Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[N:26]1[CH2:29][CH:28]([C:30](O)=[O:31])[CH2:27]1.CCN=C=N[CH2:38][CH2:39][CH2:40][N:41](C)C.Cl.Cl.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[CH:40]1([NH:41][C:30]([CH:28]2[CH2:27][N:26]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH2:12][C:11]([C:17]5[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=5)([C:13]([F:14])([F:16])[F:15])[O:10][N:9]=4)=[CH:7][C:2]=3[Cl:1])[CH2:29]2)=[O:31])[CH2:38][CH2:39]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Agent: Cl
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
To a stirred solution of 1-{2-chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 14, 0.1 g, 0.190 mmol) in dry DMF (3 mL) was added EDCl.HCl (0.055 g, 0.280 mmol), DIPEA (0.049 g, 0.380 mmol) and cyclopropyl amine (0.011 g, 0.190 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (10 mL), extracted with EtOAc (10 mL). Organic layer was washed with saturated solution of lithium chloride (3×20 mL), water (2×20 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.8% methanol in DCM to afford sticky mass, which was crystallized by chloroform:pentane (1:9) to afford off white solid (0.020 g, 20%). 1H-NMR (400 MHz, CDCl3) δ: 0.50-0.53 (m, 2H), 0.77-0.82 (m, 2H), 2.72-2.76 (m, 1H), 3.26-3.30 (m, 1H), 3.60 (d, 1H, J=17.12 Hz), 4.00 (d, 1H, J=17 Hz), 4.23-4.33 (m, 4H), 5.72 (bs, 1H), 6.47 (d, 1H, J=8.6 Hz), 7.40 (dd, 1H, J1=8.44 Hz, J2=1.88 Hz), 7.46 (d, 1H, J=1.8 Hz), 7.62 (s, 2H); LC-MS (m/z): [M−H] 563.50.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:41][C:42]1[CH:43]=[C:44]([NH2:54])[CH:45]=[N:46][C:47]=1[O:48][CH2:49][C:50]([F:53])([F:52])[F:51]>CN(C=O)C>[Br:41][C:42]1[CH:43]=[C:44]([NH:54][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[CH:45]=[N:46][C:47]=1[O:48][CH2:49][C:50]([F:51])([F:52])[F:53]
Reactant: Nc1cnc(OCC(F)(F)F)c(Br)c1
Reactant: O=C(O)c1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of nicotinic acid (454 mg, 3.69 mmol) in DMF (33 mL) were added successively TBTU (1.18 g, 3.69 mmol), N,N-diisopropylethylamine (3.16 mL, 18.4 mmol) and 5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-amine (1 g, 3.69 mmol). The brown mixture was stirred under argon for 3 h at room temperature. After evaporation of DMF, the brown oil was partitioned between ethyl acetate (50 mL) and 1M NaOH (30 mL). The aqueous layers were back-extracted with ethyl acetate (1×50 mL). The organic parts were washed with water (2×25 mL) and brine (25 mL), then dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 100% ethyl acetate in heptane) to deliver the desired product as a white solid (580 mg; 42%); MS (EI): 376.1; 378.0 (M+H).
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([F:25])[C:15]=1C(O)=O>CN(C)C1C=CN=CC=1.CC(O)(C)C>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([F:25])[C:15]=1[C:1]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1c(F)cc(F)c(F)c1F
Temperature: 40 °C
Yield: 56.3 %

Procedure:
Di-tert-butyl carbonate (3.63 g, 16.7 mmol) was added to a mixture of 2,3,4,6-tetrafluorobenzoic acid (1.60 g, 8.88 mmol), 4-dimethylaminopyridine (102 mg, 0.83 mmol) in tBuOH (20 mL) and heated at 40° C. for 16 hours. The reaction mixture was quenched with aqueous 1M HCl and extracted with EtOAc. Combined organics were washed with aqueous 1M NaOH, then brine and evaporated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 50% EtOAc in heptane to afford the title compound as a colourless oil (1.25 g, 59% yield):
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([CH2:15][NH2:16])[OH:14]>>[C:1]([N:8]1[CH2:11][CH:10]([NH:16][CH2:15][CH2:13][OH:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: NCCO
Product: CC(C)(C)OC(=O)N1CC(NCCO)C1
Yield: 62.3 %

Procedure:
N-Boc-3-azetidinone (1.0 g, 5.84 mmol) was treated with ethanolamine following Procedure 1-Method A to yield N-(N-Boc-azetidin-3-yl)-2-amino-ethanol (0.75 g, 3.46 mmol, 62.3% yield): MS m/e [M+H]+ calcd 217.1, found 217.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]#[C:6][C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)[CH3:2].[C:17]([O:21][C:22]([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[NH:42][CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[N:42]([C:6]([C:7]3[CH:15]=[CH:14][C:10]5[O:11][CH2:12][O:13][C:9]=5[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C#Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1ccc2c(c1)OCO2)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 39 %

Procedure:
The title compound was synthesized from benzo[1,3]dioxol-5-yl-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (c1), in 39% yield as an E/Z mixture. 1H NMR (CDCl3) δ7.32 (d, 1H, J=7.6 Hz), 7.10–7.04 (m, 2H), 7.00–6.90 (m, 2H), 6.85–6.71 (m, 4H), 6.56–6.49 (m, 1H), 6.10 (s, 0.6H), 6.04 (s, 0.4H), 6.03 (s, 0.8H), 6.00 (s, 1.2H), 4.40–4.35 (m, 2H), 4.13 (q, 0.8H, J=7.1 Hz), 3.98 (q, 1.2H, J=7.1 Hz), 3.76 (t, 2H, J=5.9 Hz), 3.20 (t, 2H, 6.8 Hz), 2.73 (t, 2H, 6.7 Hz), 1.95–1.89 (m, 2H), 1.519 (s, 5.4H), 1.516 (s, 3.6 H), 1.22 (t, 1.2H, J=7.1 Hz), 1.01 (t, 1.8H, J=7.1 Hz). Mass Spectrum (LCMS, ESI) calculated for C30H29N3O5 512.3 (M-Boc +1); found 512.3.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:21][CH:22]=[CH2:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:41](Br)[CH:42]=[CH2:43]>CN(C=O)C.O>[CH2:43]([N:24]([CH:20]([CH2:21][CH:22]=[CH2:23])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH:42]=[CH2:41]
Reactant: C=CCC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NS(=O)(=O)c1ccc(C)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CC=C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of N-(1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl)-4-methylbenzenesulfonamide (D9) (13 g, 26.33 mmol) in DMF (80 ml), Cs2CO3 (12.86 g, 39.49 mmol) and allyl bromide (1.8 ml, 21.06 mmol) were added and the mixture was stirred at RT for 4 hrs. The reaction mixture was diluted with water (40 ml) and extracted with EtOAc (3×60 ml). The combined organic phases were evaporated and the resulting residue was was purified by Biotage SNAP-Si (100 g) cartridge eluting with a mixture cycloexane/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D10) (10.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH2:31][C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 83.1 %

Procedure:
To a solution of 1.00 g (2.985 mmol) of the product of Example 3 in 7.5 mL of DMF was added 0.514 g (3.134 mmol) of 3-picolyl chloride hydrochloride and 1.30 g (9.50 mmol) of potassium carbonate. The rection was stirred for 18 h at room temre and then an additional 0.051 g of 3-picolyl chloride hydrochloride and 0.130 g of potassium carbonate was added and the reaction was steeed for 18 h at room temperature. The reaction was then diluted with water and extracted with ether. The combined organic layers were extrated with 6N HCl solution and the aqueous acid layer was then basified with 6N NaOH solution and then extracted with ether. The resulting ether layer was dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ether provided 1.058 g (83%) of the desired product as a white solid. Electrospray Mass Spec: 427.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:21]4[CH2:22][CH2:23][O:24][CH2:25][C:20]4=[N:19][C:14]=3[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:21]4[CH2:22][CH2:23][O:24][CH2:25][C:20]4=[N:19][C:14]=3[C:15]([NH2:38])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3c(c2)ncc2nc4n(c23)CCOC4)cc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCOC1
Temperature: 25 °C

Procedure:
A 1-liter round bottom flask was charged with 3-(benzyloxy)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (5.0 g, 15.1 millimoles (mmol)) and dichloromethane (200 mL). To this solution was slowly added in small portions 3-chloroperoxybenzoic acid (mCPBA) (5.2 g of 50% pure material, 15.1 mmol, 1.0 eq). The reaction was maintained at room temperature for 3 hours. Concentrated ammonium hydroxide (100 mL) was added followed by p-toluenesulfonyl chloride (3.2 g, 16.6 mmol, 1.1 eq) in small portions. The reaction was maintained at room temperature overnight. The reaction was quenched with water (200 mL) and stirred for an additional hour. The aqueous layer was separated and extracted with dichloromethane (3×50 mL). The combined organic fractions were concentrated to provide 3-(benzyloxy)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as an off-white solid. A small amount of product was recrystallized from acetonitrile and carried on to the next step.
Reaction SMILES: Br[C:2]1[C:3]([CH2:14][P:15]([OH:18])([OH:17])=[O:16])=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[CH:7]=1>[Pd].O>[P:15]([CH2:14][C:3]1[CH:2]=[CH:7][N:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=[C:5]2[N:4]=1)([OH:17])([OH:18])=[O:16]
Reactant: O=C(O)c1cn2cc(Br)c(CP(=O)(O)O)nc2n1
Agent: [Pd]
Solvent: O
Product: O=C(O)c1cn2ccc(CP(=O)(O)O)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-7-phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid 18 (15 mg) was introduced in a 250 mL Parr bottle with 0.5N NAOH (1 mL), water (15 mL) and Pd on Carbon (5%, 20 mg). The bottle was evacuated, filled with hydrogen and shaken for one hour at room temperature. The product was purified by passing through a strongly basic ion-exchange column. The product 19 was eluted with 1N HCl.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+]=[N-].[H][H]>[Pd].C1COCC1>[NH2:1][CH2:4][C@@H:5]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](CN)C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate (2.1 g, 7.04 mmol, 1.0 equiv) and Pd/C (10%, 200 mg) were added to a flask. THF (30 mL) was added and the flask fitted with a gas inlet connected to a balloon of hydrogen gas. The flask was evacuated and back-filled with H2 from the balloon. This was repeated twice and the reaction mixture stirred for 17 h at ambient temperature. Analysis by LC/MS showed complete conversion to the desired amine. The catalyst was removed by filtration through a pad of Celite and the mixture evaporated. This provided 1.82 g (94%) of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:11][CH3:12])[C:5]([F:10])=[C:6]([O:8][CH3:9])[CH:7]=1.C[OH:14]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:11]([CH3:12])=[O:14])[C:5]([F:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(SC)c1F
Reactant: CO
Solvent: O
Product: COc1cc(Cl)cc(S(C)=O)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 5-chloro-2-fluoro-1-methoxy-3-(methylsulfanyl)benzene (576.1 mg), MeOH (20 mL) and water (4.0 mL) was added NaIO4 (894 mg) at 0° C. The mixture was stirred at room temperature for 1 day. The mixture was concentrated. The residue was diluted with water. The precipitate was filtered off, and the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (501 mg).
Reaction SMILES: ON1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2N=N1.C(Cl)CCl.C(OCC)(=O)C.C[N:22](C)[CH:23]=[O:24]>>[C:23]([NH2:22])(=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of 175 mg (1.15 mmol) of 3-hydroxy-2-1methylbenzoic acid and 203 mg (1.5 mmol) of N-hydroxybenzotriazole in 6 mL of anhydrous N,N-dimethylformamide at 0° C., was added 220 mg (1.15 mmol) of EDC. After 20 minutes of activation at 0° C. and 1 hour at room temperature, 392 mg (1.0 mmol) of 2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine was added. After 15 hours at room temperature, ethyl acetate was added, washed with 5% citric acid, saturated sodium bicarbonate, brine, dried, filtered and concentrated to afford 590 mg of crude material. This was chromatographed on silica gel using 50-80% ethyl acetate/methylene chloride as eluent to afford 255 mg of pure benzamide, N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl, m/e=526(M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][C:27]#[N:28])[CH:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH4+].[Cl-].[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C>[N:28]1[NH:35][N:36]=[N:37][C:27]=1[CH2:26][CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])=[CH:24][CH:23]=2)[CH:19]=[C:20]1[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCc1nn[nH]n1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-cyano-ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 0.12 mmol) in anhydrous DMF (2.6 mL) was added NH4Cl (230 mg, 4.3 mmol) and NaN3(280 mg, 4.3 mmol). The reaction mixture was stirred for 30 min at 110° C. in the microwave, filtrated, and purified by preparative HPLC. The solid residue was dissolved in CDCl3(3 mL) and briefly (2 to 4 min) exposed to daylight, which initiated a color change (purple). After 2 h of stirring open to the atmosphere at room temperature, the solvent was removed and the residue was purified by preparative HPLC to give N-(1-(2-(2H-tetrazol-5-yl)ethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 473.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd]>[CH3:19][C:17]1[N:18]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[O:15][C:16]=1[CH3:20]
Reactant: Cc1nc(C2CCN(Cc3ccccc3)CC2)oc1C
Reactant: [H][H]
Agent: [Pd]
Product: Cc1nc(C2CCNCC2)oc1C
Yield: 111.5 %

Procedure:
1.48 g 1-benzyl-4-(4,5-dimethyl-oxazol-2-yl)-piperidine were stirred at RT for 28 h under 50 psi hydrogen atmosphere and 150 mg palladium charcoal. The mixture was filtered and evaporated to give 1.1 g of the desired product.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:19]=1.[N+:26]([O-])([OH:28])=[O:27]>>[F:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N+:26]([O-:28])=[O:27])=[CH:9][C:8]=1[C:14]1[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:19]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(F)cc2F)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To 85 ml of concentrated sulfuric acid was added 7.0 g of 3-(2,4-difluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-10) at 5° C. Furthermore, 9 ml of 70% nitric acid was added, and the mixture was stirred at 5° to 10° C. for 8 hours. After completion of the reaction, the reaction mixture was added to ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 7.76 g (yield, 96%) of 3-(2,4-difluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-16; m.p., 93.2° C.).
Reaction SMILES: [N:1]([C:4]1[C:5]([NH:11]C(=O)C(C)(C)C)=[N:6][CH:7]=[C:8]([F:10])[CH:9]=1)=[N+:2]=[N-:3].[ClH:18]>>[N:1]([C:4]1[C:5]([NH2:11])=[N:6][CH:7]=[C:8]([F:10])[CH:9]=1)=[N+:2]=[N-:3].[ClH:18]
Reactant: CC(C)(C)C(=O)Nc1ncc(F)cc1N=[N+]=[N-]
Agent: Cl
Product: [N-]=[N+]=Nc1cc(F)cnc1N
Reaction time: 2 h

Procedure:
N-(3-Azido-5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (275 mg, 1.16 mmol) in 3 N HCl (5 mL) was heated to 100° C. After 2 h, the volatiles were removed in vacuo, to give the title compound as its HCl salt (180 mg). MS 154.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:16][C:14]([CH2:13][CH2:19][NH:7][C:6]1[CH:8]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])=[O:15])[CH3:18]
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1cc(C)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
A mixture of 5-methyl-2-nitroaniline (3.00 g), ethyl bromopropionate (5.35 g) and potassium carbonate (8.18 g) in N,N-dimethylformamide (20 ml) was stirred at 150° C. for 4 hours and the suspension was cooled to ambient temperature. After being filtered, the filtrate was diluted with ethyl acetate and the solution was washed successively with saturated sodium bicarbonate aqueous solution and brine. Drying over magnesium sulfate, filtering and the removal of solvents afforded a crude product. The crude product was triturated with diethyl ether-n-hexane (1:1) to give N-(2-ethoxycarbonylethyl)-5-methyl-2-nitroaniline (2.83 g) as a yellow prisms.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].CN1CCCC1=O.[F:17][C:18]1[C:23]([F:24])=[C:22](F)[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[F:24][C:23]1[C:18]([F:17])=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=[CH:21][C:22]=1[O:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: Oc1c(F)cccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Oc2c(F)cccc2F)c(F)c1F
Temperature: 130 °C
Reaction time: 8 h

Procedure:
470 mg of 2,6-difluoro-phenol and 1.5 g of tetrabutylammonium bromide were added to an N-methylpyrrolidinone (13 ml) solution of 500 mg of 2,3,4-trifluoro-nitrobenzene, and the reaction liquid was stirred overnight at 130° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to obtain the entitled compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>O1CCOCC1>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:4][CH2:3][CH2:2][NH2:1]
Reactant: Clc1ccccn1
Reactant: NCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NCCOc1ccccn1
Temperature: 25 °C

Procedure:
A mixture of 500 mg of 2-aminoethanol and 328 mg of 60% sodium hydride-mineral oil dispersion in dioxane (27 mL) was heated to reflux for 30 min. After cooling to room temperature, 930 mg of 2-chloropyridine was added and the mixture was warmed to reflux and maintained at this temperature for 18 hrs. The reaction mixture was concentrated, diluted with water, and extracted with chloroform (3×). The organic extracts were washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and the residue was purified by silica gel chromatography to give the title product as a yellow oily material. MS (M+H)+=138.9.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:6][C:5]=1[I:18])=[N+:2]=[N-:3].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[C:20]#[CH:21]>C1(C)C=CC=CC=1>[I:18][C:5]1[CH:6]=[C:7]([C:8]([NH:10][CH2:11][C:12]([F:14])([F:15])[F:13])=[O:9])[CH:16]=[CH:17][C:4]=1[N:1]1[CH:21]=[C:20]([C:19]([O:23][CH2:24][CH3:25])=[O:22])[N:3]=[N:2]1
Reactant: C#CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCC(F)(F)F)cc1I
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(C(=O)NCC(F)(F)F)cc2I)nn1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a solution of 4-azido-3-iodo-N-(2,2,2-trifluoroethyl)benzamide (2.93 g, 7.92 mmol) obtained in Example 379b) in toluene (80 ml) was added ethyl propiolate (2.33 g, 23.7 mmol), the reaction mixture was stirred with heating under reflux for 18 hr. After cooling to room temperature, the precipitate was collected by filtration, washed with hexane and dried to give the title compound as a pale-yellow powder (2.80 g, 76%).