Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].CCN=C=NCCCN(C)C.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.Cl.[F:71][C:72]([F:80])([F:79])[CH:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:76]3[CH2:77][CH2:78][CH:73]([C:72]([F:80])([F:79])[F:71])[CH2:74][CH2:75]3)=[O:40])=[CH:37][CH:38]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:26])[CH3:27])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: FC(F)(F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Mix 3′,5′-Dichloro-4′-[(R)-2-oxo-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (Preparation 21) (0.94 g, 1.52 mmol), EDCI (0.358 g, 1.83 mmol), N-methylmorpholine (0.50 mL, 4.57 mmol), HOBT (0.511 g, 1.52 mmol) and 4-trifluoromethyl-piperidine hydrochloride (0.466 g, 3.05 mmol) in CH2Cl2 (15 mL). Stir for 12 hours at room temperature. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with NaHCO3, brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.586 g (51%) of the title compound: Mass spectrum (apci) m/z=753 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[NH2:29])C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:29][C:24]1[N:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([OH:30])=[O:21])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccnc1N
Reactant: O=C(O)CCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(CCCOCc1ccccc1)Nc1ncccc1C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
4-(benzyloxy)butyric acid (154 mg, 0.79 mmol) was dissolved in chloroform, thionyl chloride (158 mg) was added, and the mixture stirred at room temperature for 1 Hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, the residue was dissolved in chloroform, triethylamine (0.46 mL) and 2-aminonicotinic acid ethyl ester (110 mg, 0.66 mmol) were added, and the mixture stirred at room temperature for 2 hours. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction liquid, the mixture extracted with chloroform, and dried with anhydrous sodium sulfate. The obtained residue was dissolved in methanol, 2N sodium hydroxide aqueous solution (0.66 mL) was added, and the mixture stirred at room temperature for 2 hours. After adding hydrochloric acid aqueous solution to the reaction liquid to render it weakly acid, the solvent was distilled off under reduced pressure. Ethyl acetate and a small amount of ethanol were added to the residue, the solid precipitate was filtered off, and the target compound (166 mg, 80%) was thus obtained as a colorless solid.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:4]/[CH:5]=[CH:6]/[CH2:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:4]/[CH:5]=[CH:6]/[CH2:7][CH3:8]
Reactant: CC/C=C/CCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CC/C=C/CCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1 ml, 15 mmol) and trans-3-(3-(3-hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.90 g (75%).
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[CH3:33][C:34]([CH3:39])([CH3:38])[C:35]([O-:37])=[O:36].[Cs+].[I-].[Na+].C(#N)C>O>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:37][C:35](=[O:36])[C:34]([CH3:39])([CH3:38])[CH3:33])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: CC(C)(C)C(=O)[O-]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)OC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 30 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.40 g, 0.81 mmol), cesium 2,2-dimethyl-propionate (0.38 g, 1.63 mmol), sodium iodide (0.121 g, 0.81 mmol) and acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-4% MeOH over 1 hour and 30 minutes) to afford the title compound. Isolated yield: 30%. 1H NMR (400 MHz, DMSO-d6): δ 7.41-7.38 (m, 1H), 7.33 (t, 1H), 7.22 (dd, 1H), 6.71-6.65 (m, 1H), 4.77-4.68 (m, 1H), 4.12-3.94 (m, 2H), 3.88-3.74 (m, 2H), 3.36-3.28 (m, 2H), 3.18-3.12 (m, 1H), 3.07-3.03 (m, 2H), 2.37 (d, 3H), 2.15-2.06 (m, 2H), 2.00-1.97 (m, 2H) 1.44 (dd, 3H); 1.08 (d, 9H),
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: NC1CCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CCC2)c1
Reaction time: 16 h
Yield: 50.2 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (400 mg, 1.2 mmol) and cyclobutylamine (0.8 mL, 6 mmol) in 20 mL of DMF was added PyBOP (850 mg, 1.7 mmol) and TEA (1 mL, 7 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by ISCO CombiFlash Rf silica chromatography eluted with 88:10:2 chloroform:MeOH:H2O to give the desired product as a yellow solid (250 mg, yield 54%). MS calcd for (C19H22BN3O5S): 415.1. MS found (ESI negative): (M−H)−=414.2. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.85 (s, 1H), 9.17 (s, 1H), 8.28 (d, J=7.6 Hz, 1H), 7.42 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.10 (dd, J=8, 2 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 6.34 (dd, J=8, 2 Hz, 1H), 5.93 (bs, 2H), 4.87 (s, 2H), 4.20 (m, 1H), 3.75 (s, 2H), 2.18 (m, 2H), 1.89 (m, 2H), 1.64 (m, 2H).
Reaction SMILES: [CH:1]1[C:14]2[C:5]3=[C:6]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH2:15][C:4]3=[CH:3][CH:2]=1>[Pd].CCO>[CH:10]1[C:11]2[CH2:12][CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[C:4]4[CH2:15][C:7]([C:6]=2[C:5]=34)=[CH:8][CH:9]=1
Reactant: c1cc2c3c(c1)ccc1cccc(c13)C2
Agent: [Pd]
Solvent: CCO
Product: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Yield: 89.9 %

Procedure:
4H-cyclopenta[def]phenanthrene (4.75 g, 25 mmol) was put into a Par reactor bottle, and EtOH (200 ml) was added thereto. 5% Pd/C (3.99 g) was added to the reaction solution, and the resultant solution was incubated under a hydrogen pressure of 40 psi for 24 hours. After the reaction was terminated, the reaction solution was filtered, and the filtrate was concentrated under a reduced pressure to give a white product (4.32 g, 90%).
Reaction SMILES: [CH:1]12[NH:18][CH:14]([CH2:15][CH2:16][CH2:17]1)[CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][CH2:2]2.CO.[Cl-:21].[Mn+2:22].[Cl-:23]>CCO>[Cl:21][CH:13]1[NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][CH2:2][CH:1]2[NH:18][C:14]1([Cl:23])[CH2:15][CH2:16][CH2:17]2.[Mn+2:22]
Reactant: [Cl-]
Reactant: C1CC2CNCCNCCNCCNCC(C1)N2
Agent: [Mn+2]
Solvent: CO
Solvent: CCO
Product: ClC1NCCNCCNCCNCC2CCCC1(Cl)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
3,6,9,12,18-Pentaazabicyclo[12.3.1]octadecane prepared as in Example 38C (0.405 g, 1.59 mmol) was added to a refluxing solution of anhydrous MeOH (50 ml) containing anhydrous manganese(II) chloride (0.200 g, 1.59 mmo) under a dry nitrogen atmosphere. After refluxing for 2 h, the solution was stirred overnight at room temperature. The solution was taken to dryness. The solid was dissolved in EtOH (10 ml) and the solution was filtered through celite. Ethyl ether was added to the filtrate which induced crystallization of a white solid. The solid was collected by filtration, washed with ethyl ether and dried in vacuo to give 0.43 g (72% yield) of a white solid as product: FAB mass spectrum (NBA) m/z (relative intensity) 380 (M+, 3), 345/347 [(M-Cl)+, 100/2]; Anal. calcd for C14H31N5MnCl2 : C, 40.96; H, 7.67; N, 18.37. Found: C,40.85; H, 7.72; N, 18.32.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].O1CCCC1.C([Li])CCC.[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CCCCCC.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:7]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1ccc(Cl)cc1C1(O)CCCCC1
Temperature: -30 °C

Procedure:
A mixture of 20.75 g of 2-bromo-4-chloro-phenol, 200 ml of anhydrous tetrahydrofuran cooled to -30° C. was stirred and then 172 ml of a solution of butyllithium in hexane titrating 1.16 M/l were added thereto with stirring over 45 minutes at -30° C. The mixture was stirred for 41/2 hours at -30° C. and was then cooled to -78° C. at which 10.35 ml of cyclohexanone were added over one hour. The mixture was stirred at -75° to -78° C. for 17 hours and the temperature was then allowed to return to room temperature. The mixture was poured into a water-concentrated hydrochloric acid mixture and was then extracted with ether. The ether extracts were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 25 g of raw residue. The latter was chromatographed over silica gel H under pressure and elution with methylene chloride yielded 7 g of 4-chloro-2-(1-hydroxycyclohexyl)-phenol melting at 110° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][C:33]=1[C:34]([N:36]([O:38][CH3:39])[CH3:37])=[O:35])[CH2:12][O:13][CH2:14][C@@H:15]1[CH2:17][C@@H:16]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+].ClC1[N:52]=[CH:51][C:50]([Cl:53])=[CH:49][N:48]=1>C(Cl)Cl.O>[Cl:53][C:50]1[CH:49]=[N:48][C:24]([N:21]2[CH2:20][CH2:19][CH:18]([C@H:16]3[CH2:17][C@H:15]3[CH2:14][O:13][CH2:12][C:11]3[CH:31]=[CH:32][C:33]([C:34]([N:36]([O:38][CH3:39])[CH3:37])=[O:35])=[C:9]([F:8])[CH:10]=3)[CH2:23][CH2:22]2)=[N:52][CH:51]=1
Reactant: CON(C)C(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
TFA (1 mL) was added to a solution of product from step B (35 mg, 0.078 mmol) in DCM (1 mL) and the resulting mixture stirred at RT for 15 min. The mixture was evaporated and the residue dissolved in DMF (1 mL) and Cs2CO3 (76 mg, 0.233 mmol) and 2,5-dichloropyrimidine (13.89 mg, 0.093 mmol) added. The resultant mixture was stirred at RT overnight, diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent EtOAc/hexanes 0-100%) to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 8.02 (s, 1H), 7.44 (m, 1H), 7.17 (d, 1H), 7.13 (d, 1H), 4.72-4.62 (m, 2H), 4.61 (d, 1H), 4.55 (d, 1H), 3.66-3.53 (m, 4H), 3.53-3.47 (m, 1H), 3.38 (br s, 3H), 2.89-2.81 (m, 2H), 1.97 (d, 1H), 1.93 (d, 1H), 1.43-1.31 (m, 2H), 1.29-1.20 (m, 1H), 1.11-1.02 (m, 1H), 0.81-0.69 (m, 2H), 0.09-0.04 (m, 1H). MS (ESI) m/z 463 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[ClH:19].[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:29]3[CH2:30][CH2:31][CH:26]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:27][CH2:28]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCC(N4CCCCC4)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 93 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 4-(piperidin-1-yl)piperidine as described in Steps 5 and 6, Example 24 to give the title compound as a white solid (93% yield). LC/MS: RT 2.17 min; m/e 450; 1H NMR (δ, ppm): 11.89 (1H, br), 10.44 (1H, br), 7.64 (1H, d), 7.37 (1H, s), 7.29 (1H, d), 3.78 (2H, d), 3.50 (2H, d), 2.78-2.98 (2H, m), 2.35-2.58 (2H, q), 2.34 (3H, s), 2.20 (2H, d), 1.60-1.96 (8H, m), 1.20-1.50 (2H, m), 1.10 (3H, t).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([CH:17]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:19]=2[O:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)(=O)C>[CH2:5]([CH:17]1[C:22](=[O:23])[NH:21][C:20]2[CH:24]=[C:25]([OH:28])[C:26]([N+:1]([O-:4])=[O:2])=[CH:27][C:19]=2[O:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCCCCC1Oc2ccc(O)cc2NC1=O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCC1Oc2cc([N+](=O)[O-])c(O)cc2NC1=O

Procedure:
Fumic nitric acid (δ1.52, 1.4 ml, 0.0336 mole) in acetic acid (16 ml) was added dropwise under stirring at 15° C. to 2-n-dodecyl-6-hydroxy-2H-1,4-benzoxazin-3-(4H)-one (11.2 g, 0.0336 mole) in acetic acid. The 2-n-dodecyl-6-hydroxy-2H-1,4-benzoxazin-3-(4H)-one (5.6 g, 44%) separated as orange prisms and was used as such.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]1[C:15]([CH:20]=O)=[N:16][CH:17]=[CH:18][CH:19]=1.C(OCC)(=O)C.N1CCCCC1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:10]#[N:11])=[CH:20][C:15]3[C:14](=[CH:19][CH:18]=[CH:17][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC(=O)c1cccc(F)c1
Reactant: Nc1cccnc1C=O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: N#Cc1cc2ncccc2nc1-c1cccc(F)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(3-fluorophenyl)-3-oxopropanenitrile (0.8991 g, 5.511 mmol) and 3-amino-2-pyridinecarbaldehyde (0.6730 g, 5.511 mmol) in ethyl acetate (16.70 mL, 5.511 mmol) was added piperidine (0.04360 mL, 0.4409 mmol) and the mixture was heated under reflux (bath temp. 85° C.) with stirring. After 1 h, the mixture was cooled to room temperature and concentrated under reduced pressure to give a dark brown solid. The dark brown solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc in hexane for 25 min as eluent to give 2-(3-fluorophenyl)-1,5-naphthyridine-3-carbonitrile as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.27 (1H, d, J=0.8 Hz), 9.18 (1H, dd, J=4.1, 1.8 Hz), 8.56-8.62 (1H, m), 8.01 (1H, dd, J=8.6, 3.9 Hz), 7.76-7.85 (2H, m), 7.63-7.71 (1H, m), 7.44-7.52 (1H, m); LC-MS (ESI) m/z 249.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=2)[N:7]=[CH:6]1.O[Li].O>C1COCC1.CO.O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([OH:18])=[O:17])=[CH:11][CH:12]=2)[N:7]=[CH:6]1
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccccc3F)cnc2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(=O)n(Cc3ccccc3F)cnc2c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Methyl 3-(2-flourobenzyl)-4-oxo-3,4-dihydroquinazoline-7-carboylate 300 mg, 0.92 mmol) was dissolved In a mixture of THF-MeOH—H2O (10 mL-3 mL-3 mL) followed by the addition of LiOH—H2O (200 mg). The mixture was stirred at RT over night. The solvent evaporated and the residue was dissolved in 4 mL of water and then acidified with 2N HCl to pH˜3. The solid was filtered off dried to gave 270 mg 3-(2-flourobenzyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid in 75% yield.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:5](Cl)=[O:6])[CH3:3].[CH2:19]([N:21]([CH2:32][CH3:33])[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH3:20].C(N(CC)CC)C>O1CCCC1.CCOCC>[CH2:30]([N:27]([CH2:28][CH3:29])[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][N:21]([CH2:32][CH3:33])[CH2:19][CH3:20])[C:5]([N:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:6])[CH3:31]
Reactant: CC(C)N(CCS(=O)(=O)c1ccccc1)C(=O)Cl
Reactant: CCN(CC)CCNCCN(CC)CC
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)CCN(CCN(CC)CC)C(=O)N(CCS(=O)(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 7.67 g (0.0265 mole) of N-(1-methylethyl)-N-[2-(phenylsulfonyl)ethyl]carbamic chloride and 6.24 g (0.029 mole) of N'-[2-(diethylamino)ethyl]-N,N-diethyl-1,2-ethanediamine and 2.73 g (0.0270 mole) of triethylamine in 400 ml of tetrahydrofuran was refluxed for 6 hr and then was stirred at room temperature for 7 hr. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over sodium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in ether, and the solution was extracted with three portions of water. The ether solution was dried over sodium sulfate, and the solvent was removed in vacuo to give an oil. This was pumped under high vacuum at 56° C. for 20 hr to give the title compound as an oil.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:11]([Mg]Br)[CH3:12].C1COCC1.B(F)(F)F.CCOCC>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[NH2:7][C:6]1([C:5]2[CH:8]=[CH:9][C:2]([C:1]#[N:10])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: N#Cc1ccc(C#N)cc1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(N)CC2)cc1
Reaction time: 0.75 h
Yield: 15 %

Procedure:
Terephthalonitrile (500 mg, 390 mmol) was dissolved in 10 ml of DCM. Ti(OiPr)4 (1.1 ml, 3.9 mmol) was added to the solution, followed by a 3M solution of ethylmagnesium bromide in THF (2.3 ml, 7.0 mmol). The mixture was aged for 45 min at RT and BF3.Et2O (890 ul, 7.0 mmol) was added. The mixture was then aged for an additional 2 h at RT. The reaction was quenched with NH4Cl and 3N HCl. The layers were separated and the aqueous layer was washed with ether. The aqueous layer was then basicified using 10N NaOH (pH 9-10). EtOAc was added and the biphasic mixture was filtered. The layers were cut and the aqueous layer extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered and concentrated. Yield=15%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C1([PH2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)C2C=CC=CC=2)C=CC=CC=1.[O:31](CC(=O)C)[C:32]1[CH:37]=CC=C[CH:33]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:33][C:32](=[O:31])[CH2:37][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)COc1ccccc1
Reactant: c1ccc([PH2](c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C=CC(=O)Cc2ccccc2)ccc1O
Reaction time: 3 h
Yield: 81 %

Procedure:
4-Hydroxy-3-methoxybenzaldehyde (2.1 g, 13.8 mMol) and 3-phenoxypropane-2-one triphenylphosphorane (2.8 g, 6.9 mMol) (prepared as described by LeCorre: C. R. Acad. Sci. Paris 273 81 (1971)) are dissolved in 100 ml of toluene and warmed to reflux. After three hours, the solvent is evaporated and the residue is taken up in tHF. Sodium bisulfite (10.0 g) is dissolved in 100 ml of water and stirred with the solution for one hour. The THF is evaporated and the water is extracted with chloroform. Drying over magnesium sulfate and evaporation of the chloroform gives a yellow oil. Flash chromatography in ethyl acetate on silica gel gives 1.5 g (65%) of 1-(4'-hydroxy,3'-methoxyphenyl)-4-phenyl-1-butene-3-one; mp=85°-87° C. C, H analysis: Calcd for C17H16O4 (71.81, 5.68); Found (71.85, 5.50).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:8]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>>[N+:14]([C:11]1[CH:10]=[N:9][C:8]([N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]2)=[N:13][CH:12]=1)([O-:16])=[O:15]
Reactant: O[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Product: O=[N+]([O-])c1cnc(N2CC[C@@H](O)C2)nc1

Procedure:
This compound was prepared with the same method described before using (R)-3-hydroxypyrrolidine and 2-chloro-5-nitropyrimidine to give (R)—N-(5-nitro-pyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C8H10N4O3 m/e 210.19, obsd 211.0 (ES, M+H). Hydrogenation of the nitro compound, as above, provided (R)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.