Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9]O.[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH2:16][C:17]2=O.[OH-].[K+]>C1(C)C=CC=CC=1>[Cl:8][C:4]1[C:3]2[C:2](=[N:1][C:17]3[C:18]4[CH:19]=[C:20]([CH3:22])[CH:21]=[C:12]([CH3:11])[C:13]=4[CH2:14][CH2:15][C:16]=3[CH:9]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Reactant: Nc1cccc(Cl)c1CO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)-c1nc3cccc(Cl)c3cc1CC2
Temperature: 25 °C
Yield: 67.4 %

Procedure:
(2-Amino-6-chlorophenyl)methanol (16 g, 101 mmol), 5,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one (20.0 g, 111 mmol), RuCl2(PPh3)3 (0.971 g, 1.01 mmol), and KOH (5.7 g, 101 mmol) were refluxed in 200 mL of toluene for 12 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature and filtered through a silica gel plug and eluted with dichloromethane. The product was washed by methanol and recrystallized from hexane to obtain ˜20 gram of the desired product which was confirmed by GC-MS.
Reaction SMILES: COC([C:5]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]1=[O:12])=O.CN(C)C(=O)C.Cl.N1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:5]2[C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][CH2:9]2)=[CH:19][CH:18]=1
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(C)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 155 °C
Reaction time: 4 h

Procedure:
In 1-(4-chlorobenzyl)-3,3-dimethyl-2-oxocyclopentane carboxylic acid methyl ester (1.5 g, 0.00509 mol), N,N-dimethylacetamide (1.5 mL) and pyridine hydrochloride (0.706 g, 0.00509×1.2 mol) were added and stirred at 155° C. for 4 hours. In the reaction liquid, pyridine hydrochloride (0.177 g, 0.00509×0.3 mol) was added and further stirred at 155° C. for another 6 hours. In the reaction liquid, toluene and saturated sodium bicarbonate water were added, and the mixture was partitioned. After extracting the aqueous layer using toluene, the organic layer was dried using anhydrous sodium sulfate and concentrated. Thereafter, the dried and concentrated product was purified using a silica gel column, and a target product was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:21]([NH2:23])[CH3:22]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:23][CH2:21][CH3:22])[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NC)n1
Yield: 55.8 %

Procedure:
0.314 g (0.001 mol) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and 6.6 ml (0.1 mol) of ethylamine were stirred in 15 ml of ethanol in an autoclave at 130° C. for 3 hours. The reaction mixture was freed from solvent, the residue was suspended in 8 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.18 g (56%) of 4-amino-N-(6-ethylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 252° C. (dec.).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])[NH2:11].N1C=CC=CC=1.Cl>ClCCl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 3-bromo-4-(2,4-difluorophenoxy)aniline (328 mg, 1.1 mmol) and pyridine (178 μL, 2.2 mmol) in dichloromethane (2 ml) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir overnight, it was treated with 1N HCl (10 ml) and extracted with dichloromethane (3×10 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (430 mg, 99%) as a tan solid which was carried forward without purification. LCMS (M−H)−=391.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[N:10]([CH2:11][C:12](OCC)=[O:13])[N:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=1)([CH3:3])[CH3:2]>CO>[CH:1]([N:4]1[C:12](=[O:13])[CH2:11][N:10]2[N:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[C:6]2[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CNC(C)C
Solvent: CO
Product: CC(C)N1Cc2cc([N+](=O)[O-])nn2CC1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A mixture of 151c (400 mg, 1.48 mmol) and methanol (30 mL) was stirred at 50° C. for 16h. The mixture was the concentrated under reduced pressure. The residue was diluted with water (80 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 151d (300 mg, 90%) as a yellow solid. MS-ESI: [M+H]+ 225.3
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:46]=[CH:45][CH:44]=[CH:43][C:35]=2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:30][CH:29]=1>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:46]=[CH:45][CH:44]=[CH:43][C:35]=4[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:30][CH:29]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)Cc2ccc3c(c2)OCO3)cc1
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc3c(c2)OCO3)cc1
Yield: 69 %

Procedure:
Using the general procedure described in Example 6 the dianion derived from the product of Example 1 (0.419 g; 1.16 mmol) was alkylated with tert-butyl 2-(4-bromomethylphenyl)benzoate. The crude reaction mixture was partitioned between EtOAc and 10% aqueous NaHSO4, separated dried and evaporated. The residue was purified on a silica gel flash chromatography eluted with CHCl3 -MeOH--NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.501 g (69%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:20]([O:22][CH3:23])=[O:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:20](=[O:21])[O:22][CH3:23]
Reactant: Nc1ccncc1Br
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Nc1ccncc1Br
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of compound 3-bromopyridin-4-amine (3 g, 17.4 mmol.) in 20 mL of anhydrous THF was added a solution of LiHMDS (1M in THF, 36.4 mL, 36.4 mmol) at 0° C. After stirring for 30 min, methyl chloroformate (2 g, 20.8 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs and then at r.t. overnight. The reaction was quenched with saturated aqueous ammonium chloride. The organic solvent was evaporated and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over Na2SO4, concentrated. The crude product was purified by silica gel column chromatography (Petroleum ether:Ethyl acetate=1:2) to afford methyl 3-bromopyridin-4-ylcarbamate (2.34 g, 59%).
Reaction SMILES: CO[C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH3:11])[N:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH3:11])[N:6]=[CH:5][CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1ccnc(C)c1C#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nccc(Cl)c1C#N
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
To 4-methoxy-2-methylnicotinonitrile (Tet 6222, 2006) (100 mg, 0.67 mmol) in phosphoryl chloride (2 mL) was added phosphorus pentachloride (156 mg, 0.75 mmol). The mixture was heated to reflux under nitrogen for 15 h. The reaction was quenched with ice, stirred for 10 min, then neutralised with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane). Product containing fractions were evaporated to give the title compound as a pale pink solid, (35 mg, 34%). 1H NMR δ (ppm) (CDCl3-d): 8.56 (1H, d, J=5.46 Hz), 7.32 (2H, d, J=5.46 Hz), 2.81 (3H, s).
Reaction SMILES: [CH2:1](N1CCN(CC2C(=O)N(CC(C)C)N=C(C3C=CC(C)=CC=3)C=2)CC1)C1C=CC=CC=1.[C:33]([C:36]1[C:37](=[O:52])[NH:38][N:39]=[C:40]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)[CH:41]=1)([OH:35])=[O:34]>>[CH3:1][O:34][C:33]([C:36]1[C:37](=[O:52])[NH:38][N:39]=[C:40]([C:42]2[CH:43]=[CH:44][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:47]=2)[CH:41]=1)=[O:35]
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)n[nH]c1=O
Reactant: Cc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC(C)C)n2)cc1
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)n[nH]c1=O

Procedure:
Following the procedure of Example 1 (5), 4-carboxy-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow crystalline powder (yield: 88.5%).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2.[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:7]2
Reactant: CC(=O)O
Reactant: Brc1ccc2cnccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C=Cc2cc(Br)ccc2C1
Temperature: 60 °C

Procedure:
Sodium borohydride (1.12 g, 29.6 mmol) is added portionwise to a cooled (0° C.) solution of 6-bromoisoquinoline [J Chem Soc Perkin Trans 2, 1998, 437] (1.544 g, 7.42 mmol) in acetic acid (10 ml) and acetic anhydride (3 ml). After heating at 60° C. for 4 hours, the mixture is cooled, evaporated and diluted with water. After adjustment to pH10 with potassium carbonate and extraction with ethyl acetate, the combined organic phases are washed twice with 0.5N HCl and brine, then dried over sodium sulphate. Evaporation affords 1-(6-bromo-1H-isoquinolin-2-yl)-ethanone, MH+ 253. Glyoxylic acid (0.812 g, 8.80 mmol) is added to mixture of 1-(6-bromo-1H-isoquinolin-2-yl)-ethanone (1.50 g, 5.90 mmol) in 6N HCl (20 ml). The reaction is heated at 100° C. for 2 hours, cooled to RT and washed with ethyl acetate. After evaporation, the residue is taken into methanol (20 ml), concentrated sulphuric acid (10 drops) is added and the mixture heated at reflux for 14 hours. After partial evaporation of the solvent, the resultant solid is collected by filtration, washed with methanol and dried to afford (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester cooled (0° C.) solution of (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (50 mg, 0.18 mmol) in 3:1 THF-water (3 ml). After 1 hour the solvent is evaporated to afford (6-bromo-isoquinolin-4-yl)-acetic acid lithium salt, MH+ 266.
Reaction SMILES: C([O:5][C:6](=[O:46])[C:7]([O:10]/[N:11]=[C:12](/[C:33]1[N:34]=[C:35]([NH:38]C(OC(C)(C)C)=O)[S:36][CH:37]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH2:30][C@@H:29]([CH3:31])[O:28][C:27]1=[O:32])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][C:35]1[S:36][CH:37]=[C:33](/[C:12](=[N:11]/[O:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:46])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]2[CH2:25][N:26]2[CH2:30][C@@H:29]([CH3:31])[O:28][C:27]2=[O:32])=[O:14])[N:34]=1
Reactant: C[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Yield: 26.2 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-(((R)-5-methyl-2-oxooxazolidin-3-yl)methyl)-4-oxoazetidine-1-sulfonic acid (92 mg, 0.133 mmol), DCM (1.33 mL) and TFA (615 μL, 7.98 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (18.6 mg, 23%) as a white powder. LCMS: Rt=0.39 min, m/z=535.1 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.29 (d, J=8.8 Hz, 1H), 6.85 (s, 1H), 5.22 (dd, J=8.8, 5.7 Hz, 1H), 4.55 (dt, J=13.5, 6.5 Hz, 1H), 4.15 (q, J=6.0 Hz, 1H), 3.72-3.63 (m, 2H), 3.34-3.27 (m, 2H), 1.46 (s, 3H), 1.42 (s, 3H), 1.28 (d, J=6.3 Hz, 3H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:18]([NH:29][CH3:30])[C@@H:17]([CH3:31])[CH2:16]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH3:45])=[O:43].Cl.O1CCOCC1.C(=O)(ON1C(=O)CCC1=O)OC(C)(C)C>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C@@H:15]1[CH2:16][C@H:17]([CH3:31])[C@H:18]([N:29]([CH3:30])[C:42](=[O:43])[O:44][CH3:45])[C@H:19]([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:28])[CH2:20]1
Reactant: COC(=O)Cl
Reactant: CN[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@H]1NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C)[C@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of (+/−)-tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-3-methyl-2-(methylamino)cyclohexyl)carbamate (1.0 equiv.) in DCM (0.05 M) at 0° C. was added DIEA (3.0 equiv.) and then methyl chloroformate (1.5 equiv.). The homogeneous solution was left standing at 0° C. at for 4 hrs. The reaction was quenched partitioned between NaHCO3 solution and EtOAc. The organic layer was washed with Brine, dried over Na2SO4, concentrated and purified by ISCO chromatography. The product was treated with 4 M HCl in dioxane (30.0 equiv.) at rt for 1 hour. The volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.15 M), DIEA (5.0 equiv.) and tert-butyl 2,5-dioxopyrrolidin-1-yl carbonate (1.6 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (+/−)-methyl ((1S,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl)(methyl)carbamate in 20% yield. LC/MS (m/z)=393.2 (MH+), Rt=0.60 min.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([NH2:13])[CH2:8][O:7]2)([O-:3])=[O:2].[F:14][C:15]([F:34])([F:33])[O:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][CH:22]2[CH2:25][N:24]([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH2:23]2)=[CH:19][CH:18]=1>>[F:34][C:15]([F:14])([F:33])[O:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][CH:22]2[CH2:25][N:24]([CH2:26][CH2:27][C:28]([NH:13][C@@H:9]3[CH2:8][O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]4[CH2:10]3)=[O:29])[CH2:23]2)=[CH:19][CH:18]=1
Reactant: NC1COc2nc([N+](=O)[O-])cn2C1
Reactant: O=C(Cl)CCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1
Product: O=C(CCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 32 %

Procedure:
Similar to the manipulation of example 22, with (S)-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-amine (110 mg, 0.6 mmol) and 3-(3-(4-(trifluoromethoxy)phenoxy)azetidin-1-yl) propionyl chloride (242 mg, 0.72 mmol) as crude materials, title compound as 91 mg yellow powder was generated and yield was 32%.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24]>C(O)(C)C>[ClH:2].[C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[N:6]=[CH:5][CH:4]=[C:3]2[NH:24][C:23]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([OH:20])[CH:22]=1)#[N:14]
Reactant: Cc1ccc(N)cc1O
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1cc2nccc(Nc3ccc(C)c(O)c3)c2cc1C#N
Yield: 64.8 %

Procedure:
A mixture of 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (220 mg 0.84 mmol), (prepared as described for the starting material in Example 1), and 3-hydroxy-4-methylaniline (123 mg, 1 mmol) in isopropanol (10 ml) was heated at reflux for 1 hour. The mixture was allowed to cool, the solid product was collected by filtration, washed with acetone and dried to give 6-cyano-4-(3-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)quinoline hydrochloride (210 mg, 60%) as an orange solid.
Reaction SMILES: FC(F)(F)C(OO)=[O:4].[C:9]1([CH2:15][CH2:16][CH2:17][C:18](=[CH2:22])[C:19]([OH:21])=[O:20])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P([O-])([O-])(O)=O.[Na+].[Na+]>C(Cl)Cl>[C:9]1([CH2:15][CH2:16][CH2:17][C:18]2([C:19]([OH:21])=[O:20])[CH2:22][O:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(CCCc1ccccc1)C(=O)O
Reactant: O=C(OO)C(F)(F)F
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C1(CCCc2ccccc2)CO1
Temperature: 0 °C

Procedure:
Alternatively, the compound is obtained as follows: a solution of trifluoroperacetic acid (prepared from 1.8 ml of 85% strength hydrogen peroxide, 17 g of trifluoroacetic anhydride and 15 ml of methylene chloride) is added dropwise to a boiling mixture of 9.5 g of 5-phenyl-2-methylenevaleric acid and 28 g of disodium hydrogen phosphate in 50 ml of methylene chloride. The mixture is boiled under reflux for a further 30 minutes; 150 ml of ice-water are added; *the organic phase is separated off and, after drying over sodium sulfate, is concentrated. The title compound remains as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[CH2:24][C:25](O)=[O:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[CH2:24][C:25]([N:12]1[CH2:11][CH2:10][N:9]([C:4]2[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13]1)=[O:26]
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=C(O)CC1CC2CCC1C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CC1CC2CCC1C2)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 82 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2-(bicyclo[2.2.1]heptan-2-yl)acetic acid (100 mg, 0.65 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-(bicyclo[2.2.1]hept-2-ylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 82% yield (195 mg) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:26][CH2:27][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:30]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(CCC4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Yield: 94.9 %

Procedure:
A solution of 4-{2-[3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester (0.84 g, 1.60 mmol) in ethanol (80 ml) was hydrogenated over palladium on carbon (10%, 0.14 g) for 4 h. The catalyst was filtered off and the filtrate was evaporated in vacuo to give the title compound as an ivory solid (0.80 g, 95%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]4[CH2:20][CH:19]4[C:21]4[O:22][C:23]([NH:26][C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=5)=[N:24][N:25]=4)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:37])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:33]([F:34])([F:36])[C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:23]2[O:22][C:21]([C@@H:19]3[CH2:20][C@H:18]3[C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[NH:8][C:9](=[O:37])[CH:10]=[CH:11]4)=[N:25][N:24]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2c(=O)ccc3cc(C4CC4c4nnc(Nc5ccc(C(F)(F)F)cc5)o4)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2cc([C@@H]3C[C@H]3c3nnc(Nc4ccc(C(F)(F)F)cc4)o3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-6-(2-(5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-oxadiazol-2-yl)cyclopropyl)quinolin-2(1H)-one (35 mg, 0.065 mmol) in DCM (5 mL) was added TFA (0.5 mL, 6.49 mmol) and stirred at room temperature overnight. The solvent was concentrated to give a crude product, purified by preparative HPLC on a Sunfire C18 column (150×19, 5μ) using a gradient of 0-100% ACN in 0.1% TFA to give trans-6-(2-(5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-oxadiazol-2-yl)cyclopropyl)quinolin-2(1H)-one. 1H NMR 400 MHz, MeOD: δ 1.65-1.79 (m, 2H), 2.43-2.47 (m, 1H), 2.70-2.75 (m, 1H), 6.64 (d, J=9.20 Hz, 1H), 7.35 (d, J=8.80 Hz, 1H), 7.47 (dd, J=2.00, 8.60 Hz, 1H), 7.57 (d, J=1.60 Hz, 1H), 7.68 (dd, J=8.80, 23.20 Hz, 4H), 7.97 (d, J=9.20 Hz, 1H). LCMS, RT 1.869 min; LCMS (ES-API), m/z 412.11.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:12]([CH2:19][CH3:20])[C:8]=1[C:9]([OH:11])=[O:10])([O:3][CH2:4][CH3:5])=O.Cl.CN(C)CCCN=C=NCC>C1COCC1>[CH2:4]([O:3][C:1]1[O:10][C:9](=[O:11])[C:8]2[C:12]([CH2:19][CH3:20])=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:7]=2[N:6]=1)[CH3:5]
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])cc(CC)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1nc2cc([N+](=O)[O-])cc(CC)c2c(=O)o1

Procedure:
A solution of 2-carboethoxyamino-4-nitro-6-ethyl-benzoic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride in anhydrous THF (25 ml) was stirred at room temperature for 21/2 hrs. The solution was evaporated by dryness and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulphate and evaporated to a solid. The solid was recrystallized from methylene chloride: petroleum ether to give the title compound, 2-ethoxy-5-ethyl-7-nitro-4H-3,1-benzoxazin-4-one, m.p. 106°-107° C., Ir. 1770, 1660, 1600, 1595, 1535, 1515 cm.