Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-])=O)[CH:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](=O)([O-])[O-:25].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:12]1[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][CH:15]=[C:16]1[C:24](=[O:25])[NH:9]2
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCOC(=O)CCc1ncc[nH]1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CCc1ncc2c(=O)[nH]c3cc(Br)ccc3n12
Temperature: 100 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene 324 mg, ethyl 3-(1H-imidazol-2-yl)propanoate 248 mg, potassium carbonate 407 mg and N,N-dimethylacetamide 10 mL was heated at 100° C. for 12 hours in nitrogen atmosphere. The reaction liquid was diluted with ethyl acetate and water was added thereto to induce phase separation. The organic layer was washed with saturated brine and dried over sodium sulfate, from which then the solvent was distilled off. Thus obtained oily substance was dissolved in a liquid mixture of 10 mL of acetic acid and 10 mL of water, and to the solution 1.51 g of 85% sodium hydrosulfite was added, followed by 2 hours' heating under reflux. The reaction liquid was cooled with ice and neutralized with saturated aqueous sodium hydrogencarbonate solution. Extracting the same with ethyl acetate, the extract was washed with saturated brine, dried over sodium sulfate, and from which the solvent was distilled off. To the resulting oily substance, 358 mg of 1,1′-carbonyldiimidazole and 20 mL of 1,2-dichlorobenzene were added, followed by 5 hours' heating under reflux in nitrogen atmosphere. The solvent was distilled off, and to the residue methanol was added and stirred overnight. Thus precipitated crystals were recovered by filtration, washed with methanol and dried in flowing air to provide 112 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](SC)=[CH:10][N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][NH2:17]>CCO.CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([NH:17][CH3:16])=[CH:10][N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])Nc1ccc(Cl)nc1
Solvent: CO
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])Nc1ccc(Cl)nc1

Procedure:
In 25 ml of EtOH was dissolved 0.42 g (0.00171 mole) of 1-(6-chloro-3-pyridyl)amino-1-methylthio-2-nitroethylene, followed by addition of 0.2 g of a 40% solution of methylamine in methanol. The mixture was refluxed for 1.5 hours. The solvent was distilled off and the crystalline residue was washed with AcOEt and dried to recover 0.33 g of the title compound as white crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([CH2:13][OH:14])=[C:8]([O:15][CH3:16])[CH:7]=1.[OH:17][C:18]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)[C:19]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][CH3:29])[CH2:24][CH2:23]1)=[O:20].C(N(CC)CC)C.C1COCC1>C(#N)C>[OH:17][C:18]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[C:19]([O:21][C@H:22]1[CH2:23][CH2:24][C@H:25]([N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([O:15][CH3:16])[C:9]([CH2:13][OH:14])=[CH:10][C:11]=2[Cl:12])[CH3:29])[CH2:26][CH2:27]1)=[O:20]
Reactant: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Reactant: COc1cc(OCCCBr)c(Cl)cc1CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1cc(OCCCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO
Reaction time: 24 h

Procedure:
A mixture of [4-(3-bromopropoxy)-5-chloro-2-methoxyphenyl]methanol (intermediate 55; 386 mg; 1.25 mmol), trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5; 438 mg, 1.25 mmol) and triethylamine 0.345 ml; 2.49 mmol) in 12 ml acetonitrile and 8.7 ml THF was stirred at 70° C. for 16 hr. An additional amount of intermediate 5 (219 mg; 0.62% mmol) was added and the heating prosecuted for 24 hr. The solvent was evaporated in vacuum and the residue purified by preparative reversed-phase HPLC (hexane/EtOAc from 0 to 40%), affording the title compound (80%) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9]([F:19])[C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:20][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9]([F:19])[C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2([CH3:20])[OH:16])=[CH:4][CH:3]=1
Reactant: C[Mg]Cl
Reactant: COc1cc2c(=O)c3cc(Br)ccc3oc2cc1F
Solvent: C1CCOC1
Product: COc1cc2c(cc1F)Oc1ccc(Br)cc1C2(C)O
Yield: 100.4 %

Procedure:
To a suspension of 7-bromo-3-fluoro-2-methoxy-9H-xanthen-9-one (25 g, 73.4 mmol) in THF (500 mL) was added MeMgCl (2.0 equiv. 146.75 mmol, 48.9 mL, 3.0 M solution in THF) at −20° C. (internal temp) slowly over 30 minutes. The resulting mixture was allowed to reach ambient temperature where it was maintained for 12 hours. The reaction was quenched by adding saturated NH4Cl. The phases were separated and the aqueous layer was extracted with EtOAc (2×300 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford 25 g of 7-bromo-3-fluoro-2-methoxy-9-methyl-9H-xanthen-9-ol that was used in the next step without further purification. A solution of the derived alcohol (25 g) was dissolved in DCM (300 mL) and pPTS (250 mg, 0.995 mmol) was added. The mixture was heated to reflux for 2 hours at which time the reaction was cooled to rt and washed with NaHCO3 (100 mL). The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified via chromatography (hexanes/DCM, 3:1) to provide 7-bromo-3-fluoro-2-methoxy-9-methylene-9H-xanthene as an orange solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]([F:30])([F:29])[C:8]([N:10]1[CH2:28][CH2:27][C:13]2([C:18]3=[C:19]([CH3:22])[CH:20]=[CH:21][N:17]3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[O:14]2)[CH2:12][CH2:11]1)=[O:9].[OH-].[Na+].CN([CH:36]=[O:37])C>>[CH3:22][C:19]1[CH:20]=[C:21]([CH:36]=[O:37])[N:17]2[C:18]=1[C:13]1([CH2:27][CH2:28][N:10]([C:8](=[O:9])[C:7]([F:6])([F:29])[F:30])[CH2:11][CH2:12]1)[O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]2=1
Reactant: CN(C)C=O
Reactant: Cc1ccn2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)n2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Reaction time: 0.5 h
Yield: 24 %

Procedure:
POCl3 (38 μL, 0.41 mmol) was added dropwise at 0° C. under N2 to DMF (32 μL, 0.41 mmol). The reaction was stirred for 30 min at this temperature and a white solid formed, to which was slowly added a solution of 2,2,2-trifluoro-1-(3′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)ethanone (95 mg, 0.27 mmol) in dry DMF (0.7 mL). The reaction stirred for 4 h, poured onto ice, 0.8 ml of 1M NaOH was added and the product was extracted with dichloromethane (3×5 mL). The organic phases were combined, washed with brine, dried, filtered and concentrated and the residue was purified by silica-gel column chromatography eluting with 5-40% EtOAc in hexanes to yield 3-methyl-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (25 mg, 24%). ESI-MS m/z calc. 378.1. found 379.3 (M+1)+; Retention time 1.83 minutes (3 min run).
Reaction SMILES: [Li+].[OH-].[N+](C1C=CC(C([O:12][C@H:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([C:22]4[CH:47]=[CH:46][C:25]5[C:26]([CH:29]([C:39]6[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=6)[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:27][S:28][C:24]=5[CH:23]=4)[C:16]=3[C@H:15]([CH3:48])[CH2:14]2)=O)=CC=1)([O-])=O>C1COCC1>[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([CH:29]([C:26]2[C:25]3[CH:46]=[CH:47][C:22]([C:21]4[C:16]5[C@H:15]([CH3:48])[CH2:14][C@@H:13]([OH:12])[C:17]=5[N:18]=[CH:19][N:20]=4)=[CH:23][C:24]=3[S:28][N:27]=2)[CH2:30][NH:31][C:32](=[O:33])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:44][CH:43]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(-c3ccc4c(C(CNC(=O)OC(C)(C)C)c5ccc(Cl)cc5)nsc4c3)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc4c(C(CNC(=O)OC(C)(C)C)c5ccc(Cl)cc5)nsc4c3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
1N LiOH aqueous solution (0.30 mL, 0.30 mmol) was added to a stirred solution of (5R,7R)-4-(3-(2-(tert-butoxycarbonylamino)-1-(4-chlorophenyl)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (102 mg, 0.149 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The resulting residue was purified by column chromatography (DCM:MeOH, 60:1) to give tert-butyl 2-(4-chlorophenyl)-2-(6-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzo[d]isothiazol-3-yl)ethylcarbamate (62 mg, 78%) as an oil. LCMS (APCI+) m/z 537, 539 [M+H]+; Rt=3.99 min.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([NH:31][C:32]1[C:33]([S:41][CH3:42])=[N:34][C:35]([CH3:40])=[CH:36][C:37]=1[S:38][CH3:39])=[O:30]>CN(C=O)C.O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:28][C:29]([NH:31][C:32]2[C:33]([S:41][CH3:42])=[N:34][C:35]([CH3:40])=[CH:36][C:37]=2[S:38][CH3:39])=[O:30])[CH2:17][CH2:16]1)(=[O:12])=[O:11]
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Reactant: O=S(=O)(CCN1CCNCC1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCS(=O)(=O)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
To a solution of 1-[2-(benzimidazol-2-ylsulfonyl)ethyl]piperazine (17 mg, 0.058 mmol) in DMF (0.1 ml) were added potassium carbonate (16.0 mg, 0.116 mmol) and 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (18.6 mg, 0.058 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=5:1) to provide 19.8 mg (yield 64%) of the desired compound as pale yellow oil. IR (neat) cm−1: 3345, 1672, 1565, 1420, 1124. 1H-NMR (CD3OD) δ: 2.43 (3H, s), 2.47 (3H, s), 2.48 (3H, s), 3.00 (2H, br. d, J=12.9 Hz), 3.12 (2H, t, J=10.7 Hz), 3.34 (2H, s), 3.58-3.78 (8H, m), 6.85 (1H, s), 7.12-7.18 (2H, m), 7.43-7.48 (2H, m).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH:9](OC(=O)C)=[O:10]>C(O)=O>[CH:9]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:10]
Reactant: CC(=O)OC=O
Reactant: CC(C)[C@H](N)C(=O)O
Solvent: O=CO
Product: CC(C)C(NC=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To valine (15 g, 0.129 mol) in 88% formic acid (52 ml) is added acetic formic anhydride (33 g, 0.386 mol) over 0.75 hr at 5°. The reaction mixture is warmed to RT and stirred overnight. The reaction is worked up by distilling off (bath temp. 45°-50°) the solvent, excess anhydride and acetic acid, to give, as a white solid, 2-(N-formylamino)-3-methylbutanoic acid, recrystallized from hot ethanol, m.p. 143°-145°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.Br[C:13]1[CH:17]=[CH:16][O:15][N:14]=1.[NH2:18][NH2:19]>CO>[N:6]1[CH:5]=[CH:4][CH:9]=[C:8]([O:10][C:13]2[CH2:17][CH2:16][O:15][N:14]=2)[CH:7]=1.[O:2]1[CH:1]=[N:19][NH:18][C:3]1=[O:11]
Reactant: Brc1ccon1
Reactant: NN
Reactant: COC(=O)c1cncc(O)c1
Solvent: CO
Product: O=c1[nH]nco1
Product: c1cncc(OC2=NOCC2)c1
Reaction time: 14 h

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-231a and I-231b were prepared in 3 steps according to the following procedures: 5-hydroxynicotinic acid methyl ester is reacted with racemic bromoisoxazole I-75 using Method 5. The resulting methyl ester (1.0 equiv) is dissolved in methanol (0.08 M) after which hydrazine (50 equiv, 50% by weight in water) is added and the reaction is allowed to stir for 14 h. The reaction mixture is then concentrated under vacuum and used directly in the next step. The hydrazide is dissolved in dioxane (0.12 M with respect to hydrazide). N,N-Carbonydiimidazole (1.2 equiv) is added and the reaction is sealed and heated to reflux for 4 h. The reaction is then transferred to a separatory funnel with excess ethyl acetate and water. The organic layer was washed water and brine, drive over sodium sulfate and concentrated under vacuum to provide crude material which was purified using flash silica gel chromatography (gradient methanol/dichloromethane) to provide the desired racemic 1,3,4-oxadiazol-2(3H)-one I-231. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=423.4 m/z. Activity: B
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]([N:12]([CH3:14])[CH3:13])=[CH:10][CH:11]=1)#[N:2].[C:22]1([C@H:28]([NH2:31])[CH2:29][CH3:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1.C>C(O)(C)C>[C:1]([N:3]=[C:4]([NH:31][C@@H:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:29][CH3:30])[NH:5][C:6]1[CH:7]=[N:8][C:9]([N:12]([CH3:13])[CH3:14])=[CH:10][CH:11]=1)#[N:2]
Reactant: CN(C)c1ccc(NC(=NC#N)Oc2ccccc2)cn1
Reactant: CC[C@@H](N)c1ccccc1
Solvent: CC(C)O
Solvent: CN1CCOCC1
Product: CC[C@@H](NC(=NC#N)Nc1ccc(N(C)C)nc1)c1ccccc1
Yield: 5.2 %

Procedure:
A stirred solution of the product from Step 4 (2.00 g, 0.00711 mol), (R)-(+)-1-phenylpropylamine (1.06 g, 0.00784 mol), N-methylmorpholine (1.69 ml, 0.0154 mol) and isopropanol (13.3 ml) was refluxed, under nitrogen, until the reaction was shown to be complete by TLC (28 hours). It was then concentrated and the residue chromatographed on silica gel with 1 to 4% MeOH-CHCl3. A solution of the product thus obtained in MeOH-EtOAc was decolorized with Darco (activated charcoal) and crystallized from EtOAc-hexane to give 1.02 g, m.p. 109°-111° C. and 0.120 g, m.p. 107°-113° C. of the titled product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])C=O.C(Cl)(=O)C.[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>CCO>[Br:10][C:9]1[CH:8]=[CH:7][C:4]([CH:15]([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)Cl
Solvent: CCO
Product: CCOC(OCC)c1ccc(Br)c(F)c1
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-fluoro-4-bromobenzaldehyde (20.0 g, 98.5 mmol) in dry EtOH (120 mL) was added acetyl chloride (2.04 mL, 29.6 mmol) followed by the addition of triethyl orthoformate (6.55 mL, 39.4 mmol) and the contents were heated to 70° C. for 3 h. The contents were cooled to room temperature and shifted to a rotary evaporator and subjected to reduced pressure (280 mm Hg) with bath temperature 65° C. for 45 min. The pressure was further lowered to remove all the solvent. To this mixture, fresh Ethanol (60 mL), acetyl chloride (1.5 mL), triethyl orthoformate (5.0 mL) and heated to 70° C. for 2 h. The solvent was removed under the reduced pressure and diluted with EtOAc (200 mL), washed with saturated sodium bicarbonate (3×100 mL), brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue purified by silica gel column (basified with 5% Et3N, eluent: EtOAc/hexanes, 1/20) to afford 1-bromo-4-(diethoxymethyl)-2-fluorobenzene as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (t, J=8.1 Hz, 1H), 7.36-7.33 (m, 2H), 5.54 (s, 1H), 3.63-3.52 (m, 4H), 1.25 (m, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3([C:15]4[CH:16]=[CH:17][C:18]([C:21]5N=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=5)=[N:19][CH:20]=4)[CH2:14][CH2:13][CH2:12]3)[N:7]=2)[CH:3]=[N:2]1.[C:28](=O)([O-])[O-].[K+].[K+].O.C[CH2:36][O:37][C:38]([CH3:40])=O>CN(C=O)C>[O:37]1[CH2:36][CH:40]([N:1]2[CH:5]=[C:4]([C:6]3[O:10][N:9]=[C:8]([C:11]4([C:15]5[CH:16]=[CH:17][C:18]([C:21]6[CH:26]=[N:25][C:24]([NH2:27])=[CH:23][CH:28]=6)=[N:19][CH:20]=5)[CH2:12][CH2:13][CH2:14]4)[N:7]=3)[CH:3]=[N:2]2)[CH2:38]1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Reactant: Nc1cnc(-c2ccc(C3(c4noc(-c5cn[nH]c5)n4)CCC3)cn2)cn1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccc(C3(c4noc(-c5cnn(C6COC6)c5)n4)CCC3)cn2)cn1
Temperature: 80 °C

Procedure:
A mixture of R67 (50 mg, 0.14 mmol), R38 (51 mg, 0.28 mmol) and potassium carbonate (38 mg, 0.28 mmol) in DMF (2 ml) are stirred at 80° C. over night. After this time the reaction is cooled to room temperature and poured into water and EtOAc. The layers are separated and the aqueous phase is extracted twice more with EtOAc. The combined organics are dried (MgSO4), filtered and concentrated. The remaining residue is purified via flash chromatography (Silica gel, 0-8% MeOH/DCM) to afford the title compound (35 mg); m/z 417.3 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]1(=[O:17])[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](=[NH:25])[NH2:24])[CH3:19].C(O)C.CN(C=O)C>C(O)C>[CH2:18]([O:20][C:21]([C:22]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[C:11]2[C:10](=[O:17])[CH2:15][CH2:14][CH2:13][C:12]=2[NH:24][C:23]=1[NH2:25])=[O:26])[CH3:19]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1cccc(Cl)c1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1cccc(Cl)c1
Yield: 66 %

Procedure:
Upon boiling a solution of 7.1 g of 3-chlorobenzaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2 -amino-4-(3-chlorophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline- 3-carboxylic acid ethyl ester of melting point 266° C. (ethanol/DMF) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.CO.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+]>O>[C:15]1([N:21]([C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: NNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NN(C(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture consisting of 101.2 g. (0.602 mole) ethyl p-fluorobenzoate, 250 ml. methanol, 70.0 g. (0.646 mole) phenylhydrazine, and 33.6 g. (0.621 mole) sodium methoxide (mixed in that order) was heated at the reflux temperature for 16 hrs. After cooling the reaction mixture to about 25°C it was poured into 1500 ml. water. The aqueous mixture was filtered, and the filter cake was washed with water and recrystallized from 95% aqueous ethanol. The crystals melted at 174° to 178°C. An analytical sample of p-fluorobenzoic acid phenylhydrazide melting at 177° to 179°C. was obtained by recrystallizing once from a mixture of ethyl acetate and Skellysolve B (essentially a mixture of isomeric hexanes boiling in the range of 146° to 156°F.), and once from 75% aqueous ethanol.
Reaction SMILES: [CH3:1][C@@:2]1([OH:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].C([Mg]Cl)(C)(C)C.Cl[P:26]([NH:35][C@H:36]([C:38]([O:40][CH:41]([CH2:46][CH2:47][CH3:48])[CH2:42][CH2:43][CH2:44][CH3:45])=[O:39])[CH3:37])([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[CH3:37][C@H:36]([NH:35][P:26]([O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([O:9][CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[C@:2]([CH3:1])([OH:18])[C@@H:6]1[OH:7])=[O:27])[C:38](=[O:39])[O:40][CH:41]([CH2:46][CH2:47][CH3:48])[CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCC(CCC)OC(=O)[C@H](C)NP(=O)(Cl)Oc1ccccc1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCCC(CCC)OC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@](C)(O)[C@@H]1O)Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2′-C-Methylcytidine was diluted with THF (0.097 M). The resulting slurry was cooled to −78° C., then tert-butylmagnesium chloride (as 1.0 M solution in THF, 2.2 eq.) was added. The mixture was immediately warmed to 0° C., stirred for 30 min and again cooled to −78° C., then propylpentyl N-[chloro(phenyloxy)phosphoryl]-L-alaninate (as 1.0 M solution in THF, 2.2 eq.) was added dropwise. The reaction was allowed to reach RT overnight, and then was quenched by the addition of water. The aqueous phase was extracted three times with EtOAc, the combined organic phases were dried over Na2SO4. The crude product was purified by column chromatography on silica gel (DCM/MeOH 92:8), and the resulting off white solid was dissolved in DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 7 μm, 19×300 mm. Mobile phase: acetonitrile/H2O, water buffered with 5 mM AMBIC). Fractions containing the pure diastereoisomers were combined and freeze-dried to afford the title compounds as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:42][C:43]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][C:44]=1[O:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([N:49]1[CH2:48][CH2:47][CH:46]([O:45][C:44]2[CH:52]=[C:53]([F:56])[CH:54]=[CH:55][C:43]=2[Cl:42])[CH2:51][CH2:50]1)=[O:8])[CH3:2]
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Reactant: CCOC(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a stirred solution of malonic acid monoethyl ester (0.5 g, 0.00377 mole) in DMF (10 mL) was added DIPEA (1.18 g, 0.0094 mole), HOBt (0.608 g, 0.0045 mole) and EDCI.HCl (0.865 g, 0.0045 mole). After 2 minutes 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (1 g, 0.003 7 mole) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure to get afford 0.9 g (70%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 344.78 (M+1)+, 82.56%. To a stirred solution of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (0.9 g, 0.0026 mole) in a mixture of THF (10 mL), methanol (3 mL) and H2O (2 mL) was added LiOH.H2O (0.218 g, 0.0052 mole) at ambient temperature and the resulting mixture was stirred for 30 minutes. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The product was extracted with ethyl acetate, and the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.6 g (73%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid. LC-MS purity: 316.72 (M+1)+, 75.8%.