Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: CCCCCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (3 g) in dimethylformamide (100 ml), anhydrous potassium carbonate (0.8 g) and then amyl chloroacetate (1.9 g) were added, and the resultant mixture was heated at 70° to 80° C. for 3 hours. The reaction mixture was cooled to room temperature, admixed with water and extracted with diethyl ether. The etheral layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the compound (I) (1.8 g).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:28])[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([NH:37][C:5]([NH:6][C:7]2[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:16]=[CH:17][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:20]=4)[C:11]=3[C:24]=2[CH3:25])=[O:28])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: NC1CCCCC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)NC1CCCCC1)C(c1ccc(C(C)C)cc1)CO2
Yield: 92 %

Procedure:
Using 2,2,2,-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and cyclohexylamine, the title compound was obtained in the same manner as in Example 143.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([CH2:18]O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:26])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH2:18][F:26])=[N:9][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:12][CH:13]=1
Reactant: Nc1nccc(-n2nc(CO)c3ccc(Br)cc32)n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nccc(-n2nc(CF)c3ccc(Br)cc32)n1
Reaction time: 16 h

Procedure:
To a solution of [1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]methanol (200 mg, 0.47 mmol) in dry DCM (10 mL) at RT under an atmosphere of nitrogen was introduced (diethylamino)sulphur trifluoride (0.08 mL, 0.63 mmol). After 16 hr at this temperature, the reaction mixture was treated with sodium bicarbonate (25 mL of saturated aq NaHCO3) and extracted with DCM (2×20 mL extractions). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (Biotage, heptane/EtOAc gradient) to furnish the title compound as a colorless solid: 1H NMR (500 MHz, DMSO) delta 5.86 (2H, d, J=48.24 Hz), 7.06 (1H, d, J=5.04 Hz), 7.14 (2H, br. s.), 7.58 (1H, dd, J=8.04, 2.05 Hz), 7.92 (1H, d, J=8.98 Hz), 8.31 (1H, d, J=6.31 Hz), 9.17 (1H, d, J=1.42 Hz); LC-MS: m/z=+321.90/323.90 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[O:31]1[CH2:32][CH2:33][N:28]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=5)(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: O=S(=O)(c1cccc(F)c1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5cccc(F)c5)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-[4-(3-fluoro-benzenesulfonyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid via General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 284. NMR (DMSO): 2.55-2.58 (4H, m), 2.98-3.03 (4H, m), 3.73-3.77 (4H, m), 3.88 (2H, s), 3.90-3.94 (4H, m), 7.06 (2H, br. s), 7.32 (1H, s), 7.55-7.65 (2H, m), 7.70-7.75 (1H, m), 9.10 (2H, s). MS (ESI+): MH+ 571.20 (100%)
Reaction SMILES: [F:1][C:2]([C:6]1[C:7]([C:17]([OH:19])=O)=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([F:5])[CH2:3][CH3:4].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:28]>ClCCl>[F:1][C:2]([C:6]1[C:7]([C:17]([F:28])=[O:19])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([F:5])[CH2:3][CH3:4]
Reactant: CCC(F)(F)c1c(C(=O)O)noc1-c1ccccc1
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(F)(F)c1c(C(=O)F)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A solution of 4-(1,1-difluoropropyl)-5-phenylisoxazole-3-carboxylic acid (8.4 mg, 0.031 mmol) and pyridine (3.05 μL, 0.038 mmol) in dichloromethane (1 mL) was added cyanuric fluoride (3.18 μL, 0.038 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (2 mL) and washed with ice-water (2×1 mL). The aqueous layer was extracted with dichloromethane (2×1 mL), and the combined organic layers were washed brine (1 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 4-(1,1-difluoropropyl)-5-phenylisoxazole-3-carbonyl fluoride (7.2 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[C:16]1([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]1([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:23][CH:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH2:28][CH2:29]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Reactant: ClCCCCCCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCCc2cccnc2)CC1
Reaction time: 8 h

Procedure:
A 5-L flask equipped with a magnetic stirrer, condenser, and argon inlet tube was charged with the 191.3 g of crude, overweight 3-(8-chlorooctyl)-pyridine, 184.4 g of 4-(2,2-diphenylethenyl)piperidine, 1.0 L of N,N-dimethylformamide, 116.3 g of potassium iodide, and 74.2 g of potassium carbonate. The mixture was stirred and heated at 75° for 18 hours and then cooled to 20°. Most of the solvent was removed on a rotary evaporator at 50°/0.5 mm. The residual yellow-brown semi-solid was partitioned between 2.0 L of ether and 1.0 L of deionized water. The aqueous layer was extracted with 2×1.0 L=2.0 L of ether. The combined ether solutions were washed with 500 mL of deionized water and 500 mL of brine and dried over sodium sulfate, to which was added 20 g of Norit SG Extra charcoal. This mixture was filtered through Celite and concentrated on a rotary evaporator at 45° to an oil which solidified upon standing. The solid was triturated with 500 mL of warm hexanes. The suspension was stored overnight at -20° and filtered. The solid was washed with a total of 100 mL of cold hexanes and dried at 20°/0.1 mm over phosphorus pentoxide to give 205.9 g of 3-[8-[4-(2,2-diphenylethenyl)-1-piperidinyl]octyl]pyridine as a pale tan solid, mp 53°-54°. Liquid chromatography analysis indicated this material to be homogeneous.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[CH:17]=[CH:18][C:19]=1[F:20]>>[Br:13][C:14]1[CH:15]=[C:16]([NH:21][C:2]2[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Reactant: Nc1ccc(F)c(Br)c1
Product: Cn1ccc(Nc2ccc(F)c(Br)c2)c([N+](=O)[O-])c1=O
Yield: 40 %

Procedure:
4-Chloro-1-methyl-3-nitro-1H-pyridin-2-one was coupled to 3-bromo-4-fluorophenylamine, in the same way as in Example 1, to give 4-(3-bromo-4-fluorophenylamino)-1-methyl-3-nitro-1H-pyridin-2-one as a beige solid (2.0 g, 40%): δH (400 MHz, d6-DMSO) 3.36 (3H, s), 5.81 (1H, d, J 8), 7.33-7.37 (1H, m), 7.45 (1H, t, J 9), 7.64-7.68 (1H, m), 7.66 (1H, s), 9.73 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:26]3[C:17]4=[N:18][N:19]([CH3:25])[C:20]5[CH:21]=[CH:22][C:23](Cl)=[C:15]([C:16]=54)[C:14](=[O:27])[C:13]=3[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:26]3[C:17]4=[N:18][N:19]([CH3:25])[C:20]5[CH:21]=[CH:22][C:23]([NH:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[C:15]([C:16]=54)[C:14](=[O:27])[C:13]=3[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CN(C)CCN
Reactant: COc1ccc(COc2cncc3c2-c2nn(C)c4ccc(Cl)c(c24)C3=O)cc1
Solvent: c1ccncc1
Product: COc1ccc(COc2cncc3c2-c2nn(C)c4ccc(NCCN(C)C)c(c24)C3=O)cc1
Reaction time: 3 h

Procedure:
A solution of 10-(p-methoxybenzyloxy)-5-chloro-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one of Example 11 (0.053 g) and N,N-dimethylethylenediamine (0,115 g) in pyridine (0.5 mL) is heated at 120° C. for 3.5 h under a nitrogen atmosphere. The excess diamine and pyridine are removed by a slow stream of nitrogen gas and the resultant dark orange residue is placed under vacuo for 3 h. The crude material is purified by radial chromathography (silica gel, 2 mm thickness) using gradient elution commencing with 2% methanol/98% chloroform (100 mL) to mixtures containing 4% methanol (75 mL) to 6% methanol (60 mL). Upon removal of the 4% methanol (96% chloroform eluent, starting material is recovered (10 mg). Removal of the 6% methanol/94% chloroform eluent led to 10-p-methoxybenzyloxy-5-[[2-(dimethylamino)ethyl]amino]-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one as a pure product (22 mg).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)(C)(C)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>CCOCC.CCO>[C:27]1([CH3:37])[CH:28]=[CH:29][C:30]([S:33]([OH:36])(=[O:34])=[O:35])=[CH:31][CH:32]=1.[NH2:8][CH2:9][CH2:10][N:11]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CN(CCN)C(=O)OCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
A solution of ethyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)((2-(trimethylsilyl)ethoxy)carbonyl)amino)acetate (intermediate 125, 7.70 g, 19.72 mmol) in Et2O (50 ml) was added to a solution of para-toluene sulphonic acid (3.94 g, 20.70 mmol) in EtOH (50 ml) at room temperature. The rotated solution was then evaporated under a reduced pressure of 270 mbar at room temperature for 40 minutes and then for 1 h at 55° C. To the residue was added EtOH (50 ml), which was again removed by evaporation to give the title compound as a yellow oil. (MS) ESI-MS 291.3 [M+H]+
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=O)[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:25].[OH-].[Na+]>ClC1C=CC=CC=1>[C:1]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([Cl:25])=[C:6]([C:12]#[N:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: Clc1ccccc1
Product: CC(=O)c1cc(C#N)c(Cl)nc1C
Temperature: 100 °C

Procedure:
35 g (0.2 mol) of 5-acetyl-3-cyano-6-methyl-2-pyridone* are suspended in 400 ml of chlorobenzene, 24.2 g (0.2 mol) of N,N-dimethylaniline are added, and 37 g (0.24 mol) of POCl3 are added dropwise. The mixture is then heated at 100° C. for three hours. After cooling, the mixture is cautiously poured onto water, neutralization with dilute sodium hydroxide solution is carried out, the organic phase is separated off, and the aqueous phase is again extracted with CHCl3. The combined extracts are dried with Na2SO4 and evaporated. The residue is purified by filtration through silica gel, using CH2Cl2 /ethyl acetate as eluent.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][CH:10]2[CH:6]([CH2:7][N:8]([C:12](=[O:25])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:9]2)[C:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])([OH:26])[CH2:4]1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(N(CC)CC)C>[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([O:1][CH2:2][CH:3]2[CH2:11][CH:10]3[CH:6]([CH2:7][N:8]([C:12](=[O:25])[CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:9]3)[C:5]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])([OH:26])[CH2:4]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Cc1ccccc1N1CCCC1)N1CC2CC(CO)CC(O)(c3ccccc3F)C2C1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CC3CN(C(=O)Cc4ccccc4N4CCCC4)CC3C(O)(c3ccccc3F)C2)cc1
Yield: 26.1 %

Procedure:
The procedure is as described for Example 13, starting from 0.2 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-[2-(1-pyrrolidinyl)phenylacetyl]perhydroisoindol-4-ol, 0.168 g of p-toluenesulphonyl chloride and 0.124 cm3 of triethylamine, and gives 0.07 g of (3aRS,4RS,6SR,7aSR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-[2-(1-pyrrolidinyl)phenylacetyl]perhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]2[C:14](=[CH:15][C:16]=1Cl)[N:13]=[C:12]([CH3:18])[CH:11]=[CH:10]2)(=[O:5])=[O:4].Cl[C:29]1C=CC(C2C(O)=C(C)C=C3C=2C=CC(C)=N3)=CC=1>>[F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:29])[N:13]=[C:12]([CH3:18])[CH:11]=[CH:10]2)(=[O:5])=[O:4]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(Cl)cc2n1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(O)c(C)cc2n1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1

Procedure:
Compound 2E was prepared following the procedure used to prepare compound 1F of Example 1, except that 5-(4-chlorophenyl)-2,7-dimethylquinolin-6-ol (2D) was used instead of compound 1E. LCMS-ESI+ (m/z): 416.0, 418.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=[S:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H]1NC(=S)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Temperature: 40 °C
Yield: 170.1 %

Procedure:
To a solution of tert-butyl[(3S,5S,6R)-6-methyl-2-oxo-5-phenylpiperidin-3-yl]carbamate (796 mg, 2.62 mmol) in toluene (26.2 mL) was added Lawesson's Reagent (539 mg, 1.33 mmol) and the resulting mixture stirred at 40° C. 16 h. The mixture was cooled to ambient temperature and concentrated. Purification by silica gel chromatography (100% hexanes→60% hexanes/ethyl acetate) gave the title compound (725 mg). MS 343.3 (M+Na).
Reaction SMILES: [F:1][C:2]([F:40])([CH2:6][NH:7][C:8]([NH:10][C@@:11]([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])[CH:29]=[C:28]([F:39])[CH:27]=1)([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:3]([OH:5])=O.C(Cl)(=O)OCC.CC[N:49](CC)CC.N.O>C(Cl)Cl>[F:1][C:2]([F:40])([CH2:6][NH:7][C:8]([NH:10][C@@:11]([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:37])([F:38])[CH:34]([F:35])[F:36])[CH:29]=[C:28]([F:39])[CH:27]=1)([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:3]([NH2:49])=[O:5]
Reactant: O=C(NCC(F)(F)C(=O)O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: NC(=O)C(F)(F)CNC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To a solution of (R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanoic acid (60 mg, 0.1 mmol) in CH2Cl2 (1 mL) at 0° C. was added ethyl carbonochloridate (10 uL, 0.1 mmol), followed by NEt3 (0.021 mL, 0.15 mmol) and NH3.H2O (0.1 mL, 2.6 mmol). The reaction mixture was stirred at rt for 30 min, then concentrated under reduced pressure and purified by prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to yield (R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanamide as a white solid (12 mg, 21% yield). LCMS: RT=3.85 min [M+H] 576.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].CCCP(=O)=O.O>CN(C)C=O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1ccc(F)cc1
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccc(F)cc1)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.1 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (250 mg, 0.62 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(4-fluoro-benzyl)-amine (8k) (210 mg, 0.74 mmol) in dimethylformamide (5 mL) was added propylphosphonic anhydride (50 wt % in ethyl acetate) (1.3 g, 1.85 mmol) at 0° C. After stirring at room temperature for 20 h, water (20 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to yield 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(4-fluoro-benzyl)-amide (312) (96 mg, 23.18%) as a colourless sticky solid.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].Cl[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[O:36][CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][C:27]=3[O:36][CH3:37])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc2ccccc2c1CCl
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (406 mg, 1.28 mmol) in DMF (3.21 ml) was added 1-(chloromethyl)-2-methoxynaphthalene (318 mg, 1.54 mmol) and cesium carbonate (1.25 g, 3.85 mmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (448 mg, 72%) as an off-white solid. MS m/z 509 (MNa)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C.[C:41]([O:45][CH2:46][CH3:47])(=[O:44])[CH:42]=[CH2:43]>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:46]([O:45][C:41](=[O:44])[CH:42]=[CH:43][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9])[CH3:47]
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCOC(=O)C=Cc1ccc(F)cc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 1-bromo-4-fluoro-2-methyl-benzene (5.00 g, 26.45 mmol), palladium acetate (0.59 g, 2.64 mmol), tri-o-tolylphosphine (1.61 g, 5.29 mmol), DIPEA (13.8 mL, 79.35 mmol) and ethyl acrylate (3.34 mL, 105.80 mmol) in propionitrile (106 mL) is stirred at 90° C. under nitrogen overnight. The mixture is ed off through Celite and washed with ethyl acetate. The mixture is concentrated under reduced pressure, purified by flash chromatography by eluting with hexane:ethyl acetate 10:1 to afford the title compound (5.50 g, 99%). Rf=0.49 (hexane:ethyl acetate 5:1). 1H NMR (300 MHz, CDCl3): δ1.33 (t, 3H, J=7.3 Hz), 2.41 (s, 3H), 4.26 (q, 2H, J=7.3 Hz), 6.28 (d, 1H, J=16.0 Hz), 6.88-6.91 (m, 2H), 7.48-7.53 (m, 1H), 7.88 (d, 1H, J=15.8 Hz).