Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([Br:15])=[CH:8][N:7]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1.O>[Br:5][C:6]1[C:11]2[CH:1]=[CH:2][NH:12][C:10]=2[C:9]([Br:15])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ncc1Br
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ncc(Br)c2[nH]ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Vinyl magnesium bromide (44 ml, 1M in THF) was added to dry THF (40 ml) and the solution was cooled to 0° C. under an atmosphere of nitrogen. A solution of 2,5-dibromo-4-nitropyridine (prepared by the method of: Lee, Bang-Lin; Yamamoto, Takakazu, Macromolecules (1999), 32(5) 1375-1382.) (3.53 g) in THF (80 ml) was added dropwise over 40 mins at 0° C. The mixture was stirred at room temperature for 1 hr then cooled to 0° C. and a saturated solution of ammonium chloride (60 ml) was added. The mixture was stirred at room temperature for 15 min then added to a mixture of ethyl acetate (200 ml) and water (200 ml). The organic layer washed with water and evaporated. The residue was dissolved in a mixture of methanol (20 ml) and conc hydrochloric acid (0.5 ml). After standing at room temp for 30 mins the solution was evaporated and the residue added to ethyl acetate (50 ml) and water (50 ml) and made basic with sodium hydroxide. The organic layer washed with water (2×50 ml) then brine, dried (MgSO4) and evaporated. The residue was triturated with ether (20 ml) to give a solid which was filtered off. The filtrate was evaporated and triturated with ether to afford a second crop which on combination with the above gave the title compound (0.97 g). The filtrate was evaporated and dissolved in DCM and purified with Biotage chromatography eluting with DCM/Et2O 20:1 and evaporated to give white solid (0.38 g)
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.Br[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: Sc1nc2ccccc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(OCCSc2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of 2-sulfanylbenzimidazole (159 mg, 1.06 mmol) and DIPEA (150 mg, 200 μl, 1.16 mmol) in dry THF (3 ml) is refluxed for half an hour. After cooling to rt, 1-(2-bromo-ethoxy)-4-chloro-benzene (250 mg, 1.06 mmol) is added. After a further 4 h of reflux, the solvents are removed in vacuo and the residue purified by flash chromatography on silica gel (AcOEt/heptane, 1:9 to 3:7), yielding the title compound (285 mg) in 88% as a white solid: tR=5.40 min (LC-1), ESI-MS (neg.): m/z 303.0 [M−H]+; 1H-NMR (CDCl3): δ 3.76 (t, 2H, SCH2), 4.31 (t, 2H, OCH2), 6.76 (d, 2Harom), 7.18 (d, 2Harom), 7.22-7.32 (m, 3Harom), 7.57 (m, 1Harom).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:4].[OH-].[Na+].[CH:25]([O:27][CH2:28][CH2:29][O:30][NH2:31])=[CH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C>[CH:25]([O:27][CH2:28][CH2:29][O:30][NH:31][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:4])=[CH2:26]
Reactant: C=COCCON
Reactant: COC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1F
Temperature: 65 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
To a solution of 8-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (50 mg, 0.14 mmol) in IMS (3 mL) was added a 1.0 M aqueous solution of sodium hydroxide (0.3 mL, 0.3 mmol). The reaction mixture was heated at 65° C. for 2 hours and then cooled to room temperature and concentrated in vacuo. The resulting residue was azeotroped with toluene, and then suspended in THF (3 mL). O-(2-Vinyloxy-ethyl)-hydroxylamine (29 mg, 0.28 mmol), N-N-diisopropylethylamine (0.10 mL, 0.56 mmol), EDCI (54 mg, 0.28 mmol) and HOBt (38 mg, 0.28 mmol) were then added sequentially before the reaction mixture was stirred 18 hours at room temperature. The reaction mixture was then diluted with ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in dichloromethane) to afford the title compound as a pale yellow oil (40 mg, 65%). LCMS (method B): RT=2.98 min, [M+H]+=435/437.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[C:33](=[O:34])[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[N:26]=[CH:25]5)[C:19]=4[CH3:35])=[CH:16][N:15]=[C:14]([C:36]([NH2:38])=[O:37])[C:10]=3[NH:11]2)=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].O>ClCCl.O1CCCC1>[CH3:35][C:19]1[C:20]([N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25]2)=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[C:9]2[C:8]3[C:12](=[CH:13][C:5]([O:4][CH2:3][CH:2]=[O:1])=[CH:6][CH:7]=3)[NH:11][C:10]=2[C:14]([C:36]([NH2:38])=[O:37])=[N:15][CH:16]=1
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCCO)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCC=O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.6 %

Procedure:
To a solution of 7-(2-hydroxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (152 mg, 0.301 mmol) in dichloromethane (10 mL) and tetrahydrofuran (10.00 mL) at room temperature was added Dess-Martin periodinane (191 mg, 0.451 mmol) in one portion. The mixture was stirred at room temperature for 16 hr. To the mixture was added saturated NaHCO3 solution (10 mL) and water (10 mL). The mixture was stirred at room temperature for 20 min and extracted with ethyl acetate (3×40 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (178 mg, 0.354 mmol, 118% yield) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]3[CH2:16][CH2:17][CH2:18][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=1>>[Cl:1][C:2]1[C:7]([O:8][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]3[CH2:16][CH2:17][CH2:18][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: O=c1cc2n(c(=O)n1-c1cc(O)c(Cl)cc1F)CCC2
Product: O=c1cc2n(c(=O)n1-c1cc(Oc3ncccc3C(F)(F)F)c(Cl)cc1F)CCC2
Yield: 90 %

Procedure:
This was synthesized from 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-6,7-dihydropyrrolo-[1,2-c]pyrimidine-1,3(2H,5H)-dione and 2-chloro-3-trifluoromethylpyridine in 90% yield under similar conditions described below for the preparation of 2-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]hexabydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (Example 10.3) (compound (8-29).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:6]=[CH:5][CH:4]=1)#[N:2].NC(N)=[O:21].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][N+:6]([O-:21])=[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[C:8]=1[C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: NC(N)=O
Reactant: COC(=O)c1c(C#N)ccnc1-c1cnn(C)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(C#N)cc[n+]([O-])c1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (470 mg, 1.940 mmol) in DCM (10 mL) was added urea-hydrogen peroxide compound (1/1, 913 mg, 9.70 mmol), and 2,2,2-trifluoroacetic anhydride (1.370 mL, 9.70 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. More urea-hydrogen peroxide compound (1/1, 400 mg) was added and the mixture was stirred at RT for an additional 3 h after which was added saturated aq NaHCO3 solution and CHCl3. The aqueous phase was extracted with CHCl3 (3×), and the combined organic layers were washed with brine, dried over MgSO4, and evaporated to obtain crude 4-cyano-3-(methoxycarbonyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine 1-oxide, which was combined with phosphorus oxychloride (2 mL, 21.46 mmol). The resulting mixture was stirred at 80° C. for 5 h and then concentrated to a residue, which was neutralized with 2N NaOH. The organic phase was washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2(Hexane/EtOAc=1/1) to give the title compound as a white solid (155 mg, 41.3%). 1H NMR (500 MHz, CDCl3) δ ppm 3.96 (s, 3H), 4.03 (s, 3H), 7.41 (s, 1H), 7.81 (s, 1H), 7.94 (s, 1H). [M+H] calc'd for C12H9ClN4O2, 277. found, 277.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Mn]([O-])(=O)(=O)=[O:16].Cl[O-]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[C:12]([OH:16])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [O-]Cl
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1

Procedure:
After the hydroformylation, the obtained α-(4-isobutylphenyl)propionaldehyde is oxidized by the conventional method using, for example, permanganate or hypochlorite to obtain the ibuprofen, α-(4-isobutylphenyl)propionic acid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:34][CH2:33]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: Cc1nc2ccccc2cc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 72 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].ClC1C=CC([O-])=CC=1.[Na+].ClCC(=O)CC([O-])=O.NN>C1COCC1.C(O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: NN
Agent: O=C([O-])CC(=O)CCl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)COc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 4-chlorophenol (6.4 g, 50 mmol) in THF (25 mL) was treated with NaH (60% in mineral oil, 2 g, 50 mmol) at 0° C. In another flask, a solution of ethyl 4-chloroacetoacetate (10.21 mL, 75 mmol) in THF (25 mL) was treated NaH (60% in mineral oil, 3.5 g, 75 mmol) at −20° C. The resulting yellowish suspension was slowly added to the solution of sodium 4-chlorophenoxide, which was kept at 0° C. After the addition of DMF (10 mL), the reaction temperature was slowly raised to 70° C. After reaction mixture was stirred at 70° C. for overnight, it was cooled and evaporated to dryness. The residue was purified by flash column chromatography (ethyl acetate/hexanes=1/9) to afford TC-II-148 as a yellowish oil, which still contained some 4-chloroacetoacetate. No further purification was applied for the next step of synthesis. Exposure to hydrazine in refluxing ethanol, generated TC-II-150.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1)[CH3:9]>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13](=[O:16])[N:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=1)[CH3:9]
Reactant: Ic1ccccc1
Reactant: CCc1ccc(=O)[nH]c1
Product: CCc1ccc(=O)n(-c2ccccc2)c1
Yield: 84 %

Procedure:
Iodobenzene when caused to react with 5-ethyl-2-(1H)-pyridone following the general procedure outlined in Example 1, an 84% yield of 5-ethyl-1-phenyl-2-(1H)-pyridone is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)=[O:10].C(N(C(C)C)C(C)C)C.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[C:3]([NH:8][C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[O:10])[CH:4]=[N:5]1
Reactant: Cn1ncc(NC(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 54.1 %

Procedure:
To a solution of tert-butyl (3S)-3-({[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]carbonyl}amino)-1-pyrrolidinecarboxylate (1.8 g) and N-ethyldiisopropylamine (720 mg) in chloroform (50 ml) was added trityl chloride (1.6 g), and the mixture was stirred at room temperature for 28 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. 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 tert-butyl (3S)-3-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-pyrrolidinecarboxylate (1.7 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][C@@H:12](OC)[CH2:11]2)=[O:9])[N:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[N:3]1[CH:4]=[CH:8][N:10]2[CH2:13][CH2:14][N:10]([C:8]([C:4]3[N:3]=[C:2]([NH:17][C:18]4[S:19][C:20]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:33])[CH3:34])=[CH:28][C:27]=5[F:36])=[CH:21][C:22]=4[C:23]([NH2:25])=[O:24])[CH:7]=[CH:6][CH:5]=3)=[O:9])[CH2:11][C:12]=12
Reactant: CO[C@@H]1CCN(C(=O)c2cccc(Br)n2)C1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(=O)N4CCn5ccnc5C4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-bromo-6-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}pyridine (200 mg, 0.65 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (192 mg, 0.65 mmol) as starting materials.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>O>[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C1CNCCN1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C(c1ccc(F)cc1)N1CCNCC1
Temperature: 50 °C
Yield: 87.1 %

Procedure:
Concentrated hydrochloric acid was added dropwise to a solution of piperazine (0.124 mol) in water (110 ml) to adjust the pH to 2.8. The solution was then heated to 50° C. 4-Fluorobenzoyl chloride (0.124 mol) was added to the warm solution dropwise while maintaining the pH at 2.8 by the concurrent addition of 40% aqueous sodium acetate solution. After complete addition, a solution of potassium carbonate (47 g) in water (50 ml) was added and the mixture cooled in an ice bath. The cold mixture was extracted with chloroform (5×150 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo affording 22.5 g of a white solid (88% yield). Spectral data are consistent with the assigned structure. This material was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=O)[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-:16][C:17]#[N:18].[K+].Cl>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[C:11](=[O:13])[NH:18][C:17](=[O:16])[NH:10]2)=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc([N+](=O)[O-])cc2)N1
Yield: 82 %

Procedure:
A solution of p-nitrophenylalanine (4.2 g, Fluka) and potassium cyanate (1.62 g) in water (6 ml) was refluxed for 1 hour. C.HCl (3 ml) was added and the mixture refluxed for a further 10 minutes, then cooled, diluted with water and filtered. The residue was washed with water and dried to give the desired product as a straw-coloured solid (3.85 g). The 200 MHz 1H NMR was consistent with the proposed structure.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]1[O:16][C:15](=[O:17])[NH:14][C@@H:13]1[CH3:18].[H-].[Na+].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26]Br>CN(C=O)C.CCOC(C)=O.O>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH2:26][N:14]1[C@H:13]([CH3:18])[C@@H:12]([C:3]2[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=2[I:1])[O:16][C:15]1=[O:17]
Reactant: C[C@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)ccc1I
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 95 mg of (4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]4-methyl-1,3-oxazolidin-2-one in 1 mL of DMF was added 20 mg of sodium hydride. The mixture was stirred 10 min at 0° C.; then 94 mg of 3,5-bis(trifluoromethyl)benzyl bromide was added. The mixture was stirred 10 min at 0° C., then diluted with 10 mL of EtOAc and 10 mL of water. The phases were separated and the aqueous phase was extracted with 10 mL of EtOAc. The combined organic phases were washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 CV of 2% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 2 to 100% over 10 CV to provide the title compound. Mass spectrum (ESI) 598.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.58 (br s, 3H), 7.34 (dd, J=1.5 Hz, 8 Hz, 1H), 5.36 (d, J=4 Hz, 1H), 4.89 (d, J=16 Hz, 1H), 4.31 (d, J=16 Hz, 1H), 4.48 (dq, J=6 Hz, 4 Hz, 1H), 1.55 (d, J=6.5 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7](Cl)=[O:8].[C:10]1([CH2:16][O:17][C:18]([C:20]2([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:10]1([CH2:16][O:17][C:18]([C:20]2([NH:26][C:7]([N:3]3[CH2:4][CH2:5][NH:6][C:2]3=[O:1])=[O:8])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)N1CCNC1=O
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1NCCN1C(=O)NC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 82.2 %

Procedure:
1.38 g (9.3 mmol) of 2-oxo-1-imidazolidinecarbonyl chloride was added to a solution of 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 1.04 g (10 mmol) of triethylamine in 100 ml of chloroform, and the mixture was stirred at 60° C. for 4 days. The reaction solution was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystal was washed with diethyl ether to obtain 2.64 g (82%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][N+]([O-])=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].[O:15]=[O+][O-]>CO>[CH3:1][CH:2]([CH:8]=[O:15])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)C[N+](=O)[O-]
Reactant: O=[O+][O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(C)C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-methyl-4-nitrobutanoate (96 g, 0.596 m) in methanol (30 ml) is added dropwise to a solution of sodium methoxide (34.5 g, 0.638 m) in methanol (1 l) at room temperature under nitrogen. The resulting mixture is stirred for 1 hour, cooled to -78° C. and treated with one equivalent of ozone. The reaction mixture is then allowed to warm to room temperature and most of the solvent is removed in vacuo. The residue is filtered and the filtrate is treated with ether (500 ml). The organic phase is washed with water (3×200 ml), dried (Na2SO4) and the solvent is removed in vacuo to give the crude product, methyl 3-methyl-4-oxo-butanoate (86.3 g). This material is used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:20](=[O:21])[CH2:19][O:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]3=4)[CH2:8][CH2:7]2)[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:4][N:3]1[CH2:32][C:33]1[CH:34]=[C:35]([CH:43]=[CH:44][CH:45]=1)[C:36]([O:38]C(C)(C)C)=[O:37].Cl>O1CCOCC1>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:20](=[O:21])[CH2:19][O:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]3=4)[CH2:10][CH2:11]2)[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:4][N:3]1[CH2:32][C:33]1[CH:34]=[C:35]([CH:43]=[CH:44][CH:45]=1)[C:36]([OH:38])=[O:37]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)COc5ccccc54)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)COc5ccccc54)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl 3-((4-oxo-8-(3-(3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.1 g, 0.16 mmol) was added 4M solution of HCl in dioxane (2 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated in vacuo and lyophilized in acetonitrile/water (1:1) to obtain the title compound as a hydrochloride salt (0.095 g, 99%); 1H NMR (DMSO-d6): δ 1.92 (d, 2H, J=14 Hz), 2.03-2.07 (m, 2H), 2.85 (t, 2H, J=10 Hz), 3.25 (br, 2H), 3.62-3.72 (m, 4H), 3.99 (t, 2H, J=6.8 Hz), 4.61-4.67 (m, 6H), 6.81 (t, 1H, J=7.6 Hz), 6.96-7.10 (m, 5H), 7.23 (t, 2H, J=7.2 Hz), 7.31 (d, 1H, J=7.6 Hz), 7.48-7.57 (m, 2H), 7.87-7.89 (m, 2H), 9.96 (br, 1H), 13.03 (s, 1H); MS for C32H34N4O5 m/z 555.06 (M+H)+.