Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[C:28]1([S:34]([CH2:37][C:38]2[C:43]([C:44]([O:46][CH3:47])=[O:45])=[C:42](OS(C(F)(F)F)(=O)=O)[C:41]([CH2:56][CH3:57])=[CH:40][CH:39]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O:58]1[CH2:63][CH2:62][CH2:61][CH2:60][CH:59]1[N:64]1[C:68](B2OC(C)(C)C(C)(C)O2)=[CH:67][CH:66]=[N:65]1>>[C:28]1([S:34]([CH2:37][C:38]2[C:43]([C:44]([O:46][CH3:47])=[O:45])=[C:42]([C:68]3[N:64]([CH:59]4[CH2:60][CH2:61][CH2:62][CH2:63][O:58]4)[N:65]=[CH:66][CH:67]=3)[C:41]([CH2:56][CH3:57])=[CH:40][CH:39]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1-c1ccnn1C1CCCCO1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(benzenesulphonylmethyl)-3-ethyl-2-(trifluoromethanesulphonyloxy)benzoate (Intermediate 127) and 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester as an opaque foam which was used without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([NH2:34])=O)=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[NH4+]>C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]#[N:34])=[CH:27][CH:26]=[CH:25]4)=[CH:20][CH:21]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(N)=O)cccc3c2)cc1
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C#N)cccc3c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
To a solution of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxamide (94 mg, 0.18 mmol) and triethylamine (0.111 mL, 0.80 mmol) in methylene chloride (2 mL) at ambient temperature under nitrogen was added phosphorous oxychloride (0.068 mL, 0.71 mmol). The mixture was stirred at ambient temperature for four hours, at which time an additional equivalent of phosphorous oxychloride (0.027 mL) was added. Ammonium hydrogen carbonate (25 mg, 0.273 mmol) was then added to the mixture and the reaction was stirred at ambient temperature for 48 hours. The solvent was then removed on a rotary evaporator and the crude residue was dissolved in ethyl acetate. The organic solution was then washed with water three times, followed by saturated sodium bicarbonate, and then brine. The crude organic extract was then dried over magnesium sulfate, filtered, and then evaporated to dryness to give the title compound (89 mg, 98%). 1H NMR (CDCl3): 8.24 (d, J=9 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 8.02 (d, J=9 Hz, 1H), 7.82-7.90 (m, 2H), 7.61-7.50 (m, 3H), 7.31-7.52 (m, 3H), 6.88 (d, J=9 Hz, 2H), 4.78 (s, 2H), 3.28-3.42 (m, 1H), 1.34-1.53 (m, 6H). ESI-LCMS m/z 513 (M+H)+.
Reaction SMILES: [K+].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.[Cl-].[Mg+2].[Cl-].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]C(O)=O)=[CH:17][CH:16]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>C(#N)C.C(N(CC)CC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:4](=[O:6])[CH2:3][C:2]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
To a solution of ethyl malonate potassium salt (39 g) in acetonitrile (100 mL) was added magnesium chloride (26 g) and triethylamine (48.6 g) and the mixture was stirred at room temperature for 2 hours (solution A). To a solution of 4-chlorophenylacetic acid (18.6 g) in acetonitrile (100 mL) was added carbonyldiimidazole (19.5 g) at room temperature and the mixture was stirred at the same temperature fro 1.5 hours. To the reaction mixture was added the solution A prepared above at room temperature and the mixture was stirred at the same temperature for 30 minutes and at 80° C. for 2 hours. After cooling the reaction mixture to room temperature, thereto was added 2N HCl solution (260 mL) and the mixture was stirred. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=8/1 to 6/1) to obtain ethyl 4-(4-chlorophenyl)-3-oxobutyrate (25 g, yield: 95%) as a liquid.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 49.9 %

Procedure:
To a solution of benzyl mercaptan (1.18 mL, 10.0 mmol) in DMF (20 mL) is added potassium carbonate (1.51 g, 10.9 mmol) and ethyl bromoacetate (1.17 mL, 10.6 mmol), and the mixture is stirred at RT for 25 min. Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled (130-140° C.) to give 1.05 g of the product 402.
Reaction SMILES: [IH:1].[CH3:2][CH:3]([OH:12])[CH2:4][N:5]1[CH2:9][CH2:8][N:7]=[C:6]1SC.O.[NH2:14][NH2:15]>CC(O)C>[IH:1].[NH:14]([C:6]1[N:5]([CH2:4][CH:3]([CH3:2])[OH:12])[CH2:9][CH2:8][N:7]=1)[NH2:15]
Reactant: NN
Reactant: CSC1=NCCN1CC(C)O
Agent: I
Solvent: CC(C)O
Solvent: O
Product: CC(O)CN1CCN=C1NN
Temperature: -10 °C

Procedure:
A solution of 30.2 g of α-methyl-2-(methylthio)-2-imidazoline-1-ethanol, hydroiodide, 5.2 ml of hydrazine hydrate and 200 ml of 2-propanol was refluxed for 4 hours, clarified and cooled at -10° C. The solid was collected, washed with 100 ml of cold 2-propanol, then 200 ml of ether and dried at 60° C. in vacuo, giving 26.0 g of the desired intermediate, mp 140°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][CH2:28]O)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:18]3[C:19]4=[C:20]([CH:24]=[N:25][N:26]4[CH2:27][CH2:28]2)[N:21]=[CH:22][N:23]=3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: OCCn1ncc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(COc2ccc(N3CCn4ncc5ncnc3c54)cc2Cl)c1
Yield: 81 %

Procedure:
A solution of 2-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethanol (40 mg), 1,1′-(azodicarbonyl)dipiperidine (48 mg) and tributylphosphine (40 mg) in tetrahydrofuran (2 mL) was stirred at room temperature for 15 hrs. After the completion of the reaction, water was added to the reaction mixture and the mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→1/4) to give the title compound (31 mg) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:23]C)=[CH:15][CH:14]=1)(=[O:3])[CH3:2].Cl.N1C=CC=CC=1>>[C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([OH:23])=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2oc3ccccc3c2C(C)=O)c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1c(-c2ccc(O)c3ccccc23)oc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 13.8 g. (0.044 mol.) of 3-acetyl-2-(4-methoxynaphthyl)benzofuran and 100 g. of pyridine hydrochloride was heated at 185° for 4.5 hours. The hot reaction mixture was poured into an ice-dilute hydrochloric acid mixture and the aqueous solution was extracted with ether. The extract was dried (MgSO4) and evaporated to give 3-acetyl-2-(4-hydroxynaphthyl)benzofuran, m.p. 212°-216°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH:31]([CH3:34])[CH2:32][OH:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH:31]([CH3:34])[CH2:32][OH:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(N)CO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(CO)NCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL), and the solution was treated with 2-amino-1 propanol (0.0080 mL, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(2-hydroxy-1-methylethyl)aminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]([NH2:8])=[S:7].[CH:9]([C:21](OCC)=[O:22])([C:16](OCC)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[OH:22][C:21]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([OH:17])[N:8]=[C:6]([SH:7])[N:5]=1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(O)nc(S)nc1O
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of sodium ethoxide [prepared from sodium metal (1.6 g) and ethanol] was added thiourea (5.28 g) and triethyl 1,1,2-ethane tricarboxylate (17 g). The mixture was heated under reflux for 8 hours. The solution was cooled to room temperature and the solid collected by filtration, washed with a little ether. The solid was dissolved in water (100 ml) and the pH adjusted to 6-7 by the addition of hydrochloric acid. No solid was precipitated therefore the solution was lyophilised to give a pink solid (8.1 g)
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][CH2:7][C:8]3([C:16]42[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]4)[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1.CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.CC1CCCO1.C(=O)([O-])[O-].[K+].[K+]>[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl.[Pd].O>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:24]=[C:23]3[C:5]([CH2:6][CH2:7][C:8]4([C:16]53[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]5)[CH2:9][CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13]4)=[CH:4][CH:3]=2)[CH:29]=[N:28][CH:27]=1
Reactant: CC1(C)OB(c2cncc(Cl)c2)OC1(C)C
Reactant: COC1CCC2(CCc3ccc(Br)cc3C23N=C(C)C(N)=N3)CC1
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: CC(C)(C)[PH+](CCCS(=O)(=O)[O-])C(C)(C)C
Solvent: O
Solvent: CC1CCCO1
Product: COC1CCC2(CCc3ccc(-c4cncc(Cl)c4)cc3C23N=C(C)C(N)=N3)CC1
Temperature: 130 °C

Procedure:
7′-Bromo-4-methoxy-5″-methyl-3′,4′-dihydrodispiro[cyclohexane-1,2′-naphthalene-1′,2″-imidazol]-4″-amine (Example 5, 0.2 g, 0.51 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (123 mg, 0.51 mmol), 3-(di-tert-butylphosphonium)propane sulfonate (0.014 g, 0.05 mmol), sodium tetrachloropalladate(II) (7.54 mg, 0.03 mmol), 2-methyltetrahydrofuran (3 mL) and aq. potassium carbonate (2.0 M, 0.769 mL, 1.54 mmol) were added to microwave vial. The vial was sealed and heated in the MW for 30 min at 130° C. The same amount of ligand and Pd-catalyst were added again and the reaction was heated in the MW for 15 min at 130° C. This procedure was repeated twice more. Water and 2-Me THF were added. The water phase was eliminated and the organic phase was washed once with brine and water. The organic phase was concentrated in vacuo. The product was purified using prep HPLC to give:
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:5][CH2:6][NH:7][C@@H:8]1[C@@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:22])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:25][CH3:26])[CH2:23][CH3:24].[OH-].[Na+]>CO>[C:20]([C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@H:17]([O:18][CH3:19])[C@@H:8]([NH:7][CH2:6][CH2:5][C@H:4]([CH2:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[C:3]([OH:34])=[O:2])[C:9]2([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:14][CH:13]=1)(=[O:22])[NH2:21]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCC[C@H](CC1CCCCC1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCC[C@H](CC1CCCCC1)C(=O)O
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a solution of (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid methyl ester (12.0 g, 25.4 mmol) in methanol was added 5.0 M NaOH (25 mL) and the reaction mixture was heated at 30° C. for 8 h and then at 25° C. overnight. Most of the methanol solvent was removed by rotary evaporation at 25° C., water (100 mL) and isopropyl acetate (100 mL) was added and the resulting mixture was stirred for 15 min. The bottom two of three layers were extracted with isopropyl acetate (100 mL). Bottom layers were cooled to −5° C. and MeTHF (200 mL) was added and then concentrated HCl (˜15 mL) was added in portions until pH ˜2. Phases were separated, water layer was washed with MeTHF (100 mL) and combined organic layers were dried with Na2SO4. Most of the organic solvent was removed by rotary evaporation, ethyl acetate (200 mL) was added and the volume was reduced to 50 mL. Ethyl acetate (200 mL) was added and the resulting slurry was stirred/triturated at RT for 3 h. Product was filtered under nitrogen and dried under vacuum for 48 h to yield the hydrochloride salt of the title compound (11 g, 98.2% purity) as a white solid. 1H NMR (DMSO-d6): 6(ppm) 0.54 (t, 3H), 0.63 (t, 3H), 0.82 (m, 2H), 1.05-1.3 (m, 6H), 1.45 (m, 1H), 1.55-2.0 (m, 10H), 2.40 (m, 1H), 2.67 (dd, 1H), 3.06 (m, 1H), 3.22 (m, 1H), 3.30 (dd, 1H), 3.41 (s, 3H), 3.45 (dd, 1H), 4.05 (m, 1H), 7.19 (d, 1H), 7.50 (br, 1H), 7.69 (d, 1 h), 7.70 (s, 1H), 7.95 (br, 2H), 9.26 (br, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19]>CS(C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:19][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CS(C)=O
Product: CN(C)CCNc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A mixture of 4-chloro-3-nitrophenyl methyl sulfone (4 g, 17 mmole) and N,N-dimethylethylenediamine (3.3 g, 37 mmole) in DMSO (20 ml) was stored at 75° C. for 1 hour and poured into crushed ice. The yellow solid precipitate was collected by filtration and was dissolved in ethyl acetate. The organic phase was washed with water-brine mixture twice and brine, dried over sodium sulfate, and evaporated under reduced pressure to give the sulfone (22) (3.8 g, 78%) as a yellow solid. A pure sample (m.p. 130°-131° C.) was obtained by recrystallization from ethyl acetate.
Reaction SMILES: C[Si](C)(C)CCOC([NH:8][CH2:9][C@@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=O.[N+](CC)(CC)(CC)CC.[F-]>CC#N>[NH2:8][CH2:9][C@@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H](CNC(=O)OCC[Si](C)(C)C)CC1CCCCC1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CN)CC1CCCCC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 85.9 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-(2-(trimethylsilyl)ethoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (6.55 g, 15.4 mmol) in MeCN (100 mL) was added Et4NF (7.5 g, 50 mmol). The mixture was stirred overnight at rt and at 60° C. for 7 h. The mixture was concentrated and the oily residue was taken up in EtOAc (175 mL). The mixture was washed with water (2×50 mL) and brine (50 mL) and dried over Na2SO4. Removal of the solvent afforded (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate (3.39 g, 80%) as a syrup.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([O:26][CH2:27][CH3:28])[CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].C(=O)(O)[O-].[Na+].Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>ClCCl>[CH2:38]([O:37][C:35]([NH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([O:26][CH2:27][CH3:28])[CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1)=[NH:2])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)C(=O)OC)ccc1OC(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1cc(C(Nc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)OC)ccc1OC(C)C
Yield: 66.8 %

Procedure:
To 141D (6.7 g; 13.25 mmol) in dichloromethane (80 mL) was added sodium bicarbonate (132 mL, 1 M). Benzyl chloroformate (1.89 mL, 13.25 mmol) in dichloromethane (20 mL) was then added dropwise using an addition funnel over a period of 1 h. After the addition was complete, the suspension turned to a clear orange solution. The layers were separated and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed and the crude residue was purified by flash column chromatography to give 4.6 g of 141E as a yellow solid (69% yield). LC-MS: 520.10 (M+H)+.
Reaction SMILES: [CH:1]1([C@@:4]2([CH2:11][NH:12]C(=O)OC(C)(C)C)[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5]2)[CH2:3][CH2:2]1.[ClH:20]>CO.O1CCOCC1.C1(C)C=CC=CC=1>[ClH:20].[NH2:12][CH2:11][C@@:4]1([CH:1]2[CH2:2][CH2:3]2)[NH:5][C:6](=[O:10])[NH:7][C:8]1=[O:9]
Reactant: CC(C)(C)OC(=O)NC[C@@]1(C2CC2)NC(=O)NC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CO
Product: NC[C@@]1(C2CC2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
tert-butyl N-[[(4R)-4-cyclopropyl-2,5-dioxo-imidazolidin-4-yl]methyl]carbamate (310 g, 1151 mmol) is dissolved in MeOH (3.1 L) at 6° C. 4M HCl in dioxane (310 mL) is added and the mixture warmed to 25° C. After stirring for 22 h, a second portion of 4M HCl in dioxane (110 mL) is added and stiffing continued for an additional 16 h. The reaction is then allowed to sit with no agitation for 2 days. The mixture is then diluted with toluene (6 L). The title compound is collected by filtration of the mixture as a white solid (180 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:7]([C:8]#[N:9])([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:16]
Reactant: N#CCc1cccnc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1cccnc1

Procedure:
Prepare by the method of example 1.1.2 using pyridin-3-yl-acetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=[CH:6][C:5]=1[NH2:19])([O-])=O>[Ni]>[CH3:15][C:13]1([CH3:16])[C:12]([CH3:17])([CH3:18])[O:11][B:10]([C:8]2[CH:9]=[C:4]([NH2:1])[C:5]([NH2:19])=[CH:6][CH:7]=2)[O:14]1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: [Ni]
Product: CC1(C)OB(c2ccc(N)c(N)c2)OC1(C)C

Procedure:
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene-1,2-diamine is prepared from the commercially available 2-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine using the Ra—Ni catalyzed nitro reduction method described in Example 1 (step c).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH:20]([CH2:22][OH:23])[CH2:19][CH2:18][C:16]=2[N:17]=1>>[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH:20]([CH2:22][O:23][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:19][CH2:18][C:16]=2[N:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2c(s1)CC(CO)CC2
Product: Cc1ccc(S(=O)(=O)OCC2CCc3nc(C)sc3C2)cc1
Yield: 71 %

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV) according to the procedure described in Example 1. M.p.=70°-71° C. Yield: 71%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:6]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[N:7]2.C(O[CH:29](OCC)[N:30]([CH3:32])[CH3:31])C>O>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:6]2[C:5]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=[CH:29][N:30]([CH3:32])[CH3:31])[N:7]=2)[CH2:13][CH2:14]1
Reactant: CCOC(OCC)N(C)C
Reactant: CN1CCN(c2nc3cccc(N)c3nc2N2CCN(C)CC2)CC1
Solvent: O
Product: CN(C)C=Nc1cccc2nc(N3CCN(C)CC3)c(N3CCN(C)CC3)nc12
Temperature: 135 °C
Reaction time: 2 h

Procedure:
A 2.4 g. portion of 5-amino-2,3-bis(4-methyl-1-piperazinyl)quinoxaline prepared as in Example 3 is combined with 23.0 g. of dimethylformamide diethylacetal in a reaction flask. The suspension is heated in an oil bath at 135° C. with magnetic stirring. The solid is dissolved within four minutes and refluxing is continued for two hours. The reaction solution is cooled and stripped of solvent by water pump evacuation. The residual yellow solid is recrystallized by boiling in 200 ml. of hexane, after filtering to remove a small amount of insoluble material. The recrystallized material is collected by filtration and dried in vacuo over phosphorous pentoxide at 78° C. The above filtrate is set aside and the dried material is again recrystallized from 200 ml. of hexane in exactly the same manner as above, collected and dried to give 0.35 g. of orange solid. A yellowish-brown insoluble material removed by filtering the hot hexane prior to cooling is set aside. The final hexane cold filtrate and the initial hexane cold filtrate previously set aside are combined and the hexane is removed by water pump evacuation. The insoluble residue set aside previously is added to the combined filtrate residue and this is recrystallized from 70 ml. of hot acetonitrile by cooling at -10° C. The solid formed is collected by filtration, washed with cold acetonitrile and dried in vacuo over phosphorous pentoxide at 78° C. to give 1.6 g. of additional orange solid. The combined yield of the product of the example is 1.9 g., m.p. 183°-186° C.