Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[CH:16]1([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][N:27]=[C:22]3[NH:21][C:20]2=[O:28])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[C:12]([O:11][C:9](=[O:10])[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([N:21]2[C:22]3=[N:27][CH:26]=[CH:25][N:24]=[C:23]3[N:19]([CH:16]3[CH2:17][CH2:18]3)[C:20]2=[O:28])[CH2:3][CH2:4]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=c1[nH]c2nccnc2n1C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2c(=O)n(C3CC3)c3nccnc32)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled solution (0° C.) of tert-butyl cis-4-hydroxycyclohexanecarbamate (0.682 g, 3.17 mmol, Biofine International), 1-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.5578 g, 3.17 mmol), and triphenylphosphine (1.100 ml, 4.75 mmol, Sigma-Aldrich Chemical Company) in THF (17.49 ml) was added diethyl azodicarboxylate, 40 wt. % solution in toluene (1.870 ml, 4.75 mmol, Chem Impex International) dropwise. After 10 mins, the round bottomed flask was removed from the ice bath and allowed to warm to room temperature to stir. Reaction was allowed to stir for 5 h and was then concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.7301 g, 1.955 mmol, 61.7% yield). LCMS showed product peak at 2.13 min (m+1=374.0). NMR showed some biproduct from DEAD reagent. Product was carried on without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5](=[O:15])[CH2:4][N:3]1[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:15][CH:5]1[CH2:4][N:3]([C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C@H:2]([CH3:1])[CH2:7][CH:6]1[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: C=CCOC(=O)N1CC(=O)C(C(=O)OC(C)(C)C)C[C@H]1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCOC(=O)N1CC(O)C(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.1 %

Procedure:
To a solution of 1-allyl 4-tert butyl (2R)-2-methyl-5-oxo-1,4-piperidinedicarboxylate (1.93 g, 6.5 mmol) in methanol (40 ml) were added acetic acid (0.45 ml, 7.9 mmol) and sodium cyanoborohydride (0.49 g, 7.8 mmol), and the mixture was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to give 1-allyl 4-tert-butyl (2R)-5-hydroxy-2-methyl-1,4-piperidinedicarboxylate (1.85 g, 95%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[CH2:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[S:21](Cl)(=[O:23])=[O:22])[CH2:10][CH3:11]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:21]([C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:12]=1[CH2:9][CH2:10][CH3:11])(=[O:22])=[O:23]
Reactant: Cc1noc(N)c1Br
Reactant: CCCc1sc2ccccc2c1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCCc1sc2ccccc2c1S(=O)(=O)Nc1onc(C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-propylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (0.68 mmoles, 0.12 g) NaH (1.7 mmoles, 6.8 mg), 2-n-propylbenzo[b]thiophene-3-sulfonyl chloride (0.82 mmoles, 0.23 g) and THF (3 ml). Recrystallization from chloroform and hexanes provided 0.19 g (67%) of a yellow crystalline solid, m.p. 136-138° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:11](C(=O)C2C=CC=CC=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
45 g (0.1 mol) of di-tert-butyl 1-(1-acetylpiperidin-4-yl)-2-benzoylhydrazine-1,2-dicarboxylate were dissolved in 1 L of tetrahydrofuran and a solution of 5.8 g (0.14 mol) of lithium hydroxide monohydrate in 1 L of water were added. The mixture was stirred at room temperature for 16 hours, the tetrahydrofuran removed in vacuo and the aqueous layer extracted several times with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to dryness, giving 32 g (84% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:17]([C:20](=O)[CH3:21])[C:18]#[N:19])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].Cl.Cl.[NH2:25][NH2:26].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:17]2[C:20]([CH3:21])=[N:25][NH:26][C:18]=2[NH2:19])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1ccc(C(C#N)C(C)=O)cc1OCCOC
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COCCOc1ccc(-c2c(C)n[nH]c2N)cc1OCCOC
Yield: 73.7 %

Procedure:
To a solution of 2-(3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.57 g, 1.9 mmol) in ethanol (5 mL) was added hydrazine dihydrochloride (0.20 g, 2.2 mmol) The resulting mixture was heated at reflux for 1 hour. It was cooled, pour into a saturated sodium bicarbonate solution (10 mL), and the mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, 5% methanol-dichloromethane) to provide 4-(3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-methyl-1H-pyrazol-5-amine (0.46 g, 1.4 mmol, 74% yield). 1H NMR (400 MHz, CDCl3): 6.96-6.92 (m, 2H), 6.87-6.84 (d, d, 1H), 4.19-4.16 (m, 4H), 3.79-3.76 (m, 4H), 3.67 (s, 2H), 3.46 (s, 3H), 3.44 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)O1>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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:29]4[CH:30]=[N:31][NH:32][CH:33]=4)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CNCCO2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CNCCO2)cc1

Procedure:
2-(4-chloro-phenyl)-2-(4-Iodo-phenyl)morpholine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine)palladium (0) as the catalyst to give the title compound. LCMS (PS-A3) Rt 6.88 min [M+H+] 340. 1H NMR (Me-d3-OD) δ 2.84-2.88 (2H, m), 3.32-3.36 (1H, m), 3.45-3.49 (1H, m), 3.69-3.72 (2H, m), 7.31 (2H, d), 7.40 (4H, apparent d), 7.56 (2H, d), 7.92 (2H, br.s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[NH2:16][OH:17]>C(O)C>[OH:17]/[N:16]=[C:12](\[NH2:13])/[C:11]1[CH:10]=[CH:9][C:8]([O:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:15][CH:14]=1
Reactant: NO
Reactant: N#Cc1ccc(Oc2ccncc2)cc1
Solvent: CCO
Product: N/C(=N\O)c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
4-(Pyridin-4-yloxy)benzonitrile (293 mg, 1.49 mmol) was dissolved in ethanol (6.0 mL) and hydroxylamine (197 mg, 5.97 mmol) was added. The mixture was refluxed for 3 hours and cooled to room temperature and then concentrated in vacuo to give the product which immediately formed white crystals and was taken to the next step without further purification. A small quantity was purified by column chromatography (Hex/EtOAc 1:8) to give the pure product (323 mg, 94%). 1H NMR (500 MHz, DMSO-d6) δ(ppm): 5.95 (2H, s), 6.24 (2H, d, J=8.0 Hz), 7.56 (2H, d, J=8.8 Hz), 7.84 (2H, d, J=8.6 Hz), 8.02 (2H, d, J=7.8 Hz), 9.81 (1H, s). 13C NMR (125 MHz, DMSO-d6) δ(ppm): 118.0 (CH), 122.1 (CH), 126.7 (CH), 132.6, 139.6 (CH), 142.8, 149.8, 177.4. MS (FAB+): 230 (MH+). HRMS for C12H11N3O2 (MH+): calculated: 230.0930; found 230.0950.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH3:14])[CH:7]=[C:6]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=O.C1(P(=[CH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:51]([O:50][C:48](/[CH:47]=[CH:1]/[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH3:14])[CH:7]=[C:6]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C/C(=O)OC(C)(C)C)ccc21

Procedure:
Using a similar procedure to that described in Example 8, part e, except starting from methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoate, and using tert-butyl (triphenylphosphoranylidene)acetate, methyl E-4-[5-[2-(t-butoxycarbonyl)vinyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate was obtained (98%) as a viscous oil; partial NMR (250 MHz, DMSO-d6): 0.81(t, 3H, CH2CH3), 1.48(s, 9H, C(CH3)3), 1.75(m, 2H, CH2CH3), 3.82(s, 3H, OCH3), 3.91(s, 3H, OCH3), 6.38(d, J=15.8 Hz, 1H, CH=CH), 7.6(d, J=15.8 Hz, 1H, CH=CH).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.FC(F)(F)S(N=[C:45]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=O)=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][N:9]([CH2:10][CH2:11][NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:45]([NH:46][C:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:53])=[N:54][C:55]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:61]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: Cn1ncc(CNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(CN(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 25.2 %

Procedure:
To a solution of N-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-N′-tritylethane-1,2-diamine (7.50 g) and triethylamine (2.86 g) in chloroform (100 ml) was added di-tert-butyl ({[(trifluoromethyl)sulfonyl]imino}-methylene)biscarbamate (11.05 g). The mixture was stirred at room temperature for 4 days. The reaction mixture was washed successively with 10% aqueous citric acid solution and brine, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give N-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-N′,N″-bis(tert-butoxycarbonyl)-N-[2-(tritylamino)ethyl]guanidine (3.00 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+]>O1CCCC1>[C:12]([O:14][C:7](=[O:9])[CH2:8][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])([CH3:15])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(CC(=O)O)CC(=O)OC(C)(C)C
Yield: 25.9 %

Procedure:
3,3 Dimethylglutaric anhydride (455 mg, 3.2 mmol) in tetrahydrofuran (THF, 5 mL) was treated with sublimed potassium t butoxide (395 mg, 3.5 mmol). After 30 min the solution was concentrated, poured into saturated NaHCO3 solution and washed with ether. The aqueous phase was acidified to pH 4 with 0.5M H3PO4 and extracted with chloroform which was dried over Na2SO4 and evaporated to afford 179 mg (26%) of the desired product as an oil. NMR (300 MHz, CDCl3, ppm), 1.13 (s,6H), 1.47 (s,9H), 2.33 (s,2H), 2.45 (s,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[CH:24]2)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:11][C:9]1[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]3)[N:25]=[CH:24]2)=[O:20]
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Product: COC(=O)c1ccc2c(cnn2Cc2cc(Cl)cc3cnn(CC(C)C)c23)c1
Yield: 40 %

Procedure:
Compound 25 was prepared following general method 3A, using compound 17 as a starting material and 1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 40%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH:9]2[CH2:11][CH2:10]2)[CH:3]=1.N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[N:6]([C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[CH:9]1[CH2:11][CH2:10]1)=[N+:16]=[N-:17]
Reactant: Nc1ccc(Cl)cc1C1CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(Cl)cc1C1CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-chloro-2-cyclopropylaniline (182 mg, 1.086 mmol) in acetic acid (15 ml) and water (15 ml) was stirred and cooled to 0° C. A solution of sodium nitrite (74.9 mg, 1.086 mmol) in water (1.4 ml) was added dropwise and the mixture was stirred under ice cooling for 10 mins. A solution of sodium azide (70.6 mg, 1.086 mmol) in water (1.5 ml) was added dropwise and was stirred under ice cooling for 1 hr and then at RT 30 mins. To the product mixture was added 2M NaOH (aq) until basic and this was extracted with EtOAc. The organic extract was washed with sat. NaHCO3(aq) and dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a dark yellow/brown oil. The crude product was used in the next step without further purification.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13](=[O:29])[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.I[CH3:31].Cl>C1COCC1>[CH3:11][O:12][C:13](=[O:29])[CH:14]([CH3:31])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]1
Reactant: CI
Reactant: COC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.42 h

Procedure:
To a precooled (−78° C.) solution of 1.0M sodium bis(trimethylsilyl)amide in THF (13.1 mL, 13.1 mmol) was added dropwise under a nitrogen atmosphere a solution of tert-butyl 4-(3-methoxy-3-oxopropyl)piperidine-1-carboxylate (1.78 g, 6.56 mmol) in 11 mL of THF. After stirring for an additional 25 min, neat iodomethane (1.23 mL, 19.7 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for two more h. The reaction mixture was then poured into 1N HCl solution and the resulting mixture was extracted twice with ether. The combined ethereal layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 40% ethyl acetate/hexanes) gave tert-butyl 4-(3-methoxy-2-methyl-3-oxopropyl)piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[N:29]=[C:28]([F:30])[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>C1COCC1>[F:30][C:28]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[C:21]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])[N:29]=1
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1ccc(F)nc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)nc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To solution of 2-fluoro-4-iodoaniline (0.82 g, 3.46 mmol) in THF (10 mL) at −78° C. LiHMDS (6.00 mL, 6.60 mmol) was added. After stirring for 15 min, 2,6-difluoronicotinic acid (0.50 g, 3.14 mmol) was added to the mixture. The mixture was allowed to warm to room temperature until completion. The mixture was washed with NaOH (1 N) and extracted with ether. The aqueous layer was acidified with concentrated HCl and back-extracted with ethyl acetate. The organic layer was concentrated to afford product. Second crop of product was obtained by purifying the THF/ether layer with silica gel chromatography. LC/MS [Method B: rt. 9.09 min, m/z 377 (M+1)].
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.CC(C)=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[O:6]=[C:2]([CH3:1])[CH2:3][C:4]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:5]
Reactant: C1CCNC1
Reactant: C=C1CC(=O)O1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N1CCCC1
Yield: 97.9 %

Procedure:
9 ml (0.05 mol) of diketene-acetone adduct and a solution of 4.2 ml (0.05 mol) of pyrrolidine in 20 ml of toluene were treated as described in preparation 7. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (EtOAc/MeOH 0%→1%) yielding 7.6 g of the title compound as a dark oil.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](OC)=[O:12])(=[O:7])=[O:6]>CO>[NH:1]([C:11]([C:10]1[CH:9]=[C:8]([S:5]([NH:4][CH3:3])(=[O:7])=[O:6])[CH:17]=[CH:16][CH:15]=1)=[O:12])[NH2:2]
Reactant: CNS(=O)(=O)c1cccc(C(=O)OC)c1
Reactant: NN
Solvent: CO
Product: CNS(=O)(=O)c1cccc(C(=O)NN)c1
Temperature: 65 °C
Yield: 74.3 %

Procedure:
Hydrazine (43.3 mg, 1.352 mmol) was added to the methyl 3-(N-methylsulfamoyl)benzoate (155 mg, 0.676 mmol) in methanol and refluxed for 12 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography to yield 3-(hydrazinecarbonyl)-N-methylbenzenesulfonamide (120 mg, 0.502 mmol, 74.3% yield). 1H NMR (CDCl3, 400 MHz): δ 8.25 (m, 1H), 8.01 (m, 2H), 7.64 (m, 2H), 4.63 (m, 1H), 4.17 (m, 2H), 2.69 (d, 3H, J=5.2 Hz). ESI-MS: 230.0 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[Mg].[C:10]1(=[O:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>C(OCC)C>[Br:8][C:4]1[CH:3]=[C:2]([C:10]2([OH:20])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=C1CCCc2ccccc21
Agent: [Mg]
Solvent: CCOCC
Product: OC1(c2cccc(Br)c2)CCCc2ccccc21

Procedure:
To a solution of 1 g (4.2 mmol) 1,3-dibromobenzene in 10 mL diethyl ether was added 0.096 g (4 mmol) magnesium metal turnings. This mixture was stirred until all of the magnesium was consumed, at which time 0.29 g (2 mmol) 1-tetralone was added dropwise in 2 mL diethyl ether. The reaction was then heated to reflux for 30 min, after which the cooled reaction was quenched with a 10% HCl solution and extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate, filtered, and the solvent removed in vacuo to afford the crude product which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[C:12]1([CH3:19])[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>O>[CH3:19][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[O:18][CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccccc1O
Reactant: O=[N+]([O-])c1cccnc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1OCc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 10.4 g (48 mmol) of 2-bromomethyl-3-nitropyridine (Example 3.c), 4.8 g (44 mmol) of o-cresol, 10 g (72 mmol) of K2CO3 and 50 ml of dimethylformamide were stirred for 3 days at room temperature (approximately 25° C.). The mixture was subsequently diluted with water and extracted repeatedly using tert-butyl methyl ether. The organic phases were combined, washed and dried, and the solvent was removed under reduced pressure. The residue obtained was purified by column chromatography (cyclohexane/ethyl acetate). This gave 5 g (47%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CCN(CC)CC.Br[CH2:17][C:18](OCC)=[O:19]>CN(C=O)C>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][CH2:17][C:18]1=[O:19]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CNc2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
To a solution of o-phenylenediamine (1.08 g, 10 mmol) in DMF (50 mL) was added Et3N (2.9 mL, 21 mmol), and ethyl 2-bromoacetate (1.2 mL, 11 mmol). The reaction mixture was stirred at room temperature for 16 h, then at 80° C. for 3 h. The DMF was evaporated under reduced pressure and the reaction mixture partitioned between H2O and EtOAc. The EtOAc layer was washed with sat. NaHCO3, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue purified by flash chromatography eluting with petroleum ether/EtOAc (4/1) to give 3,4-dihydroquinoxalin-2(1H)-one (560 mg, 38%) as yellow solid. LC-MS (ES-API); rt 7.40 min; m/z calculated for C8H8N2O [M+H]+ 149.0, found 149.0.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[CH3:18][O:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][O:25][C:26](ON=C(C(OCC)=O)C(OCC)=O)=[O:27])=[CH:22][CH:21]=1>O.C(O)(C)(C)C>[CH3:18][O:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][O:25][C:26]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:27])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=NOC(=O)OCc1ccc(OC)cc1)C(=O)OCC
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(COC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
L-Phenylalanine (330 mg.) and sodium bicarbonate (202 mg.) were dissolved in water (10 ml.) under heating and allowed to stand. A solution of diethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate (1.0 g.) in tert-butyl alcohol (10 ml.) was added to the solution with stirring at room temperature and water (10 ml.) was added thereto. The mixture was then stirred for 2 hours at room temperature. The reaction mixture was brought to pH 9 by adding water (20 ml.) and a saturated sodium bicarbonate aqueous solution (10 ml.), and water (10 ml.) was added thereto. The resulting mixture was then washed twice with ethyl acetate (20 ml.). The aqueous layer was adjusted to pH 7 with a 10% citric acid aqueous solution, washed twice with ethyl acetate (30 ml.), adjusted to pH 3.5 with a 10% citric acid aqueous solution and extracted three times with ethyl acetate (30 ml.). The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give N-(4-methoxybenzyloxycarbonyl)-L-phenylalanine (410 mg.), oil.