Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][F:23])[C@@H:13]3[C@@H:18](O)[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:30])CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][F:23])[C@@H:13]3[C@H:18]([F:30])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OCCF)ccc(C#N)c1Cl
Solvent: O
Solvent: ClCCl
Product: Cc1c(C2=NN3CC[C@@H](F)[C@H]3[C@@H]2OCCF)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.1 %

Procedure:
To a stirred solution of 2-chloro-4-((3S,3aS,4S)-3-(2-fluoroethoxy)-4-hydroxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile obtained in example 16 (120 mg, 0.36 mmol) in DCM (5 mL) at 0° C. was added DAST (0.05 mL, 0.43 mmol) and stirred at room temperature for 14 h. Once the starting material had disappeared (monitored by TLC) reaction mixture was diluted with DCM, water and extracted. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 50% EtOAc in Hexane) provided the title compound (60 mg, 50%).
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:13][C:14]([NH2:16])=[NH:15].[OH-].[Na+]>CC(C)=O.O>[NH2:15][C:14]([NH:16][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[NH:13]
Reactant: N=C(N)N
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(=N)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of tert-butyl dicarbonate (57.3 g, 263 mmol) in acetone (500 mL) was added to a solution of guanidine hydrochloride (100 g, 1050 mmol) and sodium hydroxide (84 g, 2100 mmol) in water (400 mL) at 0° C. The mixture was stirred at RT for 2 hrs. The acetone was removed by rotary evaporation and the remaining suspension was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate and the solvent was evaporated to give 1,1-dimethylethyl [amino(imino)methyl]carbamate (42 g, 100%). 1H NMR (400 MHz, chloroform-d) δ ppm 6.08 (br. s., 4H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[NH:7][C:8]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][C:24]3[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([Cl:32])[CH:25]=3)[C:17]=2[F:33])=[O:13])=[C:9]([Cl:11])[N:10]=1)(=[O:4])=[O:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:11][C:9]1[N:10]=[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[NH:7][C:8]=1[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][C:24]2[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([Cl:32])[CH:25]=2)[C:17]=1[F:33])=[O:13]
Reactant: CS(=O)(=O)N(c1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Reaction time: 72 h
Yield: 46 %

Procedure:
A solution of 2-[bis(methylsulfonyl)amino]-4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.030 g, 0.049 mmol) and TBAF (0.059 mL of a 1M solution in THF, 0.059 mmol) in THF (0.5 mL) was heated overnight under reflux. Additional TBAF (0.050 mL, 0.050 mmol) was added and stirring was continued at RT for 3 days. The solution was concentrated and purified by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) to provide the title compound (0.012 g, 46%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.79 (br. s., 1H) 10.64 (br. s., 1H) 8.35 (br. s., 1H) 7.83 (s, 1H) 7.44-7.55 (m, 3H) 7.39 (t, J=6.59 Hz, 1H) 4.51 (br. s., 2H) 3.20 (br. s., 3H). ES-LCMS: m/z 532.1, 534.1, 536.0 (M+1).
Reaction SMILES: C([BH3-])#N.[Na+].Cl.[CH3:6][C:7]1[C:11]([CH3:12])=[C:10]([NH:13][S:14]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[O:30][CH:31]=[CH:32][N:33]=4)=[CH:25][C:24]=3[CH2:34][NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[O:9][N:8]=1.[CH:41](=O)[CH3:42]>CO>[CH3:6][C:7]1[C:11]([CH3:12])=[C:10]([NH:13][S:14]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[O:30][CH:31]=[CH:32][N:33]=4)=[CH:25][C:24]=3[CH2:34][N:35]([CH2:41][CH3:42])[CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[O:9][N:8]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CNCC(F)(F)F)c1C
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(Cc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C)CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
Sodium cyanoborohydride (13 mg; 0.20 mmol) was added to a mixture of N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[[(2,2,2-trifluoroethyl)amino]methyl][1,1'-biphenyl]-2-sulfonamide, monohydrochloride (55 mg; 0.10 mmol, prepared as in Example 45), 100 mg of 3 Å molecular sieves and acetaldehyde (0.10 ml; 1.80 mmol) in 1 ml of methanol at room temperature. After stirring for 18 hours at room temperature, the reaction mixture was filtered through a nylon syringe filter. The filtrate was concentrated and the residue was partitioned between EtOAc (20 ml) and saturated NaHCO3 solution (20 ml), the aqueous layer was extracted with EtOAc (20 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4) and concentrated. The residue was chromatographed on a 2.5×6 cm silica gel column, using EtOAc:Hex, 1:1 as the mobile phase. The pure fractions were concentrated to an oil that was dissolved in ~0.2 ml of MeOH. Water (3 ml) was added and the turbid mixture was frozen. Lyophilization afforded 24 mg (49%) of the title compound of this Example as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[O:14][C:13]([CH2:16][N:17]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:12][C:11]=3[CH:10]=[C:9]([Cl:28])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.Cl>C(O)C.C(O)(C)C>[Cl:28][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[O:14][C:13]([CH2:16][NH2:17])=[CH:12][C:11]=2[CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(-c3ccccc3)c2o1
Agent: CN
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: NCc1cc2cc(Cl)cc(-c3ccccc3)c2o1
Temperature: 70 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a suspension of 2-[(7-phenyl-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (0.382 g, 0.985 minol) in ethanol (10 mL) was added the methylamine (33% in ethanol, 20 mL) and the reaction mixture was heated to 70° C. and allowed to stir for 1 h. The reaction mixture was allowed to cool to room temperature and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with water (2×20 mL), saturated aqueous sodium bicarbonate (20 mL), saturated aqueous sodium chloride (20 mL), dried (magnesium sulfate), and the solvent removed in vacuo. Purification by flash column chromatography (silica, 10% ammonium hydroxide in methanol:ethyl acetate 1:9) provided a colorless oil that was dissolved in isopropanol (2 mL) and hydrogen chloride (1.0 N in diethyl ether, 5 mL) was added. The resulting precipitate was filtered, washed (diethylether), and dried to afford 0.165 g (57%) of [(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]amine as a white solid. mp>225° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1I.C(N(CC)CC)C.[C:16]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[CH:29])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:16]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]1[O:1][C:2]2=[CH:3][N:4]=[CH:5][CH:6]=[C:7]2[CH:29]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1cnccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ccncc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 829 mg (3.7 mmol) sample of 3-hydroxy-4-iodopyridine, from step 9b above, 130 mg (0.18 mmol) of (Ph3P)2PdCl2, 170 mg (0.74 mmol) of CuI, and 0.6 mL of triethylamine were combined in 10 mL of DMF at ambient temperature and stirred for 3 hours. To this mixture was added a solution of 1-BOC-2-(S)-ethynylpyrrolidine (1.5 g, 7.7 mmol, from Example 1c above) in 5 mL of DMF, and the reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ether. The ether layer was filtered, washed with 10% NaOH then 50% brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]2=[CH:18][C:9]1[NH:10][C:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Yield: 34.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-(4-fluoro-phenyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (32 mg, 34.2%) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](OCC)=[O:11]>>[CH2:8]([NH:9][CH:10]=[O:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC=O
Reactant: NCCc1ccccc1
Product: O=CNCCc1ccccc1

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-phenylethanamine (1.9 g, 15.70 mmol, 1.00 equiv). This was followed by the addition of ethyl formate (5 g, 67.57 mmol, 4.30 equiv) dropwise with stirring. The resulting solution was stirred overnight at 50° C. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (70:1). This resulted in 2.27 g (97%) of N-phenethylformamide as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]12([NH2:27])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>>[C:17]12([NH:27][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NC12CC3CC(CC(C3)C1)C2

Procedure:
The title compound is prepared from N-benzyloxycarbonyl-D-alanine and 1-adamantanamine using the usual DCC-HOBt procedure described above.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O.[OH-].[Na+].S(OC)(O[CH3:21])(=O)=O>C(Cl)Cl>[CH3:21][O:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CON=C(C(C)=O)C(=O)OC(C)(C)C
Yield: 93.3 %

Procedure:
To the tert-butyl 2-hydroxyimino-3-oxobutyrate was added water [6 l ], to which was added 30% sodium hydroxide [800 ml] at 28° C. while stirring to render the pH to 9.0. To the resultant solution was added dimethyl sulfate [1324 g] at 28° to 30° C. in the course of 20 minutes, which was stirred for 4 hours while adding thereto at 25° to 30° C. a 30% aqueous solution of sodium hydroxide [500 ml] to adjust the pH within the range of 8.7 to 9.0. After completion of the reaction, extraction was conducted with methylene chloride [4 l ], and the aqueous layer was subjected to further extraction with methylene chloride [2 l ]. The methylene chloride layers were combined and washed with a 1N aqueous solution of sodium hydroxide, 1N HCl, a 5% aqueous solution of sodium hydrogencarbonate and water, each one litre portion, successively. The resultant solution was dried over anhydrous sodium sulfate [700 g], followed by concentration under reduced pressure to obtain tert-butyl 2-methoxyimino-3-oxobutyrate [1878 g] as an oily product. The yield was 93.3%.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([NH:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-(4-chlorophenyl)acetate dihydrochloride (I112) (0.12 g, 0.32 mmol) in DCM (5 ml), were added triethylamine (0.13 ml, 0.95 mmol) and benzoyl chloride (44.0 μl, 0.38 mmol), and the reaction was stirred at RT for 3 hours. Then the solvent was evaporated, and the residue was taken up with EtOAc and washed with Na2CO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-(4-chlorophenyl)acetate (0.126 g; quantitative yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10].[OH-].[Na+].O.[C-:14]#[N:15].[K+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:14]#[N:15])=[C:4]([CH3:10])[CH:5]=1
Reactant: Cc1cc(F)ccc1CCl
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)ccc1CC#N
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
1-(Chloromethyl)-4-fluoro-2-methylbenzene (12.8 g, 81 mmol) was dissolved in CH2Cl2 (50 mL) and to the resultant solution was added a mixture of tetrabutylammonium hydrogensulphate (1.4 g, 4.0 mmol), NaOH (0.32 g, 8.1 mmol) and water (50 mL) followed by an aqueous solution of potassium cyanide (5.0 g, 77 mmol). The mixture was stirred for 5 minutes and then the pH of the aqueous layer was monitored and adjusted to the alkaline side by the dropwise addition of aqueous sodium hydroxide (5M). The mixture was refluxed for one hour, stirred at room temperature overnight and then diluted with CH2Cl2 (50 mL). The organic layer was washed thrice with water and then dried over Na2SO4. The solvent was removed by evaporation and the product was purified by chromatography on silica gel using CH2Cl2. There was obtained 11.1 g (92%) of (4-fluoro-2-methylphenyl)acetonitrile as an oil. 1H NMR (300 MHz, CDCl3): 2.3 (s, 3H), 3.6 (s, 2H), 6.8-7.0 (m, 2H), 7.3 (m, 1H).
Reaction SMILES: CO[C:3](=[O:45])[C@@H:4]([O:27][C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=3[CH3:44])[N:35]=[CH:36][C:29]=12)[CH2:5][O:6][CH2:7][CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1C=CC=CC=1)[C:11]1C=CC=CC=1.[NH2:46][C:47]1[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][N:48]=1>>[Si:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C@H:4]([O:27][C:28]1[C:29]2[CH:36]=[N:35][N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=3[CH3:44])[C:30]=2[N:31]=[CH:32][N:33]=1)[C:3]([NH:46][C:47]1[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][N:48]=1)=[O:45])([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:11])[CH3:17]
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(F)c1C
Product: Cc1c(F)cccc1-n1ncc2c(O[C@@H](COCCO[Si](C)(C)C(C)(C)C)C(=O)Nc3ccc(C#N)cn3)ncnc21

Procedure:
Prepared using a procedure analogous to that described for Intermediate AE1 using (2S)-methyl-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AF4) and 6-aminonicotinonitrile. 1H NMR (400 MHz, DMSO) d 0.89 (9H, s), 1.96 (3H, d), 3.83-3.69 (4H, m), 4.12-4.04 (1H, m), 4.17 (1H, dd), 6.02 (1H, m), 7.51-7.27 (9H, m), 7.60 (4H, m), 8.13 (1H, d), 8.22 (1H, dd), 8.51 (1H, s), 8.55 (1H, s), 8.81 (1H, d), 11.56 (1H, s). m/z (ES+) (M+H)+=716; HPLC tR=3.29 min.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:35]=[CH:34][C:9]([C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([O:25]C)=[O:24])[C:17]2=[O:33])=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[OH-:36].[Na+]>CO.O>[C:23]([CH:22]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:18][C:17](=[O:33])[N:16]([CH2:20][C:19]([OH:36])=[O:21])[CH2:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]1[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:35][CH:34]=1)([OH:25])=[O:24]
Reactant: [OH-]
Reactant: COC(=O)C(c1ccccc1)N1C(=O)CN(CCCNC(=O)c2ccc(NC(=N)N)cc2)C1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(N)Nc1ccc(C(=O)NCCCN(CC(=O)O)C(=O)NC(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
380 mg (0.76 mg) of methyl (3-(3-(4-guanidinobenzoylamino)propyl)-2,5-dioxoimidazolidin-1-yl)phenylacetate hydrochloride are dissolved in 10 ml of methanol and 10 ml of water, and 2.28 ml of 1N sodium hydroxide solution are then added. The mixture is stirred at room temperature overnight, concentrated and chromatographed, for purification, on Sephadex LH20 using an homogeneous mixture of butanol/glacial acetic acid/water.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.CN.[CH3:16][N:17](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([NH:17][CH3:16])=[O:5]
Reactant: Nc1cc(F)c(Br)cc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1cc(Br)c(F)cc1N

Procedure:
A solution of 2-amino-5-bromo-4-fluorobenzoic acid (2.00 g, 8.55 mmol), methylamine hydrochloride (0.692 g, 10.2 mmol), TBTU (2.74 g, 8.55 mmol), and DIPEA (4.46 mL, 25.6 mmol) in DCM (15.0 mL) was stirred at rt for 30 minutes. The reaction was quenched with sat. aq. NaHCO3 (10 mL) and extracted with DCM (15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to a yellow oil. The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent to afford the title compound as 2.54 g of a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.48 (d, J=7.3 Hz, 1H), 6.44 (d, J=10.4 Hz, 1H), 6.11 (br. s., 1H), 5.66 (br. s., 2H), 2.96 (d, J=4.8 Hz, 3H). MS (ESI): m/z 248.91 [M+H]+. UPLC: tR=3.26 min (ZQ3: polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-Methyl-3-nitroaniline (5 g, 32.9 mmol) was stirred in a solvent of dichloromethane (150 mL). The reaction solution was added with DIPEA (11.48 mL, 65.7 mmol) and 3-(trifluoromethyl)benzoylchloride (4.86 mL, 32.9 mmol), and stirred for about an hour at room temperature. The reaction mixture was washed with 1M aqueous HCl solution, an aqueous sodium bicarbonate and saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (10.6 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:4][C:3]=1[Cl:22]>[Ni]>[Cl:22][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(CCCC=Cc2ccc(Cl)c(Cl)c2)cc1
Agent: [Ni]
Product: Nc1ccc(CCCCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 45.9 %

Procedure:
The title compound was prepared from 1,2-dichloro-4-[5-(4-nitrophenyl)-1-pentenyl]benzene (2.5 g, 7.4 mmol), Ra—Ni (1 g) in TBF (50 mL) at 25° C. to 40° C. (ΔP=9.9 psi) using the procedure described in Example 1, Step B. This procedure yielded 1.06 g (3.4 mmol, 46%) of the desired product.
Reaction SMILES: [H-].[Na+].C(OCC)(=O)C(OCC)=O.[F:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH:24]=O>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[C:14]([F:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: CCOC(=O)CF
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(F)=Cc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of sodium hydride (0.33 g), diethyl oxalate (1.83 g), ethyl fluoroacetate (1.33 g) and anhydrous THF (10 ml) was heated under reflux for 4 hours whereupon 3,4-dichlorobenzaldehyde (2.18 g) (ex.Aldrich) in THF was added. After 18 hours at room temperature the reaction mixture was partitioned between water and ether and worked up in conventional fashion. Purification by chromatography (silica, 80:20 hexane/ether) gave (Z) ethyl 3-(3,4-dichlorophenyl)-2-fluoroprop-2-enoate (2.1 g.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=[O:4].[Na][Na].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.[OH-].[Na+].Cl>O>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]/[C:6](=[C:2](\[OH:1])/[C:3]([OH:5])=[O:4])/[C:7]([OH:9])=[O:8])=[CH:15][CH:14]=1
Reactant: O=C(O)C1OC1C(=O)O
Reactant: Nc1ccc(S)cc1
Agent: *CC*
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1ccc(S/C(C(=O)O)=C(\O)C(=O)O)cc1
Reaction time: 22 h
Yield: 50 %

Procedure:
To a solution of 70 percent epoxysuccinic acid, disodium salt (6.573 g, 26 14 mmol) in 25 mL water was added a filtered solution of 4-aminothiophenol (3.251 g, 25.97 mmol) in aq NaOH (28 mmol in 20 mL of water) via polyethylene cannula under nitrogen with stirring. After 22 hours, the cloudy reaction mixture was washed with 30 mL of ether and then acidified to pH 3 with 6M HCl, (13.3 mL, 79.8 mmol) producing a white solid precipitate. The solid was washed with 20 mL of water and dried (70° C., 0.05 mm Hg vacuum) to afford 3.364 g, (50 percent of theoretical) of 2-[4'-(amino)thiophenoxy]-3-hydroxymaleic acid; 1H NMR (DMSO-d6, d) 8.1 (2H, br), 7.13 (2H, d, J=8.3 Hz), 6.48 (2H, d, J=8.3 Hz), 4.05 (2H, d, J=7.6 Hz), 3.47 (2H, d, J=7.6 Hz); 13C NMR (DMSO-d6, d) 173.1, 171.3, 149.4, 136.0, 116.2, 114.1, 70.4, 56.0; IR (Nujol mull, cm-1) 3410 (br, m), 1710 (br, m).