([O-])=O)=[CH:23][CH:22]=[C:21]([O:28][CH3:29])[N:20]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])[CH3:3].C(O)(=O)C>CO.[Zn]>[CH3:4][C:2]([Si:5]([CH3:30])([CH3:31])[O:6][CH2:7][C@@H:8]([NH:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([O:28][CH3:29])[N:20]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc([N+](=O)[O-])c(N[C@@H](COCc2ccccc2)CO[Si](C)(C)C(C)(C)C)n1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(N)c(N[C@@H](COCc2ccccc2)CO[Si](C)(C)C(C)(C)C)n1
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
To a solution of N-((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)-6-(methyloxy)-3-nitro-2-pyridinamine (642.6 g, 1.436 mol) in MeOH (12 L) was added a suspension of zinc dust (938 g, 14.35 mol) in MeOH (4 L). Acetic acid (411 ml, 7.18 mol) was added dropwise over ˜30 min such that the temperature remained below 36° C. When the addition was complete the mixture was stirred for 15 min. The reaction mixture was filtered through celite and the cake was washed with EtOAc (8 L). The mixture was washed with brine (8 L) and the layers were separated. The aqueous phase was extracted with EtOAc (8+6 L) then the organic phases were combined, washed with saturated NaHCO3 (8 L), brine (8 L), dried over MgSO4 (1 kg) and filtered. The filtrate was evaporated to give 478 g (80%) of N2-((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)-6-(methyloxy)-2,3-pyridinediamine as a dark red viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.C(O[C:23]1(O[Si](C)(C)C)[CH2:25][CH2:24]1)C.C([BH3-])#N.[Na+]>CO>[CH:23]1([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:25][CH2:24]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.3 %

Procedure:
To a solution of 1-(4-nitrophenyl)piperazine (1.04 g, 5.00 mmol) in methanol (25 mL) under nitrogen was added molecular sieves (1.0 g), acetic acid (3.00 g, 2.86 mL, 50.0 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (5.22 g, 5.99 mL, 30.0 mmol), sodium cyanoborohydride (1.41 g, 22.5 mmol). The mixture was stirred at room temperature for 2.5 d, filtered, and concentrated. To the residue was added water and 1N aq. NaOH to adjust the PH>11. The mixture was extracted ethyl acetate, and the organic layer was dried over Na2SO4, concentrated to give the title compound (1.24 g, 100%) as a yellow solid. MS (ES+): m/z=247.8.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.C(N(CC)CC)C.[CH3:30][S:31]([Cl:34])(=[O:33])=[O:32]>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:34].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
40 mg (0.11 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzothiophene-2-carboxamide hydrochloride are dissolved in 2 ml of DMF, 6.5 mg (0.05 mmol) of N,N-dimethyl-4-aminopyridine, 59.6 μl (0.43 mmol) of triethylamine and 16.61 (0.21 mmol) of methanesulfonyl chloride are added and the mixture is stirred at room temperature for 16 h. The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of 1N aqueous hydrochloric acid and acetonitrile, then reconcentrated and dried under high vacuum. 15 mg (33.8% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][CH:21]=[C:22](Br)[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH3:28])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cncc(Br)c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cncc(-c2ccccc2C)c1
Temperature: 80 °C

Procedure:
The procedure described in Example 1: step c was followed using {[4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.08 mmol), 2-methyl phenyl boronic acid (23 mg, 0.17 mmol), Pd(PPh3)4 (19 Mg, 0.02 mmol), aqueous Na2CO3 (2M, 800 μL, 0.4 mmol), ethanol (800 μL) and toluene (1600 μL). The reaction was heated to 80° C. for 12 hours. The residue was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo resulted in a crude mixture of the product that was used without further purification or characterization.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]1.IC>C1COCC1>[CH3:1][C:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]1
Reactant: O=C(O)C1CC=CCC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CC=CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-isopropylpropan-2-amine (50.1 g, 69.5 mL, 495.5 mmol) was dissolved in 50 mL of THF. To the solution was added n-butyllithium (174.4 mL of 2.5 M solution in hexanes, 436.0 mmol) at −78° C. The resulting solution was stirred for 30 minutes at −78° C. To the reaction was then added cyclohex-3-ene-1-carboxylic acid (25.0 g, 198.2 mmol) and the reaction was allowed to warm to 60° C. for 2 hrs. The reaction was cooled to room temp and iodomethane (29.5 g, 13.0 mL, 208.1 mmol) was added and the reaction was allowed to stir overnight and then quenched with 1 N HCl until the pH<4. The crude product was extracted into CH2Cl2 and water. The organic phase was concentrated in vacuo to a yellow oil (27 g) and used without further purification.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.Br[CH:28]([CH2:33][CH3:34])[C:29]([O:31]C)=[O:30]>>[ClH:1].[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]2[CH:25]=[CH:26][C:9]([O:8][CH2:7][C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH2:34][CH2:33][CH2:28][C:29]([OH:31])=[O:30])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: c1csc(-c2ccc(Cc3ccc(OC[C@@H]4CCCN4)cc3)cc2)n1
Reactant: CCC(Br)C(=O)OC
Agent: Cl
Product: O=C(O)CCCN1CCC[C@H]1COc1ccc(Cc2ccc(-c3nccs3)cc2)cc1
Yield: 42.3 %

Procedure:
The title compound (56 mg, 42%) was prepared from the product of Example 150 (0.1 g, 0.28 mmol) and methyl bromobutyrate (0.062 g, 0.34 mmol) using the procedure of Example 147; 1HNMR (400 MHz, CD3OD) δ 8.07 (m, 1H), 7.90 (d, J=8 Hz, 1H), 7.85 (m, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.32 (m, 1H), 4.20 (m, 1H), 4.10 (m, 1H), 4.04 (s, 2H), 3.95 (m, 1H), 3.65 (m, 3H), 3.36 (m, 2H), 2.50-2.00 (m, 6H); MS.?