Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([CH2:9][CH:10]=[CH2:11])[CH2:6]C=C)([O:3][CH3:4])=[O:2]>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:4][O:3][C:1]([N:5]1[CH2:9][CH2:10][CH:11]=[CH:6]1)=[O:2]
Reactant: C=CCN(CC=C)C(=O)OC
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: COC(=O)N1C=CCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The obtained N-carbomethoxy diallyl amine (400 g) was dissolved in 1.5 l of dichloromethane purged with nitrogen for 10 minutes by bubbling nitrogen through the stirred solution. In a 5 l flask fitted with a mechanical stirrer and an addition funnel, was charged the Grubb's catalyst (bis(tricyclohexylphosphine)styrylrutheniumdichloride (3 g, 3.9 mmol) under a steady purge. Dichloromethane was added and the resultant dark solution was stirred at r.t. with nitrogen bubbling for 10 minutes. The N-carbomethoxy diallyl amine solution was added to the catalyst solution over a period of 2 hours. When the addition was complete, the solution was stirred at r.t. for 2.5 days. Then, the reaction mixture was concentrated to an oil, which was subsequently purified by vacuum distillation. The desired product was obtained as a clear colorless liquid boiling at about 90° C. (10 mm of Hg) The NMR was consistent with the expected structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>CS(C)=O>[Br:8][C:6]1[CH:5]=[CH:4][N:3]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:2](=[O:1])[CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1cc(Br)ccn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(Br)ccn1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
To a solution of 2-hydroxy-4-bromopyridine (0.10 g, 0.57 mmol) in DMSO (1.0 mL) was added KOH (0.13 g, 2.29 mmol) and the resulting reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(2-chloroethyl)morpholine (0.13 g, 0.69 mmol). The reaction mixture was then stirred at 45° C. for 30 min. After the completion of reaction (TLC monitoring), water was added to the reaction and extracted with EtOAc (3×25 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel (100-200 M, 5% MeOH-DCM) to obtain the desired product (0.085 g, 52%). MS: 287.10 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=3)[S:7][C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][NH:24][NH2:25])[CH3:20]>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]2[S:7][C:6]3[C:15]4[C:14](=[N:25][N:24]([CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])[C:2]=4[CH:3]=[CH:4][C:5]=3[CH3:18])[C:13]=2[CH:12]=1
Reactant: CCN(CC)CCNN
Reactant: Cc1ccc(Cl)c2c(=O)c3cc(Cl)ccc3sc12
Product: CCN(CC)CCn1nc2c3c(c(C)ccc31)Sc1ccc(Cl)cc1-2

Procedure:
By condensation of 1,7-dichloro-4-methyl-9-thioxanthenone with 2-(diethylamino)ethyl hydrazine was obtained 9-chloro-2-(2-(diethylamino)ethyl)-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole. To 0.13 g. of this base in acetone (3 ml.) was added 30% aqueous hydrogen peroxide (0.2 ml.). After 18 hours at room temperature the solution was evaporated to dryness under reduced pressure and the residue crystallized from acetone to give 9-chloro-2-(2-(diethylamino)ethyl)-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole N-oxide monohydrate, m.p. 134°-135° (decomp.).
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:28]3[C@H:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:28]3[C@H:24]([CH2:25][N:26]([C:8](=[O:10])[C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11][CH3:12])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
N,N'-Carbonyldiimidazole (0.49 g) is added to a solution of (S)-2-phenylbutyric acid (0.5 g) in dry dichloromethane (15 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (0.98 g) and triethylamine (0.42 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.6 cm, height 9.7 cm), eluting with a mixture of ethyl acetate and cyclohexane (80/20 by volume) and collecting 30 cc fractions. The first fraction is concentrated to dryness under reduced pressure (2.7 kPa). The residue is re-chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.3 cm, height 14.5 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 50 cc fractions. Fractions 1 to 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (3aR,7aR)-7,7-diphenyl-2-[(S)-2-phenylbutyryl]-4-perhydroisoindolone (0.54 g) is obtained in the form of a white meringue. [α]D20 =-216° (c=1, methanol).
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:2].[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[CH2:1]([O:3][N:4]([CH3:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCONC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCON(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
A solution of tert-butyl ethoxycarbamate (XCIII, 2.48 g, 15.38 mmol) in DMF (10 mL) was added dropwise to the suspension of 60% sodium hydride (0.66 g, 16.92 mmol) in DMF (5 mL) at 0° C. After 30 min. methyl iodide (1.95 mL, 31.32 mmol) in DMF (10 mL) was added, and the reaction mixture was stirred at room temperature for 24 h. Water (100 mL) was added and the product was extracted with ethyl acetate (3×50 mL), dried over Na2SO4, and concentrated in vacuo to yield tert-butyl ethoxy(methyl)carbamate (XCIV, 2.34 g, 87%). 400 MHz 1H NMR (DMSO-d6, ppm) 3.81 (2H, q, J=7.0 Hz), 3.00 (3H, s), 1.41 (9H, s), 1.12 (3H, t, J=7.0 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(C2(CO)CCCC2)C=CC=CC=1>>[C:11]1([C:5]2([CH2:3][OH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C1(c2ccccc2)CCCCC1
Agent: OCC1(c2ccccc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Product: OCC1(c2ccccc2)CCCCC1

Procedure:
This compound was prepared (1.02 g, 5.43 mmol, 62%) from the product of Step B (1.91 g, 8.76 mmol) using LiAlH4 (0.75 g, 37.95 mmol) according to the procedure for synthesizing 1-phenylcyclopentanemethanol set forth in Step B, Example 1, with the exception that this compound precipitated out of solution following the steps of: (a) destroying the excess hydride; (b) separating the aluminum salts by filtration; and (c) washing with water (3×4 mL in this Example). Filtration of the precipitate gave 1-phenylcyclohexanemethanol as a white solid, mp 63°-64° C. (compared with reported value, J. Org. Chem. 27:3434 (1962), of 63°-64° C.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.[OH-].[Na+]>CCOC(C)=O>[NH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([NH:15][C:16]2[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:13][CH2:14]1
Reactant: CN(C)c1nc(N[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CN(C)c1nc(NC2CCC(CN)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 83.5 %

Procedure:
To a suspension of trans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamic acid tert-butyl ester obtained in step B of example 6 (400 mg, 1.00 mmol) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambient temperature for 80 min. The reaction mixture was alkalized with 2 M aqueous sodium hydroxide, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, purified by medium-pressure liquid chromatography (NH-silica gel, 33% EtOAc in hexane to 3% MeOH in CHCl3) to give N2-(4-aminomethyl-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (250 mg, 83%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15][C:14]2=[CH:35][CH:36]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH:8]=[CH:7][CH2:6]1)=[O:4]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15][C:14]2=[CH:35][CH:36]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC=CCOc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: [Pd]
Agent: COC(=O)[C@@H]1C/C=C/COc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1

Procedure:
Olefin 45 (1.36 g, 2.70 mmol) was dissolved in 40 mL of EtOAc. 10% palladium on carbon catalyst was added (25%) and the reaction mixture was subjected to hydrogenation at rt and atmospheric pressure for 18 h before being filtered through celite and concentrated in vacuo to yield a brown solid, 1.36 g, 100%. m.p. 225-228° C.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[N:10]=1>C(OCC)(=O)C>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=[C:11]([N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:27])([F:29])[F:28])[C:6]([NH2:5])=[O:7])[N:10]=1
Reactant: Cc1cc(C(F)(F)F)nc(Nc2ccccc2C(F)(F)F)n1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(F)F)nc(N(C(N)=O)c2ccccc2C(F)(F)F)n1
Temperature: 3 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
At 3° C., 3.6 g (0.026 mole) of chlorosulfonyl isocyanate are added to a solution of 6.4 g (0.02 mole) of N-(4-methyl-6-trifluoromethyl-pyrimidin-2-yl)-2-trifluoromethylaniline in 100 ml of ethyl acetate. After stirring the batch for 2 hours at 3° C., 100 ml of ethyl acetate and 50 ml of ice-water are added. The aqueous phase is separated off, and the organic phase is washed with sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a rotary evaporator. The crystals remaining are triturated with hexane, filtered off and dried in vacuo at 40° C. 6.1 g (83.8%) of the title compound of formula ##STR11## are isolated in the form of crystals having a melting point of 150°-153° C. (Comp. No. 1.020).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]1[OH:9].O.[C:19]1(C)[CH:24]=CC(S(O)(=O)=O)=C[CH:20]=1.COC(OC)(C)C.C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:13][C@H:12]1[O:14][C@@H:7]([N:6]2[C:5](=[O:16])[N:4]=[C:3]([NH2:17])[C:2]([F:1])=[CH:15]2)[C@@H:8]2[O:9][C:19]([CH3:24])([CH3:20])[O:11][C@H:10]12
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 5'-deoxy-5-fluorocytidine (490 mg), p-toluenesulfonic acid monohydrate (418 mg) and 2,2-dimethoxypropane (984 μl) in acetone (10 ml) was stirred for 1.5 hour at room temperature. To the solution was added sodium hydrogen carbonate (900 mg) and the mixture was stirred for 4 hours at room temperature. The precipitate was filtered off and washed with acetone. The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 5'-deoxy-5-fluoro-2',3'-O-isopropylidenecytidine (570 mg). MS 286 (MH+); mp of the picrate 169°~171° C.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:6]=1.[OH-].[Na+]>CO>[C:27]1([CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:25][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:39])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(OC)c2)CC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(CN(CCCOc2cccc(CC(=O)O)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of (3-{3-[(2,2-Diphenyl-ethyl)-(3-methoxy-benzyl)-amino]-propoxy}-phenyl)-acetic acid methyl ester (4d). (0.2 g, 0.00038 mol) in methanol (5 mL) was treated with 2N NaOH (2.5 mL) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was dissolved in EtOAc (25 mL) and water was added (10 mL), the solution acidified to pH 3 with concentrated hydrochloric acid, then extracted into EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil. Solidification of the waxy oil from pet. ether gave white solid (5d) 0.16 g in 84% yield, mp: 42.1° C. 1H NMR (CD3OD) δ 7.39 (t, 1H), 7.28 (m, 111H), 7.07 (d, 1H), 7.03 (t, 2H), 6.89 (d, 1H), 6.69 (s, 1H), 6.67 (s, 1H), 4.46 (t, 1H), 4.40 (s, 1H), 4.09 (d, 2H), 3.97 (s, 2H), 3.76 (s, 3H), 3.62 (t, 2H), 3.57 (s, 1H), 3.30 (t, 2H), 2.24 (t, 1H), 1.99 (d, 1H); 13C NMR (CD3OD) δ 175.3, 161.9, 159.6, 141.4, 137.6, 131.7, 130.6, 130.5, 130.3, 128.8, 128.7, 124.2, 123.6, 117.7, 117.0, 116.3, 116.7, 114.0, 105.2, 66.7, 59.6, 58.3, 55.9, 53.9, 41.9, 24.7. Anal. Calcd for C33H35NO4.2.5H2O: C, 71.45; H, 6.36; N, 2.52. Found: C, 71.16; H, 6.83; N, 2.43.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:19]1([CH2:18][CH2:17][CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: C(C=Cc1ccccc1OCc1ccccc1)=Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1CCCCc1ccccc1
Yield: 94.4 %

Procedure:
The whole of this 1-(2-benzyloxyphenyl)-4-phenylbutadiene was mixed with 300 ml of ethanol, and the mixture was stirred at 60° C. for 5 hours in an atmosphere of hydrogen and in the presence of 1 g of 5% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 8.34 g (yield 94.4%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1)#[N:2].C([O-])([O-])=[O:26].[K+].[K+].OO>CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:26])=[C:4]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[CH:5]=1)[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C#N)no1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C(N)=O)no1
Reaction time: 0.08 h
Yield: 38.6 %

Procedure:
To a solution of (R)-2-(4-cyano-3-(5-methylisoxazol-3-ylamino)phenylamino)-4-methylpentanamide (15 mg, 0.045 mmol) in DMSO (1 mL), K2CO3 (150 mg, 1.08 mmol) and H2O2 (50% aq., 0.800 mL) were added. After being stirred at 90 C for 5 min, the mixture was purified by HPLC to give the titled compound (6 mg). MS 346.3 (M+H); UV 203.5, 270.0, 293.4 nm
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][C:11](=[O:13])[N:10]2[CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:16][CH:9]2[CH2:8]1)=[O:6])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:38](OCC)(=[O:44])[C:39](OCC)=[O:40]>CN(C=O)C>[OH:44][C:38]1[C:39](=[O:40])[N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:6])[N:7]2[CH2:8][C@@H:9]3[CH2:16][CH2:15][C@H:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:10]3[C:11](=[O:13])[C:12]=12
Reactant: CC(C)NC(=O)N1CC(=O)N2C(CCC2c2ccccc2)C1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)c(O)c2n(c1=O)C[C@@H]1CC[C@H](c3ccccc3)N1C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of racemic (6R,8aS)-N-isopropyl-4-oxo-6-phenylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide (0.187 g, 0.620 mmol) in DMF (3 mL) at 0° C. was added a 1M solution of lithium bis(trimethylsilyl)amide in THF (1.49 mL, 1.49 mmol), followed by diethyl oxalate (0.101 mL, 0.745 mmol). The mixture was stirred for 18 h, allowing the cooling bath to warm to ambient temperature. The resultant mixture was then treated with additional lithium bis(trimethylsilyl)amide in THF (1.49 mL, 1.49 mmol) and stirred at room temperature for 6 h. The product mixture was concentrated under vacuum and the residue was partitioned between aqueous HCl and ethyl acetate. The organic extract was concentrated under vacuum. The residue was subjected to HPLC purification on C18 stationary phase eluted with water/acetonitrile/TFA mobile phase to give the title compound as a solid. HPLC RT=3.19 min, 95% at 215 nm (Method A); ES MS (M+H)=356.2; 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.24 (m, 2H) 7.22-7.16 (m, 3H) 5.12-5.02 (m, 2H) 4.80-4.74 (d, 1H) 3.84-3.74 (m, 1H) 2.38-2.28 (m, 1H) 2.06-1.98 (m, 1H) 1.74-1.66 (m, 1H) 1.42-1.34 (dd, 6H) 1.34-1.26 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:15]=1)[CH:13]=[O:14]>CO>[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH2:13][OH:14])[CH:15]=1
Reactant: O=Cc1cc(OCCCCl)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(OCCCCl)cc1CO
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Sodium borohydride (133 mg, 0.00351 moles) was added to 5-(3-chloropropoxy)-2-nitrobenzaldehyde (570 mg, 0.00234 moles) in anhydrous methanol (12 mL) at 0° C. under nitrogen. The reaction was stirred for 1.5 hours and then concentrated with a rotary evaporator. The mixture was diluted with ethyl acetate (75 mL) and washed with 30 mL each of saturated sodium bicarbonate solution, water, and brine. The organic layer was dried with anhydrous magnesium sulfate, which was removed by filtration. The filtrate was concentrated, and the resulting residue was subject to silica gel chromatography using a gradient of 100% hexanes to 60% ethyl acetate in hexanes. The fractions containing the product were collected and volatiles were removed by rotary evaporation. The resulting residue was dried overnight to yield (5-(3-chloropropoxy)-2-nitrophenyl)methanol as a pale yellow solid (yield 69%*). 1H NMR (400 MHz, CD2Cl2) δ 8.16 (d, J=9.1 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 6.92 (dd, J=9.1, 2.8 Hz, 1H), 4.98 (s, 2H), 4.24 (t, J=5.9 Hz, 2H), 3.77 (t, J=6.3 Hz, 2H), 2.28 (p**, J=6.1 Hz, 2H). 13C-NMR (100 MHz, CD2Cl2) δ 163.99, 141.21, 128.42, 114.95, 113.90, 65.80, 63.24, 41.91, 32.52 HRMS m/z: calculated for C10H12ClNO4 [M+H]+, 246.0528. found, 246.0529.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:12][NH:13][S:14]([C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20](O)=[O:21])(=[O:16])=[O:15])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:57]1[C:61]2([CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:60][NH:59]/[C:58]/1=[N:67]\[C:68]([C:70]1[C:75]([NH2:76])=[N:74][C:73]([NH2:77])=[C:72]([Cl:78])[N:71]=1)=[O:69]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1([CH2:12][NH:13][S:14]([C:17]2[CH:25]=[CH:24][CH:23]=[C:19]([C:20]([N:64]3[CH2:65][CH2:66][C:61]4([NH:57]/[C:58](=[N:67]/[C:68]([C:70]5[C:75]([NH2:76])=[N:74][C:73]([NH2:77])=[C:72]([Cl:78])[N:71]=5)=[O:69])/[NH:59][CH2:60]4)[CH2:62][CH2:63]3)=[O:21])[CH:18]=2)(=[O:15])=[O:16])[CH2:9][CH2:10][CH2:11]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Reactant: CC(C)(C)OC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)O)c2)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(1-tert-butoxycarbonyl-cyclobutylmethyl)-sulfamoyl]-benzoic acid (Int. AC) (1.37 g, 3.71 mmol) in DMF (20 ml) was treated with N-methylmorpholine (1.631 ml, 14.83 mmol) and HATU (1.41 g, 3.71 mmol) followed by 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide (1.27 g, 3.89 mmol). The reaction mixture was stirred at RT for 2 h and then partitioned between EtOAc and water. The organic portion was separated and washed with 0.5M aqueous 1,5,7-triazabicyclo[4.4.0]dec-5-ene solution, brine, dried over MgSO4 and concentrated in vacuo. Purification of the resulting oil by chromatography on silica eluting with 5-8% MeOH in iso-hexane afforded the title compound; LC-MS Rt 1.03 mins; 676.4 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12]C)=[O:11])[CH:7]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: COC(=O)/C=C/c1cc(Cl)c(F)cc1-n1cnnn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C=C/c1cc(Cl)c(F)cc1-n1cnnn1
Reaction time: 2 h
Yield: 42.1 %

Procedure:
To Intermediate 5C (5 g, 17.7 mmol) in MeOH (50 mL) and THF (25 mL) was added 10% NaOH solution (25 mL). After 2 h, the reaction was concentrated and the residue was diluted with H2O. The pH was adjusted to 2 to 3 with 1.5 N HCl and the resultant solid was filtered and washed with petroleum ether to afford 2 g of Intermediate 5. MS (ESI) m/z: 269.0 (M+H)+.