Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH:5]([C:12]1[C:21](=[O:22])[O:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[OH:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3].C(=O)([O-])[O-].[K+:28].[K+].O>CC(O)C>[CH3:1][C:2]([CH2:4][CH:5]([C:12]1[C:21](=[O:22])[O:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[O-:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[K+:28]
Reactant: CC(=O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)CC(c1ccccc1)c1c([O-])c2ccccc2oc1=O

Procedure:
Warfarin potassium salt is prepared by refluxing the pure warfarin acid with an equivalent amount or an excess of potassium carbonate in 2-propanol. The 2-propanol may be anhydrous or may contain about 0.5% to about 10% water, preferably about 1% to about 3% water. The molar ratio of potassium carbonate to warfarin acid is between about 0.9 and about 2, and is preferably between about 1.0 and about 1.3. The reaction may be conducted at a temperature ranging from room temperature to the boiling point of the solvent for a time of from about 1 hour to about 5 hours. Preferably, the reaction is conducted at reflux temperature and the preferred reaction time is from about 2 hours to about 3 hours. The unreacted carbonate is removed by filtration. The warfarin potassium is precipitated and isolated as a pure crystalline solid by filtration and drying.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1CCOCC1.[Br:17][C:18]1[CH:19]=[C:20]([C:31](Cl)=[O:32])[C:21]2[O:26][CH:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[C:22]=2[CH:30]=1>C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:19]=[C:20]([C:31]([NH:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[O:32])[C:21]2[O:26][CH:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[C:22]=2[CH:30]=1
Reactant: NC1CN2CCC1CC2
Reactant: CC1Oc2c(C(=O)Cl)cc(Br)cc2N(C)C1=O
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Br)cc2N(C)C1=O

Procedure:
To a solution of 1.6 g of 3-aminoquinuclidine and 1.35 g of N-methylmorpholine in 25 ml of chloroform is added a solution of 4.0 g of 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo -2H-1,4-benzoxazine-8-carboxylic acid chloride in 20 ml of chloroform under cooling and stirring followed by stirring at room temperature for 3 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol-isopropyl ether to give 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide, melting at 287°-288° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[CH3:12].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>CN(C=O)C>[CH2:11]([C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])[CH2:23][CH2:24]2)=[CH:17][CH:18]=1)[CH3:12]
Reactant: O=C1CCCN1CCCCl
Reactant: CCc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(N2CCN(CCCN3CCCC3=O)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (2.0 g, 12.0 mmol), 1-(4-ethylphenyl)piperazine (2.36 g, 12.0 mmol), anhydrous Na2CO3 (0.658 g, 6.2 mmol) and NaI (0.18 g, 1.2 mmol) in dry DMF (10 ml) was stirred at 80° C. for 12 hrs. The reaction mixture was cooled, poured on water (30 ml) and the separated residue was extracted with CHCl3 (2×30 ml). The extracts were dried over Na2So4 and concentrated under reduced pressure to give 1-[4-(4-ethylphenyl)piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 2.43 g (62.0%). IR (Neat): 2940, 2800, 1660, 1440, 1000, 900,800. 1H NMR (CDCl3): 1.20(t, 3H, J=6.0 Hz, CH2CH3, 1.60-280(m, 14H, 3',4',2,1 & 2×N--CH2, CH2CH3), 3.00-3.60(m, 8H, 5', 3 & 2×N--CH2). MS: m/z 315 (M+).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([N:21]([CH2:22][CH2:23][CH2:24][CH3:25])[S:33]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)(=[O:35])=[O:34])[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCCCNC(CC)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCN(C(CC)c1nn2cccc2c(=O)n1Cc1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.1 %

Procedure:
3-Benzyl-2-(1-butylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 33, 28.0 mg, 0.0828 mmol) in CHCl3 (5 mL) was treated with 4-chloro-benzenesulfonylchloride (52.3 mg, 0.248 mmol) and Et3N (23.0 μL, 0.166 mmol), then stirred for 18 h at 25° C. The mixture was concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (3.0 mg, 7.0%) as a colorless film: LC/MS 88% at 4.13 min (ESI+) 513 (M++H).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26]1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:31]([NH:30][C:27]4[CH:28]=[CH:29][S:25][CH:26]=4)=[O:32])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccsc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccsc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-thienyl isocyanate (0.152 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 50.0 mg (16.6%) of the desired product.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.[Br:32][C:33]1[CH:34]=[N:35][C:36](Cl)=[N:37][CH:38]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[N:35][C:36]([O:3][CH2:4][CH2:5][O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:15])=[O:16])[C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[N:37][CH:38]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To sodium hydride (220 mg, 55-65% in mineral oil) was added THF (35 ml) followed by addition of 2-phenyl-ethenesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (250 mg). The mixture was stirred for 1 h at rt. Then 5-bromo-2-chloro-pyrimidine (188 mg) was added and stirring continued for 21 h at 80° C. The solvent was evaporated and diethylether (20 ml) was added to the residue. The precipitate was filtered off and washed with diethylether, dissolved in water and acidified by citric acid. The precipitate was filtered off and the crude material was purified by chromatography over silicagel with hexane/EtOAc=1/1 to give 2-phenyl-ethenesulfonic acid {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (91 mg); tR=5.39 (LC); [M+H]+=570.34 (ES+); [M−H]−=568.45 (ES−).
Reaction SMILES: O[N:2]1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:24][C:25]1([CH3:39])[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH2:35][C:36](O)=[O:37])([CH:33]=[CH2:34])[CH2:26]1.[NH4+].[OH-]>C1COCC1>[CH3:24][C:25]1([CH3:39])[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH2:35][C:36]([NH2:2])=[O:37])([CH:33]=[CH2:34])[CH2:26]1
Reactant: C=CC1(CC(=O)O)CC(C)(C)CC(C)(C)C1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC1(CC(N)=O)CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
N-Hydroxysuccinimide (0.25 g, 2.2 mmol) and N,N′-dicyclohexyl carbodiimide (0.45, 2.2 mmol) was added to a solution of cyclohexylacetic acid 17 (0.45 g, 2 mmol) in THF (5 ml). The mixture was stirred for 18 h at room temperature and cooled in an ice bath. 25% aqueous NH4OH (2 ml) was added in one portion and the mixture was stirred at room temperature for 2 h. The precipitate was filtered off and washed with diethyl ether (30 ml). The organic phase of filtrate was separated and washed with 5% aqueous KHSO4 (10 ml) and brine. The extract was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 4:1 to 1:1) to give 18 (0.34 g, 76%) as a colorless solid with m.p. 44-46° C. 1H-NMR (CDCl3, TMS): 0.91 (6H, s, 3,5-CH3); 1.02 (6H, s, 3,5-CH3); 1.00-1.30 (4H, m, 4-CH2 and 2,6-CH); 1.85 (2H, d, 14 Hz, 2,6-CH); 2.13 (2H, s, CH2C═O); 5.18 and 5.19 (total 2H, both d, 18 and 11 Hz, ═CH2); 5.40 and 5.60 (total 2H, both br s, NH2) and 6.03 ppm (1H, dd, 18 and 11 Hz, ═CH).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[CH:9]=2)[CH2:4][C:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:19]2.[C:27](=[N:33][Si](C)(C)C)=[N:28][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:14]([C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][C:3]2([CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]2)/[C:2]/3=[N:28]/[C:27]#[N:33])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(Cc4ccccc4C2)C3)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\c2cc(-c3cccc(C#N)c3)ccc2CC12Cc1ccccc1C2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 100.2 %

Procedure:
To a solution of 3-(1-oxo-1,1′,3,3′-tetrahydro-2,2′-spirobi[indene]-6-yl)benzonitrile (34 mg, 0.1 mmol) in DCM (5 mL) was added TiCl4 (76 mg, 0.4 mmol) dropwise, the mixture was stirred at 50° C. at Ar2 under microwave for 5 minutes, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (74 mg, 0.4 mmol) was added dropwise. The mixture was stirred at 60° C. at Ar2 under microwave for 10 minutes and poured into ice-water (10 mL). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude ((Z)—N-(5-(3-cyanophenyl)-1′,3′-dihydro-2,2′-spirobi[indene]-3(1H)-ylidene) cyana mide (36 mg, 99%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[CH:11][CH:12]=2)[CH2:7][N:6]([N:24]=[CH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:5]1=[O:32])(=[O:3])[CH3:2].S(=O)(=O)(O)O>[C].[Pd].CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:23])([C:19]([F:20])([F:21])[F:22])[C:15]([F:17])([F:18])[F:16])=[CH:11][CH:12]=2)[CH2:7][N:6]([NH:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:5]1=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)N(N=Cc2cccnc2)Cc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc21
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)N(NCc2cccnc2)Cc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 60 °C

Procedure:
In a 200-ml autoclave were placed 9.25 g (20 mmol) of 1-acetyl-3,4-dihydro-3-(3-pyridylmethylideneamino)-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone, 0.21 g (0.05 mmol) of 5% palladium-carbon (containing 50% water), 0.4 g (98%, 4 mmol) of concentrated sulfuric acid and 50 ml of dimethylformamide. They were heated to 60° C. with stirring and the reaction was carried out at a hydrogen pressure of 2 kg/cm2 until the hydrogen absorption rate decreased. After the reaction mixture was cooled to room temperature, the catalyst was removed by filtration. The filtrate was analyzed by high performance liquid chromatography. The result is shown in Table 1 below.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[Cl:24][C:25]1[CH:51]=[CH:50][C:28]2[S:29][CH:30]=[C:31]([CH2:32][N:33]3[CH2:37][CH2:36][N:35]([C:38]4[S:39][C:40]([C:44]([O:46]CC)=[O:45])=[C:41]([CH3:43])[N:42]=4)[C:34]3=[O:49])[C:27]=2[CH:26]=1>>[Cl:24][C:25]1[CH:51]=[CH:50][C:28]2[S:29][CH:30]=[C:31]([CH2:32][N:33]3[CH2:37][CH2:36][N:35]([C:38]4[S:39][C:40]([C:44]([OH:46])=[O:45])=[C:41]([CH3:43])[N:42]=4)[C:34]3=[O:49])[C:27]=2[CH:26]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Yield: 59 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 59% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.06 (d, J=6.0 Hz, 1H), 7.98 (d, J=3.0 Hz, 1H), 7.90 (s, 1H), 7.45-7.41 (m, 1H), 4.69 (s, 2H), 4.00 (t, J=6.0 Hz, 2H), 3.48 (t, J=6.0 Hz, 2H), 2.50 (s, 3H); MS (ES+) m/z 408.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[CH2:14][CH2:13]1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1cc(C)cc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c1

Procedure:
58 mg of the target compound (0.16 mmol, 19.5%) was obtained using 1-(3,5-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:57])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:56])[CH:48]([NH2:55])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[O:58]1[CH2:63][CH2:62][CH:61]([CH2:64][C:65](O)=[O:66])[CH2:60][CH2:59]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3](=[O:57])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:56])[CH:48]([C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)[NH:55][C:65](=[O:66])[CH2:64][CH:61]6[CH2:62][CH2:63][O:58][CH2:59][CH2:60]6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(O)CC1CCOCC1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)CC6CCOCC6)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.085 g, 0.097 mmol), (Tetrahydro-pyran-4-yl)-acetic acid (0.017 g, 0.117 mmol), and N-methylmorpholine (0.032 mL, 0.292 mmol) were suspended in DMF (0.972 mL) at room temperature. Solid HATU (0.055 g, 0.146 mmol) was added and the suspension was allowed to stir at room temperature overnight. Upon completion, the reaction was quenched with a small amount of formic acid and purified by reverse phase HPLC (10-45% acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving {2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester (0.062 g, 62%) as a white solid. LCMS-ESI+: calc'd for C52H58N8O6: 890.45 (M+); Found: 892.4 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:19]=[CH:18][C:12]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[C:21]1([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23][C:22]1=[O:29].CCCCC=CCCCC.C1(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F>C(#N)C>[CH2:33]([O:32][CH2:31][CH2:30][C:21]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:19]=[CH:18][C:12]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)[C:22](=[O:29])[NH:23][C:24](=[O:28])[NH:25][C:26]1=[O:27])[CH3:34]
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: CC(=O)NCc1ccc(Oc2ccc(O)cn2)cc1
Agent: CCCCC=CCCCC
Agent: FC(F)(F)C1(C(F)(F)F)OC(F)(F)C(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)O1
Solvent: CC#N
Product: CCOCCC1(Oc2ccc(Oc3ccc(CNC(C)=O)cc3)nc2)C(=O)NC(=O)NC1=O

Procedure:
Following the procedure outlined for the preparation of Example 1, N-[4-(5-hydroxy-pyridin-2-yloxy)-benzyl]-acetamide (0.25 g, 0.97 mmol) when treated with 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (0.20 g, 0.80 mmol), 1,5,7-trazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (PTBD, Fluka, 0.77 g) and 4 mL of acetonitrile, will afford N-(4-{5-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-pyridin-2-yloxy}-benzyl)-acetamide. Expected MS (m/z, APCI): 455 [M−H]−.
Reaction SMILES: [NH4+:1].[Cl-].[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[CH2:4].[OH-].[Na+]>O>[N:8]1[CH:9]=[CH:10][C:5]([CH2:3][CH2:4][NH2:1])=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: C=Cc1ccncc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCc1ccncc1

Procedure:
A solution of NH4Cl in 200 ml of H2O was placed in a 1L Flask. 4-Vinyl pyridine (56.4 ml, 0.52 mol) was added along with 150 ml CH3 OH and on the mixture heated at 60° for 18 h. The reaction solution was cooled to 0° in an ice bath and made basic by the addition of 30% NaOH. The basic solution was extracted with CH2Cl2 (5×100 ml) and the pooled extracts dried, then evaporated. Vacuum distillation of the residue afforded 12-1 as a colorless liquid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:9]([NH2:11])=[NH:10].[ClH:24]>>[ClH:24].[NH:8]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:9]([NH2:11])=[NH:10]
Reactant: COC(=O)c1ccc(NC(=N)N)cc1OC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NC(=N)N)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
384 mg of methyl 4-guanidino-2-methoxybenzoate trifluoroacetate was dissolved in 8 ml of 3 M hydrochloric acid, and they were stirred at 80° C. for 2.5 hours. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13](O)=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13]([Cl:22])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: c1ccccc1
Product: O=C(Cl)COc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 8.3 g (0.0298 mol) of 4-(4-chlorophenoxy)-phenoxy-acetic acid (CRL 40 333) prepared as indicated in Example 19 and of 10.8 ml (0.1500 mol) of thionyl chloride is heated to the reflux temperature for 30 minutes. After having taken up the reaction mixture in benzene and evaporated the solution to dryness under reduced pressure, 8.7 g of a beige powder are obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30]>C1COCC1>[F:27][C:26]1[C:25]([F:28])=[CH:24][CH:23]=[C:22]([N+:29]([O-:31])=[O:30])[C:21]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-fluoro-4-iodoaniline (11.40 g, 47 mmol) in 100 ml anhydrous THF at 0° C., 47 ml of a 1M solution of LHMDS in THF (47 mmol) was added dropwise. The color of the solution turned dark purple. The solution was transferred via cannula to a dropping funnel, and the solution (containing the amine free base) was added in small portions to a solution of 2,3,4-trifluoronitrobenzene (8.321 g, 47.0 mmol) in anhydrous THF (50 ml) at 0° C. After completion of addition the mixture was stirred under argon at room temperature for 15 hours. The volume of the solvent was reduced, followed by extraction using ethyl acetate and brine. The organic layer was dried over sodium sulfate, the solvent was removed, and the obtained dark oil was purified by flash chromatography (EtOAc/hexane 1:5, Rf=0.58) yielding the crude product, which became a brown solid upon drying in vacuo (yield: 6.23 g, 33.6%): In/z=393 [M−1]−.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([N:12]1[CH2:30][CH2:29][CH2:28][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH-:36].[H][H]>>[NH2:1][C@@H:2]([C:10]([N:12]1[CH2:30][CH2:29][CH2:28][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[CH2:35]([NH-:36])[C:34]1[CH:37]=[CH:38][CH:39]=[CH:32][CH:33]=1
Reactant: [NH-]Cc1cccc(I)c1
Reactant: [H][H]
Agent: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](N)Cc1ccccc1)C(=O)O
Product: [NH-]Cc1ccccc1

Procedure:
(D)Phe-Pro-Arg-3-iodo-benzylamide, 10 mg, was dehalogenated as described in Example 9, Step H, using hydrogen gas instead of tritium gas.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[CH:12](C1C=CC(C#N)=C(OC)C=1C)=[CH2:13]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:10][C:8]1[CH:9]=[C:2]([CH:12]=[CH2:13])[CH:3]=[C:4]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: C=Cc1ccc(C#N)c(OC)c1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C=Cc1cc(F)c(C#N)c(F)c1

Procedure:
2,6-Difluoro-4-vinylbenzonitrile was prepared from 4-bromo-2,6-difluorobenzonitrile using potassium vinyl trifluoroborate and PdCl2(dppf)2 in an analagous fashion as described for 4-ethenyl-3-methyl-2-(methyloxy)benzonitrile above.