Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C@@H:2]1C[N:5]([C:7](OC(C)(C)C)=O)[C@H:4]([C:14](=[O:24])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.Br[C:37]1C=C(C(F)(F)F)C=CN=1>>[CH3:7][NH:5][C@H:4]([C:14]([NH:15][C@@H:16]1[C@@H:23]2[C@@H:19]([CH2:20][N:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=3)[CH2:22]2)[CH2:18][CH2:17]1)=[O:24])[CH:3]([CH3:2])[CH3:37]
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Product: CN[C@H](C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21)C(C)C

Procedure:
The title compound was prepared by substituting tert-butyl methyl{(2S)-3-methyl-1-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylamino]-1-oxobutan-2-yl}carbamate from Example 733 for (2S,4S)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate and 2-bromo-5-(trifluoromethyl)pyridine for 2-bromo-4-(trifluoromethyl)pyridine in the procedure described in Example 637: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.63 (dd, J=1.6, 0.8, 1H), 8.31 (d, J=7.5, 1H), 7.67 (dt, J=19.9, 10.0, 1H), 6.40 (d, J=8.9, 1H), 4.50-4.37 (m, 1H), 3.83 (d, J=10.4, 1H), 3.72-3.63 (m, 1H), 3.61-3.51 (m, 1H), 3.33 (d, J=8.4, 1H), 2.94 (d, J=5.8, 1H), 2.81-2.67 (m, 2H), 2.43 (s, 3H), 2.23-1.87 (m, 4H), 1.69 (dq, J=12.7, 8.2, 1H), 1.41 (dtd, J=13.2, 8.0, 5.0, 1H), 1.08 (dd, J=6.9, 2.1, 6H); MS (ESI+) m/z 385 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH:34]1[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:34]2[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: O[C@@H]1CCNC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CC[C@@H](O)C1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), (R)-pyrrolidin-3-ol (34 mg, 0.2 mmol), HOBt (20 mg), EDAC.HCl (40 mg) and TEA (40 mg, 3 eq.) in DMF was stirred at 40° C. for 3 days. The reaction was concentrated and purified on a silica gel column to give the titled compound. MS m/z 572 [M−1].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].[C:13](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.IC>[CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 53 %

Procedure:
340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 195 mg (53%) of the title compound and 110 mg (30%) of the compound of Preparative Example 13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[C:22]([O:27]C)=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C([O-])(O)=O.[Na+]>Br.CC(O)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[C:22]([OH:27])=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:30])[F:31]
Reactant: COc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1cccnc1O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzene sulfonamide (10 mg, mmol) in 30% HBr in AcOH (1 mL) was stirred at 50° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (1 mL) and treated with saturated aqueous NaHCO3 solution slowly till pH 5-6. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was column purified (SiO2, 10% MeOH in CH2Cl2) to afford 4-chloro-N-[5-chloro-2-(2-hydroxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (6 mg) in 61.8% yield. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, 1H), 8.17 (d, 1H), 8.15 (d, 1H), 7.97 (dd, 1H), 7.72 (dd, 1H), 7.63 (d, 1H), 7.43 (dd, 1H), 6.37 (t, 1H); ESMS m/z (relative intensity): 491.9 (M+H)+ (100).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc2c(c1)CCC2=O)c1ccccc1
Reaction time: 8 h

Procedure:
Benzoyl chloride (126.9 g, 0.900 mol) was added slowly to a stirred mixture of the product of Step A (121 g, 0.818 mol), triethylamine (99.1 g, 0.982 mol) and catalytic amount of DMAP (1 g, 8.18 mmol) in dichloromethane (1 L) at rt under nitrogen. The mixture was stirred overnight and diluted with dichloromethane (1 L). Then the solution was washed with water, hydrochloric acid (0.5 M, 2×1 L), and brine. The organic layer was dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was dried in vacuo to give the compound. 1H-NMR (400 MHz, CDCl3): δ 8.19-8.22 (m, 2H), 7.83 (d, J=8.1 Hz, 1H), 7.65-7.69 (m, 1H), 7.52-7.55 (m, 2H), 7.37 (s, 1H), 7.22 (dd, J=8.1 Hz, J=2.0 Hz, 1H), 3.17-3.20 (m, 2H), 2.73-2.76 (m, 2H) ppm.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]([NH:23][C@H:24]3[C@@H:28]([OH:29])[CH2:27][NH:26][CH2:25]3)=[O:22])=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1.Cl[C:31]1[CH:36]=[C:35]([C:37]([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)=[O:38])[CH:34]=[CH:33][N:32]=1>C(O)CCC>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]([NH:23][C@H:24]3[C@@H:28]([OH:29])[CH2:27][N:26]([C:31]4[CH:36]=[C:35]([C:37]([C:39]5[S:40][CH:41]=[CH:42][N:43]=5)=[O:38])[CH:34]=[CH:33][N:32]=4)[CH2:25]3)=[O:22])=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(c1ccnc(Cl)c1)c1nccs1
Reactant: O=C(N[C@@H]1CNC[C@@H]1O)c1cnc(-c2cccc(F)c2)nc1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CN(c2cc(C(=O)c3nccs3)ccn2)C[C@@H]1O)c1cnc(-c2cccc(F)c2)nc1
Temperature: 85 °C
Yield: 34 %

Procedure:
To a vial was added cis-2-(3-fluorophenyl)-N-(4-hydroxypyrrolidin-3-yl)pyrimidine-5-carboxamide-TFA salt (50 mg, 0.12 mmol), n-butanol (0.2 mL), TEA (0.016 mL, 0.12 mmol) and (2-chloropyridin-4-yl)(thiazol-2-yl)methanone (40.5 mg, 0.18 mmoL). The reaction mixture was heated to 85° C. for 4 hrs and then cooled to rt. The residue mixture was purified by RP-HPLC to give the desired product, cis-2-(3-fluorophenyl)-N-(4-hydroxy-1-(4-(thiazole-2-carbonyl)pyridin-2-yl)pyrrolidin-3-yl)pyrimidine-5-carboxamide (20 mg, 34%). HRMS (M+H) expected=491.1302, observed=491.1357.
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]([NH-:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])=[CH:7][CH:6]=1.C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C@H:30]1[CH2:32][C@@H:31]1[C:33](Cl)=[O:34]>ClCCl>[OH:2][CH2:3][C@H:4]([NH:17][C:33]([C@H:31]1[CH2:32][C@@H:30]1[C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])=[CH:7][CH:6]=1
Reactant: CC[C@H](C)COc1ccc([C@@H]([NH-])CO)cc1
Reactant: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)COc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (1.08 g, 6.45 mmol) in dichloromethane (50 ml) in an ice-bath was added oxalyl chloride (6.50 ml, 64.4 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 250 ml round-bottom flask was charged with {(R)-2-hydroxy-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide HCl (6.47 mmol), dichloromethane (60 ml) and triethylamine (4.30 ml, 32.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×30 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (1.42 g, 58% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (d, J=8.6 Hz, 2H), 7.09 (m, 1H), 6.91 (m, 3H), 6.82 (d, J=3.5 Hz, 1H), 6.23 (d, J=6.1 Hz, 1H), 5.06 (td, J=6.3, 4.3 Hz, 1H), 3.91 (m, 2H), 3.78 (m, 2H), 2.75 (m, 2H), 1.88 (m, 1H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C21H28NO3S 374.5].
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[CH2:10][C:11]#[N:12]>>[CH2:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:11]#[N:12])[CH2:5][CH2:4]1)[CH3:2]
Reactant: N#CCCl
Reactant: CCC1CCNCC1
Product: CCC1CCN(CC#N)CC1

Procedure:
The title compound was prepared according to general procedure G described in Scheme 3 from 4-ethylpiperidine and 2-chloroacetonitrile. The crude solution was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][NH2:13].O1CCCC1>C(Cl)Cl.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:13][CH3:12])[C:5]2=[N:4][CH:3]=1
Reactant: CN
Reactant: Brc1cncc2ncc(Br)n12
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CNc1nccn2c(Br)cnc12
Temperature: 70 °C
Yield: 50 %

Procedure:
3,5-Dibromo-imidazo[1,2-a]pyrazine (D) (2.0 g, 7 mol) was added to 2M methylamine in THF (tetrahydrofuran) (100 ml, 30 eq.). The mixture was heated at 70° C. in sealed tube for 3hr. The mixture was then cooled to rt, diluted with DCM (200 ml) and water (100 ml). The organic layer was washed with brine, dried and concentrated. The residue was purified on a silica gel column to give (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (yield 50%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.[CH:34]12[O:40][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39]2.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[OH:40][C@H:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C@@H:34]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:6][CH:7]=1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C1CCC2OC2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C)n(-c2ccc(O[C@H]3CCCC[C@@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and cyclohexene oxide (1.20 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.25 g), and the mixture was stirred at 100° C. for 20 hr. After allowing to cool, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.93 g, 76%).
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC=C(O)C=2)[C:31](F)=[CH:30][N:29]=1.NC1C=C2C(=CC=1)NC=C2>>[F:18][C:17]1[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)=[N:13][C:14]([NH:19][C:20]2[CH:21]=[C:22]3[C:23](=[CH:24][CH:25]=2)[NH:29][CH:30]=[CH:31]3)=[N:15][CH:16]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1ccc2[nH]ccc2c1
Product: Oc1cccc(Nc2nc(Nc3ccc4[nH]ccc4c3)ncc2F)c1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 5-aminoindole were reacted to yield 5-fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine. LCMS: ret. time: 17.31 min.; purity: 94%; MS (m/e): 366 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1Cl
Solvent: ClCCl
Product: COc1cc(CBr)ccc1Cl
Reaction time: 3 h
Yield: 23.5 %

Procedure:
To a solution of 4-chloro-3-methoxytoluene (5.65 g) and N-bromosuccinimide (6.74 g) in anhydrous dichloromethane (60 mL) was added 2,2′-azolbis(4-methoxy-2,4-diaethylvaleronitrile) (674 mg). After stirring for 3 hours under reflux, the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with hexane to give 4-chloro-3-methoxybenzyl bromide as white powders (2.00 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([NH:6][CH2:7][CH3:8])=[CH:4][CH:3]=1.[C:11]1([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1.C(N(CC)CC)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH2:7][CH3:8])[C:21]([NH:20][S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:19])=[O:18])=[O:22])=[CH:4][CH:3]=1
Reactant: CCNc1ccc(Br)cc1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(C(=O)NS(=O)(=O)c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution was prepared containing 4.0 g (0.2 mole) of 4-bromo-N-ethylaniline in 25 ml of benzene and one drop each of triethylamine and dibutyltin dilaurate. A solution of 3.7 g (0.02 mole) of benzenesulfonylisocyanate was added to the first solution. The temperature was allowed to rise to 35° C. The mixture was stirred for 2 hours at room temperature and for one-half hour at 40°-45° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[CH:11]=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:24]=1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[CH:11]=[C:12]2[CH2:13][CH2:14][N:15]([C:30]([NH:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:16][CH2:17]2)=[CH:21][CH:22]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Agent: Cl
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(F)cc3)c2)CC1
Yield: 94.4 %

Procedure:
Following the procedure in Example 1, step 6, 4-[3-(4-fluoro-phenoxy)-benzylidene]-piperidine hydrochloride (200 mg, 0.625 mmol, from Example 18, Step 3) and phenyl pyridin-3-ylcarbamate (147 mg, 0.688 mmol) were used to provide the title compound (238 mg). MS (APCI 10 V) AP+ 404.3, AP− 402.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.43 (td, J=5.79, 1.10 Hz, 2H) 2.52 (td, J=5.89, 1.01 Hz, 2H) 3.51-3.55 (m, 2H) 3.60-3.66 (m, 2H) 6.40 (s, 1H) 6.78-6.84 (m, 2H) 6.95-6.98 (m, J=7.67, 1.53, 0.75, 0.75 Hz, 1H) 6.98-7.04 (m, 2H) 7.05-7.15 (m, 2H) 7.30 (t, J=7.77 Hz, 1H) 7.34 (ddd, J=8.41, 4.84, 0.76 Hz, 1H) 7.91 (ddd, J=8.38, 2.60, 1.45 Hz, 1H) 8.16 (dd, J=4.85, 1.46 Hz, 1H) 8.58 (dd, J=2.62, 0.67 Hz, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:48][CH2:49][O:50][CH3:51])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:48][CH2:49][O:50][CH3:51])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(CCOC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(CCOC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A mixture of hydroxylammonium chloride (3.1 g), sodium hydrogen carbonate (4.5 g) and dimethyl sulfoxide (24 mL) was stirred at 50° C. for 30 min, 4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-(2-methoxyethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (24 mL), N,N′-carbonyldiimidazole (1.1 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.0 g, 55%) as a colorless solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]1[CH:20]1[CH:27]2[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2)=[O:12])(=O)C.O.C(=O)(O)[O-].[Na+].O>CO.O1CCCC1>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:16]([CH3:17])([CH3:18])[C:15](=[O:19])[N:14]1[CH:20]1[CH:27]2[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2)=[O:12]
Reactant: CC(=O)Oc1ccccc1C(=O)N1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73.1 %

Procedure:
A solution of 2-{[4,4-dimethyl-3-oxo-2-(adamantan-2-yl)-1,2-diazetidin-1-yl]carbonyl}phenyl acetate (15.0 mg, 0.0378 mmol) prepared in Example 137 in methanol-tetrahydrofuran was dropped with saturated sodium bicarbonate water (0.5 mL), and the resultant was stirred at room temperature for 4.5 hours. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (9.80 mg, 73.7%) was obtained as a white crystalline powder.
Reaction SMILES: [OH2:1].[C:2]([OH:5])(=[O:4])[CH3:3].O[NH:7][C:8]([C:10]1[CH:11]=[C:12]([NH:16][CH:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[O:19])[CH:13]=[CH:14][CH:15]=1)=[NH:9]>CO>[C:8]([C:10]1[CH:11]=[C:12]([NH:16][CH:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:23][CH:22]=2)=[O:19])[CH:13]=[CH:14][CH:15]=1)(=[NH:7])[NH2:9].[CH3:38][C:33]([CH2:17][C:18]([CH2:3][C:2]([OH:5])=[O:4])=[O:19])=[O:1]
Reactant: CC(=O)O
Reactant: O
Reactant: N=C(NO)c1cccc(NC(C(=O)Nc2ccc(N3CCOCC3)cc2)c2ccccc2)c1
Solvent: CO
Product: CC(=O)CC(=O)CC(=O)O
Product: N=C(N)c1cccc(NC(C(=O)Nc2ccc(N3CCOCC3)cc2)c2ccccc2)c1
Reaction time: 18 h

Procedure:
500 mg of water-moist Raney nickel and 0.1 ml of acetic acid are added to a solution of 150 mg (0.337 mmol) of 2-[3-(N-hydroxyamidino)phenylamino]-N-(4-morpholin-4-ylphenyl)-2-phenylacetamide in 5 ml of methanol, and the mixture is hydrogenated at room temperature and atmospheric pressure for 18 hours. The reaction mixture is filtered, and the residue is evaporated, giving 2-(3-amidinophenylamino)-N-(4-morpholin-4-ylphenyl)-2-phenylacetamide, triacetate, ESI 430; IC50 (Xa)=3.4×10−8 M; IC50 (VIIa)=2.2×10−8 M;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][C:2]=1[CH3:10].[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]2[CH2:42][CH2:41][CH2:40]2)=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:4]4[CH:5]=[CH:6][N:1]=[C:2]([CH3:10])[CH:3]=4)=[CH:29][C:28]=3[C:34]([F:36])([F:35])[F:37])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]2[CH2:40][CH2:41][CH2:42]2)=[O:18])[CH2:14][CH2:15]1)#[N:12]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCC2)CC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: Cc1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@H](OC4CCC4)[C@@H](C(=O)NC4(C#N)CC4)C3)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 using 2-picoline-4-boronic acid instead of 2,4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-cyclobutoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 182) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 548.1 (M+H)+.