Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][C:31]1[N:35]([C@@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)[C:34]2[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=[CH:51][C:33]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:49]3[CH:50]=[CH:51][C:33]4[N:32]=[C:31]([CH3:30])[N:35]([C@@H:36]5[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37]5)[C:34]=4[CH:48]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
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: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n([C@@H]5CCN(C(=O)OC(C)(C)C)C5)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (53 mg, 0.11 mmol), (R)-tert-butyl 3-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate (92 mg, 0.21 mmol), then Pd(PPh3)4 (23 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (2 mL) and to this was added 2M aqueous K2CO3 (0.2 mL, 0.4 mmol). The vial was sealed then heated to 100° C. for 16 hours and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-10% MeOH/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C39H46ClN4O5S: 717.3 (M+H+); Found: 717.1 (M+H+).
Reaction SMILES: [NH3:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Zn+2:7].[S:8](=[O:12])(=[O:11])([OH:10])[OH:9]>>[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Zn+2:7].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[NH4+:1].[NH4+:1]
Reactant: O=S(=O)(O)O
Reactant: N
Agent: O=S(=O)([O-])[O-]
Agent: [Zn+2]
Product: [NH4+]

Procedure:
A more preferred process for the direct reduction of ammonia from a waste stream includes reacting an aqueous ammonia stream with a zinc sulfate and sulfuric acid solution to produce a spent regeneration solution of zinc sulfate and ammonium sulfate and treating such solution to cause crystallization of zinc ammonium sulfate hydrate. Preferably, the crystallization is caused by concentrating the stream by removing water. Typically this is accomplished by evaporation by conventional heating, vacuum or a combination of the two. The crystallization may also be caused by reducing the temperature of the zinc sulfate/ammonium sulfate solution or by a combination of concentration and cooling.
Reaction SMILES: [Na].[CH3:2][CH:3]([SH:5])[CH3:4].[N+:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Cl)([O-:8])=[O:7]>CO>[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][S:5][CH:3]([CH3:4])[CH3:2])[CH:10]=1)([O-:8])=[O:7]
Reactant: CC(C)S
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [Na]
Solvent: CO
Product: CC(C)SCc1cccc([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of sodium methoxyde (15.5 mL, 25 wt % in methanol) was diluted with methanol (85 mL) and treated with 2-propanethiol (6.3 mL) at room temperature for 60 minutes, cooled to −15° C., treated with 3-nitrobenzylchloride (10 g) in 3 portions, kept for 2 hours at −15° C., then the temperature was increased to room temperature. The reaction mixture was concentrated in vacuo, treated with diethyl ether (300 mL), washed with water (2×100 mL) and brine (100 mL), dried with sodium sulfate and evaporated to dryness. The title compound (12.3 g) was thus obtained and used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12][C:13]([CH3:15])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:13]([CH3:15])[CH3:12])=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.2 %

Procedure:
To a stirring solution of 8.0 g (49.6 mmol) of 4-trifluoromethylaniline in 80 mL of 1,2-dichloroethane at RT is added 4.0 mL (54.6 mmol, 1.1 equiv) of acetone, 5 drops of glacial acetic acid, and 13.7 g (64.5 mmol, 1.3 equiv) of sodium triacetoxyborohydride. The solution is stirred at RT for 72 h, cooled to 0° C., and then quenched by addition of H2O (200 mL). The organic layer is separated, washed with brine (1×200 mL), dried (MgSO4) and the solvents removed in vacuo to afford 10.1 g of crude (4-trifluoromethyl-phenyl)-isopropyl amine. A solution of 2.0 g (9.5 mmol) of this material in 50 mL of DCM is cooled to 0° C. and 1.5 mL (10.8 mmol, 1.5 equiv) of triethylamine is added, followed by dropwise addition of 0.90 mL (10.3 mmol, 1.05 equiv) of bromoacetyl bromide. The solution is stirred at RT for 4 h and then poured into Et2O (200 mL). The organics were washed with 1N HCl (2×50 mL), brine (1×50 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane 1/10 as eluent afforded 2.09 g of the title compound: 1HNMR (CDCl3, 300 MHz) δ7.78 (d, 2H, J=8.5), 7.40 (d, 2H, J=8.5), 5.01 (m, 1H), 3.51 (s, 2H), 1.08 (d, 6H, J=6.9).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Br:8].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:8][C:7]1[CH:6]=[N:5][N:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3](=[O:9])[C:2]=1[Br:1]
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]ncc(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc(Br)c(Br)c1=O
Yield: 110.8 %

Procedure:
4,5-Dibromopyridazin-3(2H)-one (5.0 g, 19.7 mmol) in N,N-dimethylformamide (50 mL) was stirred with ethyl bromoacetate (3.28 g, 29.5 mmol) and potassium carbonate (4.08 g, 29.5 mmol) at 80° C. for 1 hour and 40 minutes. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride three times and with saturated aqueous sodium chloride once, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (7.42 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:27]3[CH2:32][C@H:31]([CH3:33])[C@@H:30]([OH:34])[C@H:29]([NH:35]C(=O)OC(C)(C)C)[CH2:28]3)=[C:20]3[CH2:26][CH2:25][CH2:24][C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:43].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][C@H:29]1[C@H:30]([OH:34])[C@@H:31]([CH3:33])[CH2:32][N:27]([C:19]2[C:18]([NH:17][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:43])=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[N:14]=3)=[O:16])=[CH:23][N:22]=[C:21]3[CH2:24][CH2:25][CH2:26][C:20]=23)[CH2:28]1
Reactant: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
A mixture of tert-butyl {(3R,4R,5S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate (6.0 mg, 0.010 mmol), DCM (0.09 mL) and TFA (0.085 mL, 1.1 mmol) was stirred at room temperature for 20 min. After concentration, the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a white powder (4.6 mg, 92%). LCMS calc. for C26H27F3N5O2 (M+H)+: m/z=498.2. Found: 498.3.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][O:24][CH3:25]>CN(C=O)C>[CH3:25][O:24][CH2:23][CH2:22][CH2:21][NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: COCCCBr
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccccc2)c1NCCCOC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
Ethyl 5-amino-1-phenyl-1H-pyrazole-4-carboxylate (1.26 g) was dissolved in DMF (10 ml), NaH (0.25 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. 1-Bromo-3-methoxypropane (0.83 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:10-4:6) was concentrated under reduced pressure to give the object compound (1.1 g).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=[O:11])[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]1=O)C.Cl.[NH2:21][OH:22]>CO>[OH:22][N:21]=[C:6]1[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:10]2[O:11][N:2]=[CH:4][C:5]1=2
Reactant: NO
Reactant: CN(C)C=C1C(=O)CN(C(=O)OC(C)(C)C)CC1=O
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(=NO)c2cnoc2C1
Temperature: 20 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
12 mg (44.7 mmoles) of 1,1-dimethylethyl 4-[(dimethylamino)methylene]-3,5-dioxo-1-piperidinecarboxylate with 7.82 mg (112 mmoles) of hydroxylamine hydrochloride is introduced into 144 ml of methanol in a flask, the reaction medium is then agitated for 16 hours at 20° C. and then the solvent is evaporated off under reduced pressure. The mixture is poured into 10 ml of water followed by extracting with ethyl acetate (3×10 ml). The phases organic obtained are collected, dried over Na2SO4, filtered then the solvent is evaporated off under reduced pressure. 3.93 g of 1,1-dimethylethyl 4,7-dihydro-4-(hydroxyimino)-isoxazolo[5,4-c]pyridine-6(5H)-carboxylate, of molecular formula C11H15N3O4 is obtained (M=253.26 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([NH:20]C(=O)C4C=CC=CC=4)=[S:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.I[CH3:30]>CC(C)=O>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([S:20][CH3:30])=[NH:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CI
Reactant: CN1CC=C(c2c[nH]c3ccc(NC(=S)NC(=O)c4ccccc4)cc23)CC1
Solvent: CC(C)=O
Product: CSC(=N)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Yield: 19.1 %

Procedure:
A solution of compound 64 (0.2 g, 0.698 mmol) in acetone (10 mL) was treated with iodomethane (0.26 mL, 4.189 mmol) at room temperature and the resulting solution was refluxed for over night (14 h). The reaction was brought to room temperature and solvent was evaporated. The crude was diluted with sat. NaHCO3 solution (10 mL) and compound was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (10 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 74 (0.04 g, 19%) as a solid. mp 260-162° C.; 1H NMR (DMSO-d6) δ 2.29 (s, 3H), 2.33 (s, 3H), 2.50-2.59 (m, 4H), 3.06 (brs, 2H), 6.01 (s, 1H), 6.64 (brs, 1H), 7.22-7.30 (m, 3H), 10.91 (s, 1H); ESI-MS m/z (%): 301 (M+, 36), 285 (55), 258 (66), 242 (100).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4](OCC)=O.BrC[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:25]Br)[CH:21]=2)[CH:16]=1.Cl>C(O)C>[C:2]([CH2:3][CH2:25][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([CH2:4][CH2:3][C:2]([OH:10])=[O:9])[CH:16]=2)[CH:21]=1)([OH:10])=[O:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1ccc2cc(CBr)ccc2c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCc1ccc2cc(CCC(=O)O)ccc2c1
Temperature: 0 °C
Yield: 265.2 %

Procedure:
First, 228 mg of metallic sodium was dissolved in 10 ml of absolute ethanol, and after adding 3.02 g of diethyl malenate, the mixture was refluxed for 5 minutes and cooled. After adding 504 mg of diethyl malonate and then 1.41 g of 2,6-bis(bromomethyl)naphthalene at once, the mixture was refluxed 2 hours. After cooling and adding 20 ml of ice water, the reaction mixture was adjusted to pH 6.0 with 1N hydrochloric acid and extracted twice with 100 ml of benzene. The extracts were combined, washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered, and evaporated under a reduced pressure. To the resulting pale yellow oil were added 15 ml of acetic acid and 15 ml of concentrated hydrochloric acid, and the mixture was refluxed for 23 hours, cooled and concentrated. After adding 5 ml of water, the resulting crystal was collected by filtration, washed with water and dried in air and then under a reduced pressure to obtain 1.136 g of the title compound as colorless crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:18][N:19](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[C:18]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Temperature: 150 °C
Yield: 88.9 %

Procedure:
tert-Butyl [2-(4-bromophenyl)ethyl]carbamate (0.52 g, 1.73 mmol) was dissolved in dry DMF (17 mL) under nitrogen atmosphere. Zinc cyanide (0.41 g, 3.46 mmol) and tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol) was added. The reaction mixture was heated in a microwave reactor at 150° C. for 20 mins. The procedure was repeated two more times with equal amount of starting material and the resulting three mixtures were combined. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and water, dried with Na2SO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system (40+M column, isocratic run DCM/MeOH (99.5:0.5, 960 mL), gradient run DCM/MeOH (99.5:0.5-92:8, 240 mL), isocratic run DCM/MeOH (92:8, 720 mL)) affording the title compound (1.14 g, 88.9%). 1H NMR (500 MHz, CDCl3): δ 1.44 (s, 9H), 2.88 (t, 2H), 3.40 (q, 2H), 4.58 (bs, 1H), 7.32 (d, 2H), 7.61 (d, 2H); Mass Spectrum: M+H+ 247.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B(O)O)[CH:29]=2)[CH:24]=[N:23]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl.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>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[N:23][N:22]3[CH3:21])=[CH:26][CH:27]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: Cn1ncc2ccc(B(O)O)cc21
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccc4cnn(C)c4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 29.5 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 180.0 mg, 0.61 mmol) in dioxane (1 mL) was added 1-methyl-1H-indazol-6-ylboronic acid (276.0 mg, 1.57 mmol), K3PO4 (391.2 mg, 1.85 mmol), and Pd(PPh3)4 (35.0 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 20 min at 90° C., the reaction mixture was dissolved in dichloromethane (30 mL), washed with water (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.05%-0.2% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-6-yl)quinoxaline-6-carboxylate as a light yellow solid (70 mg, 29%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[CH2:14][OH:15].C([Sn](CCCC)=O)CCC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1(C)C=CC=CC=1>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[C@H:3]1[CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Reactant: CS(=O)(=O)Cl
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1COS(C)(=O)=O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A suspension of (2R,3S)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.04 g, 23.20 mmol) and dibutyloxostannane (7.07 g, 27.84 mmol) in toluene (50 mL) is refluxed in a 130° C. oil bath for 2 h. The mixture is cooled to 0° C. in an ice bath for 30 min and treated with methanesulfonyl chloride (2.15 mL, 27.84 mmol) at once. The reaction is stirred for 30 min at 0° C. and then the mixture allowed to gradually warm to ambient temperature overnight. The solution is concentrated and the resulting residue purified by medium pressure liquid chromatography, eluting with ethyl acetate:hexane (8:2). Fractions containing pure product are combined and concentrated to give 6.14 g (96%) of dense oil as the title compound. LC-ES/MS m/z 318.2 [M+Na]+, TR=2.34 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.I[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCI
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCNc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
A solution of methyl p-aminobenzoate (0.45 g, 3.0 mmole) in 6 mL tetrahydrofuran (THF) was cooled to −78° C. and treated dropwise with 2.5 M n-butyllithium solution (1.32 mL). The reaction mixture was allowed to warm to 0° C. over a one hour period. Iodopentane (0.78 mL) was introduced at −40° C. and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 50 mL of a saturated aqueous sodium bicarbonate solution and extracted with three portions of 50 mL of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, giving a brown oil. The product was purified by flash chromatography (SiO2, 10%-20% ethyl acetate/hexanes) to provide 140 mg (23%) of methyl 4-pentylaminobenzoate (43) as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[S:7][C:6]([CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[C:2]([C:3]1[S:7][C:6]([CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:5][C:4]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:1])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(Cc1cc(-c2ccccc2)c(C(O)c2ccccc2)s1)C(=O)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CN(Cc1cc(-c2ccccc2)c(C(=O)c2ccccc2)s1)C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To a solution of tert-butyl ({5-[hydroxy(phenyl)methyl]-4-phenyl-2-thienyl}methyl)methylcarbamate (385 mg) in toluene (5 mL) was added manganese dioxide (1.1 g) and the mixture was stirred at 120° C. for 8 hr. The reaction mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a pale-yellow oil (yield 236 mg, yield 62%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:18]2[CH:9]1[C:10]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:11]1[C:16]([CH2:17]2)=[CH:15][CH:14]=[C:13]([OH:19])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:41][OH:42]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[C@H:18]([O:42][CH3:41])[CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[C:10]1([CH2:20][CH3:21])[CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CCC1(CC)c2cc(O)ccc2CC2C1N2C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a slurry of 7,7-diethyl-5-hydroxy-1a,2,7,7a-tetrahydro-1-aza-cyclopropa[b]naphthalene-1-carboxylic acid tert-butyl ester (170.0 g, 535.6 mmol) and methanol (1700 mL) was added pyridinium p-toluenesulfonate (13.4 g, 53.6 mmol) and the reaction mixture was stirred at 40° C. for 4 h. The volume was reduced by rotary evaporation to ˜300 mL resulting in a thick white slurry. The product was isolated by filtration; the filter cake was washed with cold methanol (50 mL) and dried in air for 3 h to yield the title compound (150 g). The filtrate was reduced to ˜50 mL and stirred at 0° C. for 2 h, filtered, and dried to yield additional product (25 g). *In this and the following examples, the prefix trans refers to a mixture of the (2S),(2S) diastereomer and the (2R),(2R) diastereomer.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@H:5]([CH:24]([CH3:26])[CH3:25])[NH:6][C:7](=[O:23])[C@H:8]([CH3:22])[NH:9][C:10](=[O:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)C>C(Cl)(Cl)Cl.CO>[N+:18]([C:14]1[CH:13]=[C:12]([CH2:11][C:10]([NH:9][C@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:27])=[O:3])[CH:24]([CH3:25])[CH3:26])=[O:23])[CH3:22])=[O:21])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O

Procedure:
Following General Procedure AF and using N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl ester (from Example 143 above), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.05 in 9:1 CHCl3/MeOH).