Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:7][C:8]1[N:13]=[C:12](Cl)[C:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[C:10]([CH3:28])[N:9]=1>CN1C(=O)CCC1.CCOC(C)=O>[NH2:7][C:8]1[N:9]=[C:10]([CH3:28])[C:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[C:12]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:13]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OC)c1
Reactant: CCCCCN
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1OC
Temperature: 150 °C
Reaction time: 15 h

Procedure:
Pentylamine (7.2 mL) was added to a solution of the product from step (iii) (5 g) in NMP (80 mL). The resulting solution was stirred at 150° C. for 15 h. The reaction mixture was allowed to cool, diluted with EtOAc and washed with water and brine. The organic phase was dried and evaporated under reduced pressure. The residue was suspended in diethyl ether (20 mL) and the solid was collected by filtration to give the subtitle compound as a colourless solid 1.2 g that was used without further purification.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][N:9](C(OCC1C3C=CC=CC=3C3C1=CC=CC=3)=O)[CH2:10]2)(=[O:5])=[O:4])[CH3:2].N1CCCCC1.C(=O)([O-])[O-]>CN(C=O)C.CO.C(Cl)Cl>[CH2:1]([S:3]([N:6]1[CH:7]2[CH2:13][CH2:12][CH:11]1[CH2:10][NH:9][CH2:8]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1C2CCC1CN(C(=O)OCC1c3ccccc3-c3ccccc31)C2
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1C2CCC1CNC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude 9H-fluoren-9-ylmethyl 8-ethylsulfonyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate obtained from step 3 was dissolved in DMF (500 μL) and treated with piperidine (4 mg, 5 μL, 0.05 mmol). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with methanol/DCM and treated with carbonate resin. The reaction mixture was filtered and concentrated under reduced pressure to yield 8-ethylsulfonyl-3,8-diazabicyclo[3.2.1]octane which was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[O:16][CH2:15][C@@H:14]([S:17]C(=O)C)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[O-].[Na+].CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[O:16][CH2:15][C@@H:14]([SH:17])[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](CS(=O)(=O)c2ccc(F)cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(C[C@H]1C[C@H](S)CO1)c1ccc(F)cc1

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.955 gof product from Example 31, 0.72 ml of 25% sodium methoxide/methyl alcohol and 10 ml of tetrahydrofuran to give 0.523 g of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[C:12]([N:15]1[CH2:20][CH2:19]C(C2C=CC=CC=2)=[CH:17][CH2:16]1)(=[O:14])[CH3:13]>C(Cl)Cl>[C:12]([N:15]1[CH2:20][CH2:19][C:8]2([O:10][CH:17]2[CH2:16]1)[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CC=C(c2ccccc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)N1CCC2(c3ccccc3)OC2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.0 G. of 85% m-chloroperbenzoic acid was added portionwise to a solution of 5.8 g. of 1-acetyl-4-phenyl-1,2,5,6-tetrahydropyridine dissolved in 100 ml. of methylene chloride, the latter being cooled during the addition using an ice bath. The mixture was stirred 18 hours at room temperature, then washed with water, sodium bisulfite solution, sodium carbonate solution and, finally, again with water. After evaporation 4.8 g. of solid remained, which was recrystallised from ether to give 3.9 g. of the desired product which was found to have a melting point of 68°-71° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[C:14]([S-:16])#[N:15].[K+]>CO.[O-]S([O-])(=O)=O.[Cu+2]>[NH2:15][C:14]1[S:16][C:11]2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=[C:3]([O:12][CH3:13])[C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(OC)c2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
To a solution of methyl 4-amino-3-methoxybenzoate (307 g, 1.696 mol) in anhydrous methanol (4 L) was added an intimated mixture of KSCN (1640 g, 16.9 mol) and anhydrous CuSO4 (1350 g, 8.44 mol) in one portion. The mixture was heated to reflux for 4 h. TLC (EtOAc/Petroleum ether 1:4) showed the reaction was complete. The mixture was filtered and the filtrate was diluted with water. The solution was heated to boiling until a slightly clear solution formed. The mixture was cooled to ambient temperature and left standing for 1 day. A dark yellow solid was formed, which was collected by filtration to afford the desired product (338 g, 84%) as a dark yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.000-8.200 (br, 2H), 8.052 (s, 1H), 7.435 (s, 1H), 3.927 (s, 3H), 3.827 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[C:15]([CH3:35])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:12])[CH3:9].[CH3:36][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:36][O:33][C:32](=[O:34])[CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]3[O:17][N:16]=[C:15]([CH3:35])[C:14]=3[NH:13][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:12])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To (4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid (0.050 g, 0.1 mmol) in benzene (17 mL) and methanol (2 mL) was added (trimethylsilyl)diazomethane (2M in hexanes; 0.1 mL, 0.2 mmol), and the reaction was stirred at room temperature for 5 minutes. Additional (trimethylsilyl)diazomethane (2M in hexanes; 0.25 mL, 0.5 mmol) was added, and the reaction was stirred until no starting material was seen by analytical LCMS. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed twice with water and once with brine, and then dried and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)[O:9][CH:8]([C:22]([F:25])([F:24])[F:23])[C:7]([C:26]([O:28]CC)=[O:27])=[CH:6]2)[CH3:2].[OH-].[Li+].C(O)C>O1CCCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)[O:9][CH:8]([C:22]([F:25])([F:24])[F:23])[C:7]([C:26]([OH:28])=[O:27])=[CH:6]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(CC)c(Oc3ccnc(SC)n3)cc2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCc1cc2c(cc1Oc1ccnc(SC)n1)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Yield: 52.7 %

Procedure:
To the solution of 100 mg (0.23 mmol) intermediate isolated from step 2 in 1.5 mL of tetrahydrofuran was added a solution of 48 mg (1.2 mmol) lithium hydroxide in 2.5 mL of water, followed by addition of 2.5 mL of ethanol. The reaction was then heated to reflux for one h. After cooling to room temperature, the volatiles were removed, the residue was diluted with water, then acidified at 0° C. with dilute hydrochloric acid to pH=1.0. The product was extracted with ethyl ether. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concd in vacuo to afford 50 mg (53%) of a yellow solid: 1H NMR (CDCl3/400 MHz) 8.40(d, J=6 Hz, 1H), 7.85(s, 1H), 7.17(s, 1H), 6.78(s, 1H, 6.58(d, J=5.6 Hz, 1H), 5.66(q, J=7.2 Hz, 1H), 2.48(q, J=7.2 Hz, 2H), 2.29(s, 3H), 1.l4(t, J=7.6 Hz, 3H); MS (ES+) 413 (M+l, 100), HRMS (EI) m/z calcd for (C18H16F3N2O4S) 413.0777, found 413.0768.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18]P(=O)(OCC)OCC)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:35])[N:13]2[C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:34].[H-].[Na+].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=[C:48]2[CH2:49][CH2:50][N:45]([C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])[CH2:46][CH2:47]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:35])[N:13]2[C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:34]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of diethyl [5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylphosphonate (422 mg, 0.762 mmol) in a mixture of THF (9 mL) and DMF (2 mL) at 0° C. was added sodium hydride (60%, 61 mg, 1.52 mmol). The resulting mixture was stirred at rt for 20 min and then cooled to 0° C. again. To this was added a solution of t-butyl-4-oxo-1-piperidinecarboxylate (310 mg, 1.524 mmol) in THF (2 mL). Then the reaction was stirred at rt for 22 h. The mixture was quenched with brine, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by flash chromatography using 20% acetone/hexane as eluent provided tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylene}piperidine-1-carboxylate as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.48 (s, 9H), 2.24 (brs, 2H), 2.31 (t, 2H, J=5.7 Hz), 3.31 (t, 2H, J=5.5 Hz), 3.45 (t, 2H, J=5.5 Hz), 4.35 (abq, 2H, J=14.4 Hz), 5.10 (s, 1H), 5.96 (s, 1H), 6.21 (s, 1H), 6.74 (s, 1H), 7.30-7.58 (m, 7H). MS (API-ES+): 600 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=O)[CH3:2].Cl.CN(C)CCCN=C=NCC.[C:29]1([C:35]2[N:36]=[C:37]([NH2:40])[S:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([NH:40][C:37]1[S:38][CH:39]=[C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:36]=1)=[O:8])[CH3:2]
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)C(=O)Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-Benzyl-malonic acid monoethyl ester (150 mg, 0.67 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.74 mmol) in DMF (4 mL) at 25° C. was added 4-phenyl-thiazol-2-ylamine (119 mg, 0.67 mmol), the resulting mixture was stirring at 25° C. for overnight and concentrated in vacuo, and the residue was dissolved in CH2Cl2 (20 mL) was washed with 5% NaHCO3, dried with MgSO4 and concentrated in vacuo. The residue was purified by HPLC. The product was obtained 170 mg (67%) as white solid.
Reaction SMILES: C([Li])CCC.[CH2:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Br.[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=[O:36])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1>[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]([OH:36])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:6]2)[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccc1OCC1CCCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1ccccc1OCC1CCCCC1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
10 ml of tetrahydrofuran was cooled to −78° C., 5.11 ml of n-butyllithium (1.6 M, hexane solution) was added thereto, and the mixture was stirred. A solution of 2.000 g of (2-cyclohexylmethyloxy)bromobenzene dissolved in 5 ml of tetrahydrofuran was added dropwise thereinto. After one hour, a solution of 1.93 g of 1-benzyl-4-piperidineacetaldehyde dissolved in 5 ml of tetrahydrofuran was added dropwise thereinto, and the mixture was further stirred for one hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (n-hexane:ethyl acetate=4:1), to give 2.986 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:4][C:3]=1[C:17]([NH:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)=[O:18]>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:4][C:3]=1[C:17]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1)=[O:18]
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(OCc3ccccc3Cl)ccc2Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1ccc(CNC(=O)c2cc(OCc3ccccc3Cl)ccc2Cl)cc1
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution of methyl 4-({[(2-chloro-5-{[(2-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}methyl)benzoate (113 mg, 0.25 mmol) in acetic acid (10 ml) and 2M HCl (10 ml) was heated at 90° C. for 6 hours. Heating continued at 90° C. overnight. A solid crashed out on cooling. The resulting solid was filtered, washed with water and dried to give the title compound as a white solid (67 mg). MS (ES+) m/z 430 [M+H]+ (C22H1735Cl2NO4). 1H-NMR (400 MHz, d6-DMSO) δ 4.51 (2H,d, J 6.0), 5.20 (2H,s), 7.11-7.16 (2H,m), 7.37-7.54 (6H,m), 7.59-7.62 (1H,m), 7.91-7.94 (2H,m), 9.10 (1H,t, J 6.0), 12.89 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:11][C:12]([CH3:14])=O.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:12]([CH3:14])[CH3:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)C1(CN)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(CNC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a solution of ethyl1-(aminomethyl)cyclopropane-1-carboxylate (Intermediate 114; 20.65 g, 250 mmol) in DCM (200 mL) was added acetone (3.74 mL, 51 mmol). After stirring at room temperature for 15 minutes, sodium acetate (4.185 g, 51 mmol) was added, followed by sodium triacetoxyborohydride (15.905 g, 75 mmol). The suspension was stirred at room temperature for 2 days then partitioned between DCM and an aqueous solution of saturated sodium hydrogen carbonate. The organic layer was separated, then dried over sodium sulphate evaporated to yield the title compound as a clear oil (9.2 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:53][CH2:52][CH2:51][CH:50]2[C:54]([O:56][CH3:57])=[O:55])=[CH:45][CH:44]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:53][CH2:52][CH2:51][CH:50]3[C:54]([O:56][CH3:57])=[O:55])=[CH:45][CH:44]=2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)C1CCCN1c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCCN1c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmole) in dichloromethane (6 ml) were added N,N-DIISOPROPYLETHYLAMINE (104 mg, 140 μl, 0.802 mmol) and methyl 1-(4-aminophenyl)pyrrolidine-2-carboxylate hydrochloride (50.2 mg, 0.196 mmol, Beta Pharma) followed by N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (90.3 mg, 0237 mmole, Chem-Impex) and the reaction mixture was stirred at rt for 1 hr. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 5% to 100% EtOAc in hexanes) to give methyl 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylate (72.4 mg, 84%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 669. found: 669.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([CH:18]=O)=[CH:13][N:12]=1>>[C:1]1([C:7]2[C:8]([NH2:9])=[N:17][C:15]3[N:16]=[C:11]([NH2:10])[N:12]=[CH:13][C:14]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: N#CCc1ccccc1
Product: Nc1ncc2cc(-c3ccccc3)c(N)nc2n1

Procedure:
Following the procedure of Example 1, phenylacetonitrile was reacted with 2,4-diamino-5-pyrimidine-carboxaldehyde to give the title compound; mp 317-318° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][C:3]=1[CH:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1.C([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[C:23](F)[CH:24]=2)[C:19](=[O:28])[C:18]([C:29]([OH:31])=[O:30])=[CH:17]1)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][C:3]=1[CH:8]1[NH:9][CH2:10][CH2:11][N:12]([C:23]2[CH:24]=[C:25]3[C:20]([C:19](=[O:28])[C:18]([C:29]([OH:31])=[O:30])=[CH:17][NH:16]3)=[CH:21][C:22]=2[F:27])[CH2:13]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: Cc1cc(C)c(C2CNCCN2)o1
Solvent: c1ccncc1
Product: Cc1cc(C)c(C2CN(c3cc4[nH]cc(C(=O)O)c(=O)c4cc3F)CCN2)o1
Yield: 21.9 %

Procedure:
The 1.4 g of 2-(3,5-dimethyl-2-furanyl)piperazine was dissolved in 5 ml of pyridine, 0.66 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid added and the mixture heated at 95°-100° C., under argon, in a pressure bottle for 4 hours, then cooled. The solvent was removed in vacuo, the residue evaporated twice from toluene and the residue chromatographed, giving 700 mg of crude product. This product was recrystallized from methanol, giving 220 mg of the desired product, mp 230°-232° C.
Reaction SMILES: [CH2:1]1[C@@H:14]2[C@@:5]([C:15]([OH:17])=[O:16])([C:6]3[C:11]([CH2:12][CH2:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[I-:23].[K+].II.S(=O)(O)[O-].[Na+]>O>[I:23][CH:2]1[CH:3]2[CH2:4][C:5]3([C:6]4[C:11]([CH2:12][CH2:13][CH:14]3[CH2:1]1)=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:15](=[O:17])[O:16]2
Reactant: O=C(O)[C@]12CC=CC[C@H]1CCc1ccccc12
Reactant: [I-]
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: O
Product: O=C1OC2CC13c1ccccc1CCC3CC2I
Yield: 87.9 %

Procedure:
A mixture of the compound from Example 6 (10 g, 44 mmol) and sodium bicarbonate (4 g, 48 mmol) in 150 ml water was heated on a steam bath until a solution was obtained. Potassium iodide (14.6 g, 88 mmol) and iodine (22.4 g, 88 mmol) were dissolved in 150 ml water and added to the reaction mixture via an addition funnel. The reaction mixture was placed in a separatory funnel and shaken with sodium bisulfite and then extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated to give the title compound as a yellow solid (13.7 g, 88% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]4)=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC(Nc2ncc3c(n2)N(C2CCCC2)CCC(=O)N3C)CC1
Temperature: 105 °C
Yield: 12.1 %

Procedure:
2-Chloro-9-cyclopentyl-8,9-dihydro-5-methyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.357 mmol) and ethyl 4-aminopiperidine-1-carboxylate (129 μl, 0.714 mmol) in isopropylalcohol (2 ml) were heated at 90° C. for 24 hours. Diisopropylethylamine (125 μl, 0.714 mmol) was added and the reaction mixture was heated at 105° C. for another 24 hours. The crude mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound (18 mg) as an off-white powder. NMR DMSO D6 1.20 (3H, t), 1.28-1.91 (14H, m), 2.80-2.96 (2H, m), 3.11 (3H, s), 3.50-3.58 (2H, m), 3.70-3.85 (1H, m), 3.90-3.98 (2H, m), 4.03 (2H, q), 4.60-4.70 (1H, m), 6.65 (1H, br s), 7.88 (1H, s); HPLC rt(min): 8.09; MS (ES+) 417, (ES−) 415.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([O:33]C)=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1.[OH-].[Na+]>CO>[CH3:14][C:4]1[CH:5]=[C:6]([O:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@@H]5CCOC5)cc4C)c3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 3 h
Yield: 77.1 %

Procedure:
Methyl 2-((S)-6-((2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 2d (201 mg, 0.41 mmol) was dissolved in 15 mL of methanol. The reaction solution was added with 2M aqueous sodium hydroxide solution (2 mL, 4.10 mmol) and stirred for 3 hours. The resulting solution was concentrated under reduced pressure, mixed with 10 mL of water, and 1M hydrochloric acid was added dropwise to adjust the pH to 2-3. The solution was extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 2-((S)-6-((2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 2 (150 mg, yield 77.1%) as a white solid.