Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[Br:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH:24]([CH3:26])[CH3:25])/[C:16](=[N:18]/O)/[NH2:17]>N1C=CC=CC=1>[Br:12][C:13]1[CH:14]=[C:15]([C:16]2[N:18]=[C:7]([C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[O:8][N:17]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Br
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C#N)cc3)n2)cc1Br
Temperature: 200 °C
Yield: 90.7 %

Procedure:
A 25 mL microwave vial equipped with a stirring bar was charged with 4-cyanobenzoyl chloride (0.4 g, 2.416 mmol), (Z)-3-bromo-N′-hydroxy-4-isopropoxybenzimidamide (0.5 g, 1.831 mmol) and pyridine (15 ml) to give an orange solution. The vessel was capped and the reaction heated at 200° C. for 20 min under microwave irradiation (Biotage Optimizer, 300 W). The solution was cooled, the reaction mixture was partitioned between aqueous HCl (10%, 150 mL) and DCM (40 mL) mixture, the DCM layer was drained, and the aqueous layer was extracted by DCM (2×20 mL). The combined DCM layers were washed by water (2×20 mL) and concentrated to afford white solid, which was purified via silica gel chromatography (40 g, 40% EtOAc:Heptane) to afford 4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile (0.638 g, 1.660 mmol, 91% yield) as white solid. LC/MS (Method c) Rt=3.17 min.; MS m/z: 386.19 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSO) ppm 8.40-8.32 (m, 2H), 8.23 (d, J=2.13 Hz, 1H), 8.14 (dd, J=8.14, 0.61 Hz, 2H), 8.05 (dd, J=8.65, 2.15 Hz, 1H), 7.36 (d, J=9.12 Hz, 1H), 4.89-4.77 (m, 1H), 1.35 (d, J=6.03 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]([O:16][CH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(COC)OC>[C:12]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OCc1cccc(B(O)O)c1
Reactant: CC(=O)Nc1ccc(Br)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)Nc1ccc(-c2cccc(COC(C)(C)C)c2)cn1
Temperature: 90 °C
Yield: 72.1 %

Procedure:
Under an argon stream, 1.0 g of N-(5-bromopyridin-2-yl)acetamide, 967 mg of 3-(tert-butoxymethyl)phenylboronic acid and 269 mg of tetrakis(triphenylphosphine)-palladium are placed in a round-bottomed flask containing 30 ml of dimethoxyethane and 15 ml of a 2M solution of sodium carbonate degassed beforehand. The mixture is heated at 90° C. for 15 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The residue is taken up between dichloromethane and water, the organic phase is separated and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue is then purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. The solid obtained is triturated with diethyl ether, recovered by filtration and then dried. 1.0 g of compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]2)[C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:39].O1CCOCC1>O1CCOCC1>[ClH:39].[CH3:1][C:2]1[C:3]([N:8]([C@@H:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1N(C(=O)c1ccc(-c2cnn3cccnc23)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccnc1N(C(=O)c1ccc(-c2cnn3cccnc23)cc1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound from Step 2 (R)-tert-butyl 3-(N-(3-methylpyridin-2-yl)-4-(pyrazolo[1,5-a]pyrimidin-3-yl)benzamido)piperidine-1-carboxylate (737 mg, 1.44 mmol) in 1,4-dioxane (10 mL) was added HCl/1,4-dioxane (7.2 mL of 4 M, 28.8 mmol) dropwise at 0° C. The reaction was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparatory HPLC to deliver the hydrochloride salt of the title compound (325 mg, 52%) as a yellow solid
Reaction SMILES: [CH3:1]C1C(O)=CC=CN=1.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][CH2:22][CH:21]([O:27][C:28]1[C:29](C)=[N:30][CH:31]=[CH:32][CH:33]=1)[C:20]2=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][CH2:22][CH:21]([O:27][C:28]1[CH:29]=[N:30][C:31]([CH3:1])=[CH:32][CH:33]=1)[C:20]2=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ncccc1OC1COc2ccc(OCc3ccccc3)cc2C1=O
Reactant: Cc1ncccc1O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OC2COc3ccc(OCc4ccccc4)cc3C2=O)cn1

Procedure:
By the same methods, 2-methyl-3-hydroxypyridine (7.30 g, 0.067 mol) was converted to 1.17 g of 6-benzyloxy-3-(2-methyl-3-pyridyloxy)-4-chromanone [1H-NMR includes delta 2.48 (s, 3H), 4.6 (m, 2H) and 4.93 (dd, 1H); MS includes 361 (M+) and base peak at 91; IR (CHCl3) 1697, 1486 cm-1 ].
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
EX-1A) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (50 g, 0.24 mol) and N-bromosuccinimide (42.75 g, 0.24 mol) in 100 mL of carbon tetrachloride under nitrogen was added 2,2′-azobisisobutyronitrile (0.71 g, 0.004 mol). The resultant mixture was refluxed for 2 h, then cooled to room temperature and quenched with 300 mL of water. The organic layer was collected, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 66.0 g (96%) of the desired crude 3-(1,1,2,2-tetrafluoroethoxy)bromomethylbenzene product as a yellow oil. 1H NMR indicates that this oil is a mixture of products: 7% dibrominated, 67% monobrominated, and 20% starting material. The crude product was used without fuirther purification. ESMS m/z=287 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24]([OH:26])=O)[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7].Cl.[O:28]([NH2:30])[CH3:29]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24]([NH:30][O:28][CH3:29])=[O:26])[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(Cl)n3)CC2)cc1Br
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)nc(Cl)n1

Procedure:
Title compound was synthesized by an analogous method to Example 8 by coupling 6-(4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-chloropyrimidine-4-carboxylic acid (Example 31) with methoxylamine hydrochloride (commercially available).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1.S(Cl)([Cl:18])=O>>[Cl:18][CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1
Reactant: O=C1Nc2ccccc2SC1CCCO
Reactant: O=S(Cl)Cl
Product: O=C1Nc2ccccc2SC1CCCCl
Yield: 59.1 %

Procedure:
By a process similar to that in Reference Example 13-(2), 2-(3-hydroxypropyl)-2H-1,4-benzothiazin-3(4H)-one was allowed to react with thionyl chloride to obtain 2-(3-chloropropyl)-2H-1,4-benzothiazin-3(4H)-one. The yield was 59.1%. Recrystallization from ethyl acetate-hexane gave prisms, m.p. 98°-99° C.
Reaction SMILES: [CH2:1]([C:8]([OH:26])([CH2:13][C:14]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[O:24]C)([CH3:16])[CH3:15])[C:9]([F:12])([F:11])[F:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>ClCCl.O>[CH2:1]([C:8]([OH:26])([C:9]([F:10])([F:12])[F:11])[CH2:13][C:14]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[OH:24])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccccc1)C(F)(F)F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CC(O)(Cc1ccccc1)C(F)(F)F)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
To a solution of 49 mg (0.13 mmol) of 2-benzyl-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (Example 4) in 0.5 mL of dichloromethane, 1 mL (1.0 mmol) of 1 M solution of boron tribromide in dichloromethane was added. The mixture was stirred at room temperature for 3 hours and was then cautiously added to cold MeOH and stirred for 20 minutes. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed on silica gel using first hexanes then EtOAc-hexanes (0.5:99.5 to 1:99) to afford 31 mg (65%) of the title compound as a clear oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[C:14]2[CH:9]([CH2:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([O:17][CH3:18])=[O:16])=[O:4].[K].[C:22]1(C)C=CC=CC=1.IC>C1COCC1.O>[CH3:22][C:6]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:8][CH:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH2:10]2)[N:5]1[C:3](=[O:4])[C:2]([F:1])([F:19])[F:20]
Reactant: COC(=O)C1CCC2CC=CC=C2N1C(=O)C(F)(F)F
Reactant: Cc1ccccc1
Agent: [K]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C)CCC2CC=CC=C2N1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
To a solution of N-trifluoroacetyl-2-methoxycarbonyltetrahydroquinoline (8.7 g, 30.3 mmol)in THF (100 mL) was added slowly 0.5N potassium hexamethylsilazide in toluene (66.6 mL, 33.3 mmol) over 15 min at -78° C. The mixture was stirred for 10 min followed by addition of iodomethane (2.3 mL, 36.4 mmol) at the same temperature. The mixture was allowed to warm to room temperature, stirred 5 h, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated to give 8.98 g of 2-methyl-N-trifluoroacetyl-2-methoxycarbonyltetrahydroquinoline (98%): 1H NMR (270 MHz, CDCl3) δ7.18 (m, 3H), 7.07 (m, 1H), 3.71 (s, 3H), 2.90 (td, 1H, J=13.9, 3.3 Hz), 2.50 (dt, 1H, J=13.9, 3.3 Hz), 2.28 (dt, 1H, J=13.9, 3.3 Hz), 1.56 (s, 3H), 1.53 (td, 1H, J=13.9, 3.3 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[F:12].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[F:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CN2CCCC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a stirred solution of 1-(bromomethyl)-2-fluoro-3-nitrobenzene (2.00 g, 8.54 mmol) and pyrrolidine (0.91 g, 12.82 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.72 g, 17.08 mmol) dropwise at 0° C. The mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was diluted with water (15 mL) and extracted with EtOAc (2×30 mL). The EtOAc solution was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 1-(2-fluoro-3-nitrobenzyl)pyrrolidine (1.20 g, 63%) as a viscous oil. 1H NMR (400 MHz, CD3OD): δ 8.02-7.97 (m, 1H), 7.81-7.76 (m, 1H), 7.36 (td, 1H, J=8.0, 1.2 Hz), 3.81 (d, 1H, J=2.0 Hz), 2.62-2.58 (m, 4H), 1.84-1.80 (m, 4H).
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4]1.[CH:10](=[O:12])[CH3:11]>C(O)C.O>[S:3]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:11][CH:10]=[O:12])=[CH:4]1
Reactant: O=Cc1ccsc1
Reactant: CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=CC=Cc1ccsc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of sodium hydroxide (1.0 g, 25 mmol) in a mixture of ethanol (6 ml) and water (12 ml) was added thiophen-3-carbaldehyde (4.5 g, 40.1 mmol), and the mixture was stirred at 0° C. for 10 minute. To the mixture was dropwise added 40% acetaldehyde (10 g, 90.8 mmol) over 3 hours at the same temperature, and the mixture was further stirred for 30 minutes. The reaction mixture was treated in a similar manner to that in Reference 6 to give compound B4 (3.58 g, 64.6%) as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(O)c1cc(Br)ccc1F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.1 %

Procedure:
To a solution of 1-(5-bromo-2-fluoro-phenyl)-ethanol (37 g, 168 mmol) in CH2Cl2 (400 mL) and pyridinium dichromate (127 g, 337 mmol) were added molecular sieves (10 g). The mixture was stirred at room temperature for 20 hours. The mixture was filtered through diatomaceous earth, washed with CH2Cl2 (3×100 mL) and concentrated. The crude product was purified by column chromatography (60-120 mesh silica gel) using 10% ethyl acetate in pet-ether to afford of 1-(5-bromo-2-fluoro-phenyl)-ethanone (23 g, 63%) as pale brown oil. 1H NMR (CDCl3): δ 7.9-8.1 (d, 1H), 7.5-7.7 (m, 1H), 6.95-7.1 (t, 1H), 2.6-2.7 (d, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][N:10]=1.O>N1C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH:14]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
Trimethylacetyl chloride (4.22 g, 35.0 mmol) was added dropwise to a solution of 2-amino-4-chloropyridine (3.00 g, 23.3 mmol) in pyridine (11 mL) at 0° C. The resulting solution was stirred for 12 h at r.t. Water (20 mL) was added and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (MgSO4). The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate and hexane (2/8), to give the title compound as a colourless solid (4.9 g, 99%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:4](OCC)=O.[NH2:17][C:18]([NH2:20])=[S:19].[O-]CC.[Na+]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:9]([C:3]2[C:2](=[O:1])[NH:17][C:18](=[S:19])[NH:20][CH:4]=2)[CH3:10])[CH:12]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(CO)C(C)c1cccnc1
Agent: CC[O-]
Agent: [Na+]
Product: CC(c1cccnc1)c1c[nH]c(=S)[nH]c1=O

Procedure:
Treatment of ethyl 2-(hydroxymethyl)-3-(3-pyridyl)-butyrate with thiourea and sodium ethoxide, followed by acidification gave 5-(1-(3-pyridyl)ethyl)-2-thiouracil m.p. 225°-228°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:39])[CH:34]=[C:35]([CH2:37][OH:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O.O.Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:39][C:33]2[CH:34]=[C:35]([CH2:37][OH:38])[CH:36]=[C:31]([Br:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: OCc1cc(O)cc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Temperature: 70 °C
Yield: 97.9 %

Procedure:
To a solution of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (4.2 g, 8.9 mmol), 3-Bromo-5-hydroxymethyl-phenol (1.5 g, 7.4 mmol) in N,N-dimethylformamide (40 mL) and acetone (80 mL) was added potassium carbonate (10.2 g, 74.2 mmol) at room temperature. The resulting suspension was heated to 70° C. for 24 h. Then, the reaction mixture was cooled to room temperature and diluted with water and 10% aq. HCl. The organic compound was extracted into ethyl acetate and the combined organic extracts were washed with water and brine solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (Isco™ 120 g) with 0-50% ethyl acetate/hexanes as eluting solvents to afford the title compound (4.3 g, 99%) as a colorless oil. HR-ES(+) calcd for C30H41O7Br [M+Na]+ 615.1928, observed 615.1926.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])[C:7](I)=[C:8]([C:10]#[N:11])[N:9]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:37][C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1B1OC(C)(C)C(C)(C)O1)[C:41]([O:43][CH3:44])=[O:42].C([O-])([O-])=O.[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(COC)OC>[NH2:37][C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[C:7]1[N:6]([CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])[CH:5]([CH2:4][O:3][CH2:1][CH3:2])[NH:9][C:8]=1[C:10]#[N:11])[C:41]([O:43][CH3:44])=[O:42]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(N)c1
Reactant: CCOCc1nc(C#N)c(I)n1CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCOCC1NC(C#N)=C(c2ccc(C(=O)OC)cc2N)N1CC(C)(C)O
Temperature: 100 °C
Yield: 71 %

Procedure:
In an inert atmosphere 2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-5-iodo-1H-imidazole-4-carbonitrile (3.66 g, 10.5 mmol) was combined with dimethoxyethane (43 mL) to give a light brown solution. To this solution were added Pd(OAc)2 (118 mg, 524 μmol), triphenylphosphine (275 mg, 1.05 mmol) and methyl 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4.36 g, 15.7 mmol) with stirring. Finally Na2CO3 (2 M, 15.7 mL, 31.4 mmol) was added. The reaction mixture was heated to 100° C. and stirred for 1 hour. After cooling to room temperature the mixture was partitioned between ethyl acetate (70 mL, 2×50 mL) and water (70 mL). The organic phases were combined, dried over MgSO4, concentrated in vacuo and purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound (2.79 g, 71%) as light brown foam that was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)C>[F:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccc(F)cc1)c1ccccc1
Reaction time: 3 h

Procedure:
52.0 g. (433 mmoles) of acetophenone is added to a solution of 21.8 g. (545 mmoles) of sodium hydroxide in a mixture of 196 ml. of water and 122.5 ml. of 95% ethanol stirred at 20°-25° C., the resulting suspension is cooled to 0°-5° C., and 53.74 g. (433 mmoles) of 4-fluorobenzaldehyde is added portionwise, the temperature of the reaction mixture rising to 20° C. during the addition. The solidified reaction mixture is kept at 20°-25° C. for 3 hours and refrigerated for 16 hours. The solid is collected by filtration, rinsed with about 2 l. of water until the rinses are neutral, rinsed with 200 ml. of cold 95% ethanol and recrystallized from 95% ethanol to obtain the product as yellow flakes (66.25 g. (68%)), m.p. 83°-86° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:14])OCC.[O-]CC.[Na+].[N:19]#[C:20][NH2:21]>C(O)C>[C:20]([N:21]=[C:10]([NH2:14])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])#[N:19]
Reactant: CCOC(=N)Cc1ccccc1C
Reactant: N#CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1CC(N)=NC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A solution of Example 1B (4 g, 18.72 mmol)) in absolute ethanol (50 ml) was treated with a 21% sodium ethoxide solution in ethanol (7 ml, 18.72 mmol) and the precipitated sodium chloride was filtered off. The filtrate was then treated with a solution of cyanamide (0.79 g, 18.72 mmol) in absolute ethanol (25 ml) and stirred at room temperature for one hour. The solvent was evaporated under reduced pressure. The residual oil was triturated with ether to afford white crystals that were filtered and dried to yield 2.5 g of product. MS (ESI+) m/z 174 (M+H)+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH:31]=[CH:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:30]=4)=[O:2])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccc(C=Cc2ccccc2)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(C=Cc4ccccc4)cc3)(CC1)CC2
Yield: 27.5 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminostilbene (66.4 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-styrylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (21.3 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([C:17]([N:19]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:37])=[C:31]([CH:36]=3)[C:32]([O:34]C)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[OH-].[Li+].O.Cl>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([C:17]([N:19]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:37])=[C:31]([CH:36]=3)[C:32]([OH:34])=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:18])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(Cc1ccc(F)c(C(=O)O)c1)C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.69 h
Yield: 93.2 %

Procedure:
To a solution of methyl 5-{[{4-[(4-butylphenyl)ethynyl]benzoyl}(hexyl)amino]methyl}-2-fluorobenzoate (350 mg; 0.66 mmol) in THF (7 mL) were added lithium hydroxide monohydride (278 mg; 6.63 mmol) and water (3 mL).The reaction mixture was stirred under MW at 100° C. for 2500 s. Then an aqueous solution of HCl 1N (10 mL) was added and the mixture extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate and the solvent was removed under reduced pressure to give 316 mg (93%) of the title compound as a colorless oil. HPLC, Rt: 5.64 min (purity=98.7%). LC/MS: M+(ESI): 514, 1H NMR (MeOD) δ: 7.88 (m, 1H), 7.50 (d, J=7.9 Hz, 2H), 7.33 (d, J=9.0 Hz, 5H), 7.1 (d, J=7.9 Hz, 3H), 4.78 (m, 1H), 4.60 (m, 1H), 2.54 (t, J=7.5 Hz, 2H), 1.51 (q, J=7.6 Hz, 5H), 1.38 (s, 3H), 1.14 (t, J=7.16 Hz, 4H), 1.02 (m, 3H).