Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH3:15][C:16]1[N:21]=[C:20]([NH:22][CH3:23])[N:19]=[C:18]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31](O)=[O:32])[CH2:26]2)[N:17]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:31]([CH:27]2[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:18]3[N:17]=[C:16]([CH3:15])[N:21]=[C:20]([NH:22][CH3:23])[N:19]=3)[CH2:26]2)=[O:32])=[C:4]([O:10][C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: NCc1ccc(Br)cc1OC(F)(F)F
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nc(C)nc(NC2CCCC(C(=O)NCc3ccc(Br)cc3OC(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A mixture of ({4-bromo-2-[(trifluoromethyl)oxy]phenyl}methyl)amine (0.4 g, 1.041 mmol), 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (0.276 g, 1.041 mmol), 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.507 g, 1.146 mmol) and diisopropylethylamine (0.364 ml, 2.083 mmol) in N,N-Dimethylformamide (DMF) (5 ml) was stirred overnight at RT. The reaction mixture was treated with water which caused a precipitate to form. The precipitate was filtered and washed with water, and dried to give N-({4-bromo-2-[(trifluoromethyl)oxy]phenyl}methyl)-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide (0.35 g, 0.543 mmol, 53%) as an off-white solid. MS (ES) m/e 517, 519 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH:10]([CH:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[O:48]1[CH:52]=[CH:51][C:50]([CH:53]=O)=[CH:49]1>C(Cl)Cl>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[N:27]([CH2:53][C:50]5[CH:51]=[CH:52][O:48][CH:49]=5)[CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:29]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2Cc1ccoc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 9-(8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthene-3-carboxylic acid diethylamide, 9a (0.65 g, 1.7 mmol) in CH2Cl2 (20 mL) were added tetramethylammonium triacetoxyborohydride (0.53 g, 2.5 mmol) and 3-furaldehyde (0.17 mL, 2.0 mmol). The mixture was stirred at rt for 24 h, diluted with CH2Cl2 (10 mL), and washed with 1 N NaOH. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (eluent: 5% 0.5 M NH3 in methanol in CH2Cl2) to yield title compound 9-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide, 10a (0.25 g, 0.53 mmol). MS m/z=471.2 (MH+).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18](S(Cl)(=O)=O)=[CH:17][CH:16]=1>C(#N)C.Cl.CN(C)C>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H](C)Oc1ccc(C)cc1
Yield: 116 %

Procedure:
A solution of methyl (R)-(+)-lactate (6.66 g) in acetonitrile (33 ml) was cooled to 5° C. and triethylamine (9.8 ml) added followed by trimethylamine hydrochloride (0.62 g). A separate solution of p-toluenesulfonyl chloride (11.6 g) in acetonitrile (33 ml) was added dropwise over 20 mins maintaining the temperature below 5° C. The reaction mixture was filtered and concentrated. Diethyl ether and water were added and the organic fraction dried (MgSO4) and concentrated in vacuo to give the sub-title compound as a yellow oil (13.71 g).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH3:10])([O-:9])=[O:8].Cl[C:12]1[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1.Cl>CS(C)=O>[Cl:18][C:17]1[C:12]([CH2:10][N+:7]([O-:9])=[O:8])=[N:13][CH:14]=[C:15]([Cl:19])[CH:16]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])Cc1ncc(Cl)cc1Cl
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To 30.74 g of potassium tert-butoxide in 100 ml of dimethylsulfoxide, 16.72 g of nitromethane was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. Then, the reaction mixture was cooled with ice again, and to the reaction mixture, 25.00 g of 2,3,5-trichloropyridine in 100 ml of dimethylsulfoxide was added dropwise with stirring, and after the addition, the mixture was stirred at 70° C. for another 6 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, poured into 200 ml of 10% aqueous hydrochloric acid with stirring under cooling with ice and extracted with ethyl acetate (200 ml×1). The resulting organic layer was washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 10:90) as the eluent to obtain 10.10 g of the desired product as a pale yellow oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.C([O:14][C:15](=O)[CH:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:17])C.OS(O)(=O)=O>O>[CH2:19]([O:18][CH:16]([CH3:17])[CH2:15][OH:14])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCOC(C)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCOC(C)CO
Reaction time: 5 h
Yield: 60.6 %

Procedure:
2.2 g of LiAlH4 was added to 80 ml of ether and the mixture was stirred for 5 hours. To the mixture was added dropwise 13.6 g of (-)-ethyl-2-decyloxypropionate in the same manner as in Example 7, and themixture was stirred for 15 minutes. Then, 50 ml of water and further 50 ml of 5% H2SO4 aqueous solution were added thereto. The ether layer was separated, dried with MgSO4 and filtrated. Ether was distilled off and the residue was subjected to distillation under reduced pressure, whereby 6.9 g of (+)-2-decyloxypropanol was obtained by collecting a fraction of 94°-96° C./1 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl[CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>O>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][CH2:22][CH:21]([OH:30])[CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:6][CH:7]=2)[CH:25]=1
Reactant: Oc1ccc(-c2cccnc2)cc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc(-c2cccnc2)cc1
Yield: 38.2 %

Procedure:
Prepared according to the method as described in Example 24b) from 3-(4-hydroxyphenyl)pyridine (1.68 g), ethanol (30 ml), sodium hydroxide (0.393 g), water (10 ml) and (±)-α-(chloromethyl)-3-pyridinepropanol (0.91 g, Example 24a)) to give the title compound as a pale yellow solid (0.6 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)=[CH:15][C:14]=1[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[OH:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:27])=[CH:22][CH:21]=2)=[CH:15][C:14]=1[CH3:29]
Reactant: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1OCCO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl bromide (0.127 mL) was added to a mixture of 4′-(2-hydroxyethoxy)-3′,5′-dimethylbiphenyl-4-carboxylic acid (0.292 g) and potassium carbonate (0.169 g) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3-1/2) to afford the title compound (0.381 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[O:7]=[C:4]1[CH2:5][CH2:6][C:2](=[O:1])[N:3]1[O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:20](=[O:21])[N:19]([CH3:18])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:12][CH:11]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-Hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized from methanol (74%, white crystals).
Reaction SMILES: OS(O)(=O)=O.C[C:7]1[C:12](C)=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:14].C([O-])([O-])=O.[Na+].[Na+].[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:14])([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 400 mL of concentrated H2SO4 was added slowly 130 g of impure 2,3-dimethylpyridine N-oxide. Fuming HNO3 (330 mL) was slowly added at a rate to keep the temperature between 120° C. and 170° C. After addition was complete, the temperature was held at 103° C. for 3 hours and then the reaction was cooled. The crude reaction was added to 1 kg ice in a large pan, then, with stirring, 1.1 kg Na2CO3 was added. After cooling to room temperature, the solids were removed by suction filtration from the solution. The filtrate was extracted with chloroform. The solids were washed with hot chloroform (3 times). The combined reduced organic extracts yielded 110 g of the crude desired nitropyridine N-oxide as an orange solid. ##STR8##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
To 110 ml of carbon tetrachloride, were added 10.5 g of 4'-methyl-2-cyanobiphenyl, 9.79 g of N-bromosuccinimide and 120 mg of 2,2'-azodiisobutylonitrile, followed by heating under reflux for 2 hours. After hot filtration of the insoluble matter, the filtrate was allowed to cool to room temperature. Crystals so precipitated were collected by filtration, whereby 6.6 g of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH:14]1[O:18][CH2:17]CC1.CC(C)([O-])C.[Na+].C1COCC1.N1C=CN=C1.O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:14]2[CH2:17][O:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: CC1CCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H]2CO2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
(S)-34S)-1,2-Dihydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (230 g, 990 mmol, 1.0 eq.) was combined with MeTHF (4.9 kg, 57 mol) and cooled to 0° C. 2.0 M Sodium t-butoxide in THF (994 mL, 2.0 eq.) was added drop wise over 20 minutes. The mixture was stirred at −1° C. for 15 minutes, then cooled to −7° C. p-Tolylsulfonyl)imidazole (243 g, 1.1 mol, 1.1 eq.) was added and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was quenched with cold H2O (5.7 kg, 320 mol). Hexanes (1.8 kg, 21 mol) was added and the mixture was warmed to 23° C. and stirred for about 30 minutes. The layers were allowed to settle, the phases were separated, and the reaction vessel was rinsed with MeTHF (100 mL). The organic layer (˜8 L) was removed and stored at 5° C. overnight, then filtered through Na2SO4 and concentrated at 60 torr to 30 torr with a water bath at 25° C. to yield the title compound (220 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: CS(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CS(=O)(=O)CCCNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(3-methanesulfonyl-propyl)-amine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 384. NMR: CDCl3: 1.99-2.05 (2 H, m, CH2), 2.80 (2 H, t, J 7.2, CH2), 2.81 (3 H, s, Me), 3.10-3.13 (2 H, m, CH2), 3.85-3.88 (4 H, m, CH2), 4.01-4.06 (6 H, m), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1H, s, Ar). MS: (ESI+): MH+ 487.20
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:9]1)C1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24]>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH2:9]1)=[O:24])[CH:27]=[CH2:28]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCN(Cc2ccccc2)C1
Reactant: C=CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of 1-benzyl-3-t-butyldimethylsilyloxymethylpyrrolidine (60.10 g) and allyl chloroformate (25.27 ml) in toluene (600 ml) was heated at 60° C. for one hour. The mixture was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (500 g), and eluted with a mixture of ethyl acetate and hexane (1:9-3:7, V/V) to give 1-allyloxycarbonyl-3-t-butyldimethylsilyloxymethylpyrrolidine (30.00 g).
Reaction SMILES: [C:1]([C:3]1[CH:48]=[CH:47][C:6]([CH2:7][C@@:8]2([CH3:46])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([NH:24][C:25]5([C:28]6[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=6)[C:31]([OH:33])=O)[CH2:27][CH2:26]5)=[O:23])[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=3)[C:9]2=[O:45])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:73][C:74]([CH3:78])([CH3:77])[CH2:75][OH:76]>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]2([CH3:46])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22](=[O:23])[NH:24][C:25]5([C:28]6[CH:29]=[C:30]([C:31](=[O:33])[NH:73][C:74]([CH3:78])([CH3:77])[CH2:75][OH:76])[CH:34]=[CH:35][N:36]=6)[CH2:27][CH2:26]5)[CH2:20][CH2:21]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=3)[C:9]2=[O:45])=[CH:47][CH:48]=1)#[N:2]
Reactant: CC(C)(N)CO
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(C(=O)O)ccn5)CC4)CC3)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)c1ccnc(C2(NC(=O)C3(NC(=O)c4cnc5n4[C@](C)(Cc4ccc(C#N)cc4)C(=O)N5c4cc(Cl)cc(Cl)c4)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
To a stirred solution of 2-{1-[(1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-amino]-cyclopropyl}-isonicotinic acid (30 mg, 0.044 mmol), in 3 mL DMF was added HATU (25 mg, 0.66 mmol) diisopropylethylamine (0.3 mL) and 2-amino-2-methyl-propan-1-ol (5.8 mg, 0.66 mmol). The solution was allowed to stir at room temperature overnight (18 h). The reaction was diluted with water (5 mL), then extracted with a 5% methanol/dichloromethane solution (3×10 mL). The organic layers were combined, dried (MgSO4) and concentrated. The resulting oil was purified by reversed phase HPLC to afford 28 mg of the title compound, m/z 755.7.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=1.[CH3:27][NH:28][CH3:29].C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[CH3:27][N:28]([CH3:29])[C:14]([C:12]1[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=[C:8]([Cl:7])[N:13]=1)=[O:16]
Reactant: CNC
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
Oxalyl chloride (0.38 mL, 4.5 mmol) and N,N-dimethylformamide (0.03 mL) were added to a suspension of 2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid (303 mg, 1.0 mmol) in dichloromethane (20 mL). The mixture was stirred at 20° C. for 3 h and then evaporated under reduced pressure. The residue was dissolved in dichloro-methane (25 mL) and the solution was stirred together with 60% aqueous dimethylamine (1.2 mL, 13.3 mmol) and saturated aqueous sodium hydrogencarbonate solution (8 mL) for 1 h at 20° C. The mixture was diluted with dichloromethane (25 mL), and the organic layer was washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-40% ethyl acetate as eluent to give the title compound (215 mg, 65%) as a white solid. MS ISP (m/e): 330.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.24 (d, 2H), 7.99 (s, 1H), 7.80 d, 2H), 3.17 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C([O-])=O.[NH4+]>[Fe].O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(OCc2ccccc2)c(F)c1
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A mixture of 1-benzyloxy-2-fluoro-4-nitro-benzene (44 g, 178 mmol), toluene (400 ml), ammonium formate (35 g), iron (30 g), and water (400 ml) was heated to reflux with stirring overnight. The reaction mixture was filtered through celite and washed with ethyl acetate (400 ml). The organic layer was separated and washed with brine (300 ml), dried over sodium sulfate and concentrated to give 4-benzyloxy-3-fluoro-phenylamine as an oil (33.7 g, 87%). 1H NMR (400 MHz, CDCl3): δ 7.41-7.29 (m, 5H), 6.79 (t, 1H), 6.45 (dd, 1H), 6.14 (dd, 1H), 5.02 (s, 2H), 3.50 (s, 2H). LC/MS: (M+1) 218.
Reaction SMILES: C(O[C:5](=[O:16])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13]CC)C=C.N1C(=O)CC(=O)NC1=O.[C:26]([NH:34][CH:35]1[C:42](=[O:43])[N:41]2[CH:44](C(O)=O)[CH2:45][CH2:46][CH:40]2[CH2:39][CH:38](C)[CH2:37][CH2:36]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(O)(C(F)(F)F)=O>ClCCl.O>[OH:13][CH:8]1[CH:7]([NH:6][C:5]([C@H:44]2[N:41]3[C:42](=[O:43])[C@@H:35]([NH:34][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]3[CH2:46][CH2:45]2)=[O:16])[CH2:11][C:10](=[O:12])[O:9]1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCC
Reactant: CC1CCC(NC(=O)c2ccccc2)C(=O)N2C(CCC2C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CC(=O)NC(=O)N1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CC(NC(=O)[C@@H]2CC[C@@H]3CCCC[C@H](NC(=O)c4ccccc4)C(=O)N32)C(O)O1
Reaction time: 0.17 h

Procedure:
To a solution of (2-Ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (183 mg, 0.8 mmol) in dichloromethane (6 mL) is added barbituric acid (300 mg, 1.9 mmol) and tetrakis triphenylphosphine palladium (92 mg, 0.08 mmol). The solution is stirred for 10 minutes and 6-benzoylamino-9-methyl-5-oxo-decahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid, 20, (105 mg, 0.32 mmol) is added followed by HOBt (99 mg, 0.74 mmol) and EDCI (141 mg, 0.74 mmol). The solution is stirred for 6 hours. Water is added and the organics are washed with NaHSO4, Brine, NaHCO3, and water. The organics are dried with MgSO4 and concentrated under reduced pressure. The residue is purified over silica to afford an oil which is dissolved in dichloromethane and treated with TFA (5 mL) and water (1 mL). The solution is stirred for 2 hours and the solvent is removed. The residue is purified over silica to afford the desired product as a white powder. 1H NMR (CDCl3): δ 7.83 (m, 2H), 7.56–7.39 (m, 3H), 7.26 (m, 2H), 5.51 (d, J=5.2, 1H), 5.16 (m,1H), 4.72 (m, 1H), 4.56 (t, J=8.1 Hz, 1H), 4.35 (m, 1H), 3.95 (m, 1H), 3.71 (m, 2H), 2.90 (m, 1H), 2.52–2.38 (m, 2H), 2.26–2.05 (m, 4H), 1.87–1.61 (m, 5H), 1.32 (t, J=6.9 Hz, 3H). 13C NMR (CDCl3): δ 173.7, 172.2, 171.7, 166.6, 131.9, 128.8, 127.3, 101.3, 65.9, 60.8, 59.5, 50.6, 48.6, 36.9, 36.3, 33.1, 32.4, 25.7, 25.6, 23.6, 15.2. ESI MS: 458.16 (M+H), 480.11 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH2:20][CH3:21])=[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Br:27]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH2:20][CH3:21])=[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=2)[C:5]([Br:27])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(Cl)ccc1CC
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2nc(N)ncc2Br)[nH]c1-c1cc(Cl)ccc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1H-pyrrole-3-carboxylate (450 mg, 1.21 mmol) in DMF (7.5 mL) was treated with N-bromosuccinimide (216 mg, 1.21 mmol). The mixture was stirred overnight at room temperature, then poured into water, extracted with EtOAc (2×30 mL). The separated organic phase was dried over sodium sulfate and the solvent evaporated. Crystallization from diethyl ether afforded the title compound (420 mg, 77%).