Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:8])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd](Cl)Cl.CCO>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[CH:12][CH:13]=1)=[O:8])[CH3:2]
Reactant: CCOC(CNC(=O)c1ccc(Cl)s1)OCC
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(CNC(=O)c1ccc(-c2ccc(Cl)cc2)s1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
Add 5-chloro-thiophene-2-carboxylic acid (2,2-diethoxyethyl) amide (50.15 g, 0.18 mol), 4-chlorophenylboronic acid (29.84 g, 0.18 mol), potassium carbonate (50 g, 0.36 mol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)(3-chloropyridyl)] palladium (II) dichloride (4.40 g, 0.006 mol), and EtOH (1000 mL) to a 2 L three-necked round bottom flask equipped with a overhead stirrer, reflux condenser, nitrogen inlet/outlet, addition funnel, and thermocouple. Heat the resulting slurry for 35 minutes, then add activated carbon (5.8 g) and heat for an additional 0.5 h. Filter the resulting slurry through glass microfibre filter and rinse solids with EtOH (500 mL). Remove solvent from the filtrate under reduced pressure until 15-20% solvent remains. To this filtrate, add water (1300 mL) and stir the resulting slurry at room temperature for 1 h, then at 0-5° C. for 0.5 h. Filter the slurry, rinse the solids with water (1000 mL), and dry to afford 66 g of crude 5-(4-chlorophenyl)-thiophene-2-carboxylic acid (2,2-diethyoxyethyl) amide. Reflux the crude 5-(4-chlorophenyl)-thiophene-2-carboxylic acid (2,2-diethyoxyethyl) amide in heptane (1625 mL) for 1 h then filter through a glass microfibre filter. Transfer the filtrate to a round bottom flask and remove solvent until 725 mL of solvent remained. Stir the mixture under chilled conditions for 40 min. Filter the resulting slurry, rinse with heptane (100 mL), and dry to afford 41 g (64%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.54 (d, J=9.0 Hz, 2H), 7.45 (d, J=4.5 Hz, 1H), 7.38 (d, J=9.0 Hz, 2H), 7.24 (d, J=4.5 Hz, 1H), 6.20 (bs, 1H), 4.62 (t, J=5.5 Hz, 1H), 3.73-3.79 (m, 2H), 3.57-3.62 (m, 4H), 1.25 (t, J=7.0 Hz, 6H),
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1[CH2:40][O:39][CH2:38][CH2:37]1.COCCBr>CN(C=O)C>[CH3:40][O:39][CH2:38][CH2:37][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:5][C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Reactant: C1CCOC1
Agent: COCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: COCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 15.3 %

Procedure:
To a cooled (−15° C.) solution of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.100 g; 0.295 mmol) in dry DMF (1.5 mL) was wadded a 1N solution of LHMDS in THF (0.324 mL; 0.324 mmol) dropwise and the mixture was stirred at (−15° C.) for 15 min, followed by the dropwise addition of 2-bromoethyl methyl ether (0.083 mL; 0.884 mmol). After stirring for 2 h at (−15° C.) the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride and the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.018 g (15%) of the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2.Cl.N1C=CC=CC=1.[OH-].[NH4+]>O>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([OH:2])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc2cnccc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2cnccc2c1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
Heat a mixture of 6-methoxy-isoquinoline (2.1 g, 13.2 mmol) and pyridine hydrochloride (30 g) in a heavy walled screw cap sealed tube at 160° C. overnight. Cool to room temperature, add water and concentrated ammonium hydroxide to bring the pH of the mixture to 10-11, extract with ethyl acetate (4 times), wash the combined organic extracts with water (4 times), and concentrate under reduced pressure. Purification by medium pressure liquid chromatography eluting with 0-3% of 2N NH3/MeOH in dichloromethane afford the title compound (520 mg, 27%): δH (DMSO-d6, 400 MHz): 7.09 (s, 1H), 7.19 (dd, 1H, J=9, 2 Hz), 7.56 (d, 1H, J=6 Hz), 7.94 (d, 1H, J=9 Hz), 8.29 (d, 1H, J=6 Hz), 9.05 (s, 1H), 10.36 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:3]=1.[CH3:17][N:18]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:10]([O:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=1)[C:17]#[N:18])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)[Si](C)(C)OCc1cc(C#N)ccn1
Temperature: 95 °C
Yield: 26 %

Procedure:
To a stirring solution of 4-bromo-2-((tert-butyldimethylsilyloxy)methyl)pyridine INT-70 (0.800 g, 2.6 mmol) in 3 mL of 1-methy-2-pyrrolidine (NMP) was added zinc cyanide (0.610 g, 5.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol). The solution was degassed with N2 and the reaction mixture heated at 95° C. for 12 h. Upon cooling, the reaction mixture was diluted with saturated NaHCO3 and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (MeOH/DCM) to produce 0.170 g (26%) of 2-((tert-butyldimethylsilyloxy)methyl)isonicotinonitrile INT-71 as a light yellow solid. LCMS-ESI (m/z) calculated for C13H20N2OSi: 248.4; found 249.1 [M+H]+, tR=4.21 min (Method 1).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]#[CH:18])[C:6](=[O:19])[C:5]=1[CH3:20])([OH:3])=O.Cl.[CH3:22][NH:23][CH3:24].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:22][N:23]([CH3:24])[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]#[CH:18])[C:6](=[O:19])[C:5]=1[CH3:20])=[O:3]
Reactant: C#CCn1c(-c2ccccc2)nc(C(=O)O)c(C)c1=O
Reactant: CNC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2)nc(C(=O)N(C)C)c(C)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 31.7 %

Procedure:
To a stirred solution of 0.87 g (3.2 mmol) of crude 6-carboxy-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone, 0.32 g (3.9 mmol) of dimethylamine hydrochloride and 2 mL of pyridine in 10 mL of THF was added 0.74 g (3.6 mmol) of solid N,N'-dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 4 days and filtered to remove insoluble material. The filtrate was diluted with 150 mL of ethyl acetate, washed with 50 mL of 5% aqueous HCl and 50 mL of saturated aqueous sodium bicarbonate and dried over MgSO4. Removal of the solvent left 0.40 g of crude product which was purified by flash chromatography on a 30 g column of silica gel, eluted with 60, 80 and 100% ethyl acetate in hexanes to furnish 0.30 g (32%) of 6-dimethylaminocarbonyl-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (compound 19), mp 137°-140° C. 1H-NMR (CDCl3) δ 2.15(3H,s), 2.40(1H,t), 3.00(3H,s), 3.10(3H,s), 4.65(2H,d), 7.55(3H,m), 7.70(2H,m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C:8]([C:10]1[S:11][C:12]([S:41][CH3:42])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=S)=[CH:26][C:25]=3[CH3:40])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[NH3:44]>CO.[Hg]=O>[C:1]([O:5][C:6](=[O:43])[NH:7][C:8]([C:10]1[S:11][C:12]([S:41][CH3:42])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:44])=[N:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:26][C:25]=3[CH3:40])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCCNC(=S)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Reactant: N
Agent: O=[Hg]
Solvent: CO
Product: CCCCCCN=C(N)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
({4-[4′-(3-Hexyl-thioureido)-2′-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (33 mg, 0.14 mmol. Example 136: step a) was dissolved into ammonia in methanol (2.0 M, 4 mL). To this was added mercury(II) oxide (33.9 mg, 0.16 mmol) and the reaction stirred at RT for 2 hours. Additional mercury(II) oxide (154 mg, 0.08 mmol) was added and the reaction was heated to 40° C. overnight. The reaction was filtered with 0.2 μM disk and washed with EtOAc followed by removal of solvents in vacuo that yielded the title compound which was used without further purification (30 mg). ESI-MS (m/z): Calcd. for C31H41N5O4S3: 644.2 (M+1); found: 644.1.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[P:26]([O-:34])([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27]>>[P:26]([O:34][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27]
Reactant: ON=C1CCCCC1
Reactant: CCOP(=O)([O-])OCC
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CCOP(=O)(OCC)OC1(N=O)CCCCC1

Procedure:
Diethyl 1-nitrosocyclohexyl phosphate was prepared from cyclohexanone oxime, lead tetraacetate and diethyl phosphate using conditions of General Method 3. 1H NMR (400 MHz, benzene-d6) δ 3.90-4.15 (3H, m), 1.24-1.78 (10H, m), 0.88-1.10 (7H, m)
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH3:14])=[C:7]([NH:15][CH:16]([CH3:20])[CH:17]([CH3:19])[CH3:18])[N:6]2[N:21]=[CH:22][C:23]([C:24](Cl)=[O:25])=[C:5]2[N:4]=1.C(OCC)(=O)C>O1CCCC1>[Cl:2][C:3]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH3:14])=[C:7]([NH:15][CH:16]([CH3:20])[CH:17]([CH3:19])[CH3:18])[N:6]2[N:21]=[CH:22][C:23]([C:24]([NH2:1])=[O:25])=[C:5]2[N:4]=1
Reactant: Cc1ccsc1-c1c(Cl)nc2c(C(=O)Cl)cnn2c1NC(C)C(C)C
Reactant: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccsc1-c1c(Cl)nc2c(C(N)=O)cnn2c1NC(C)C(C)C
Temperature: 22 °C
Reaction time: 16 h

Procedure:
At room temperature, 15 ml of concentrated aqueous ammonia were added to 4.0 g (10 mmol) of 5-chloro-7-(1,2-dimethylpropylamino)-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]pyrimidine-3-carbonyl chloride in 30 ml of tetrahydrofuran. The mixture was stirred at 22° C. for 16 hours, and 50 ml of ethyl acetate were then added. The organic phase was separated off, dried over sodium sulphate and concentrated under reduced pressure. This gave 3.0 g of 5-chloro-7-(1,2-dimethyl-propylamino)-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide (logPs=3.5; content according to HPLC: 94%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.C(N(CC)C(C)C)(C)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:6]2[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(Cl)c2NC=O)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a suspension of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (10.0 g, 48.3 mmol) in 1,4-dioxane (400 mL) were added N,N-diisopropylethylamine (12.7 mL, 72.5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (9.8 g, 53.1 mmol). The mixture was stirred at 55° C. for 1 h. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The aqueous phase was extracted with further DCM and the combined organic fractions were washed with brine, then dried (Na2SO4) and evaporated in vacuo to give the title compound (17.1 g, 100%) as a white solid. LCMS (ES+) 357.4 (M+H)+, RT 1.08 minutes (method 3).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ccccc1-c1cccc2[nH]ccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To a mixture of 4-bromoindole (5.5 g, 28 mmol), and 2-chlorophenylboronic acid (4.4 g, 28 mmol) in THF (96 mL) were added Palladium catalyst Pd(PPh3)4 (0.975 g, 0.8 mmol) and the freshly prepared sodium hydroxide solution (3.4 g, 84 mmol in 40 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 2.41 g (38%) of 4-(2-chloro-phenyl)-1H-indole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]3[N:23](O)[C:24]([CH3:27])=[N:25][CH:26]=3)[CH:19]=[C:18]([O:29][CH2:30][CH3:31])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([O-])(O)=O.[Na+]>O.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]3[NH:23][C:24]([CH3:27])=[N:25][CH:26]=3)[CH:19]=[C:18]([O:29][CH2:30][CH3:31])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2cnc(C)n2O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2cnc(C)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.6 %

Procedure:
A 20% solution of TiCl3 in H2O was added dropwise at 0° C. to a solution of the ethyl (RS)-(4-cyano-phenylamino)-[3-ethoxy-5-(3-hydroxy-2-methyl-3H-imidazol-4-yl)-phenyl]-acetate (355 mg, 0.844 mmol) obtained in Example 247.1 in MeOH (4.2 ml). The mixture was stirred for 3 h. at room temperature, subsequently poured into NaHCO3 solution/ice-water and extracted with CH2Cl2. The organic phase was dried, filtered and concentrated. The residue was purified by chromatography (SiO2, CH2Cl2->CH2Cl2/MeOH 95:5). There were obtained 50 mg (15%) of ethyl (RS)-(4-cyano-phenylamino)-[3-ethoxy-5-(2-methyl-3H-imidazol-4-yl)-phenyl]-acetate as a yellowish solid; MS: 405 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][S:14]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:29][C@@H:30]([CH2:44][C:45]1[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH3:42])[CH:36]=1.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:29][C@@H:30]([CH2:44][C:45]1[CH:46]=[C:47]([F:52])[CH:48]=[C:49]([F:51])[CH:50]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH3:42])[CH:36]=1)=[O:26])[CH2:13][S:14]([CH:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])(=[O:15])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(CC)c1
Reaction time: 3 h

Procedure:
N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine (LXXXIV, 4.0 g, 10 mmole) and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (1.2 g, 12 mmole) are mixed in anhydrous methylene chloride (50 ml). To the reaction mixture is added NMM (5.6 ml, 51 mmole), hydroxybenzotriazole (1.7 g, 13 mmole) and lastly 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.1 g (16 mmole). After stirring at 20–25° for 3 hours, HPLC analysis indicates complete reaction. The reaction mixture is diluted with methylene chloride and washed with saturated sodium bicarbonate solution, citric acid (0.5 M), and saline. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give N2-[(benzyloxy)carbonyl]-N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninamide (LXXXV).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([O:30]C)=[O:29])[CH2:23]2)=[CH:18][CH:17]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]2)=[CH:20][CH:21]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(N4CC(C(=O)O)CC4=O)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-5-oxopyrrolidine-3-carboxylate (Step 2, 0.5 ng, 1.18 mmol) in MeOH/THF (2 mL: 2 mL) solution was added 1.77 mL of 1 N NaOH. The reaction was stirred at RT for 8 h. The solution was concentrated in vacuo to dryness and acidified with 1 N HCl. The white precipitate was collected by filtration and washed with 50% EtOAc/hexanes to give the title compound as white solid. MS (ESI pos. ion) m/z: 409.3 (M+H). Calc'd Exact Mass for C22H20N2O6: 408.4.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].CN(C)[CH:29]=[O:30]>O1CCCC1>[Si:20]([O:19][CH2:18][CH2:17][CH2:16][N:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:7]([CH:29]=[O:30])[C:8]=2[CH:9]=[CH:10]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(Br)cccc21
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(C=O)cccc21
Temperature: 0 °C

Procedure:
Add tert-butyl lithium (27.07 ml, 46.03 mmol, 1.7 M in pentane) to a solution of 4-Bromo-1-[3-(tert-butyldimethyl-silyloxy)prop-1-yl]-1H-indole (6.76 g, 18.41 mmol) in anhydrous tetrahydrofuran (100 ml) at −78° C. Stir the reaction at −78° C. for 30 min, quench with N,N-dimethylformamide (4.7 ml, 64.45 mmol), warm to 0° C., quench with pH=7 buffer, and extract into ethyl acetate. Combine the organic layers, dry over magnesium sulfate, and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexane gradient (100% hexane to 50% ethyl acetate:hexane over 45 minutes) gives the title compound as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C:4]=2[NH:5][N:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:30]([O:29][C:27]([NH:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C:4]=2[NH:5][N:6]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2[nH]nc(NC(=O)OCc3ccccc3)c2C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To the product from Step A (133 mg) in dichloromethane (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.21 mL) followed by benzyl chloroformate (0.1 mL). The reaction mixture was stirred at 0° C. for 90 min, then diluted with dichloromethane (10 mL) and poured into saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified on a Biotage Horizon® system (silica gel, 0 to 80% ethyl acetate/hexanes gradient) to give the title compound. LC/MS 359.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([C@H:40]2[CH2:45][CH2:44][C@H:43]([O:46][CH2:47][CH3:48])[CH2:42][CH2:41]2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:47]([O:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([C:32]2[CH:31]=[CH:30][C:29]([NH:28][C:21]3[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:11][CH:12]=4)[N:22]=3)=[C:37]3[C:33]=2[CH2:34][N:35]([CH3:39])[C:36]3=[O:38])[CH2:45][CH2:44]1)[CH3:48]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CCO[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OCC)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (40.0 mg, 0.0944 mmol) and 7-amino-4-(trans-4-ethoxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 166B). 1H NMR (DMSO-d6, 400 MHz): δ=1.11 (t, J=6.95 Hz, 3H), 1.18 (t, J=6.95 Hz, 6H), 1.21-1.33 (m, 2H), 1.54-1.68 (m, 2H), 1.80 (d, J=12.63 Hz, 2H), 2.09 (dd, J=12.63, 3.28 Hz, 2H), 3.08 (s, 3H), 3.18-3.27 (m, 2H), 3.49 (q, J=6.99 Hz, 2H), 3.91-4.01 (m, 4H), 4.52 (s, 2H), 7.26 (dd, J=8.72, 1.89 Hz, 2H), 7.40 (d, J=8.59 Hz, 1H), 7.56 (br. s., 2H), 8.45 (s, 1H), 8.67 (s, 1H), 9.89 (s, 1H), 10.58 (br. s., 1H). MS (ES+): m/z=676.25 [MH+] (TOF, polar).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.O[CH2:24][CH2:25][C:26](=[O:28])[CH3:27]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: CC(=O)CCO
Product: CC(=O)CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIm was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 4-hydroxybutan-2-one following the general procedure for the Mitsunobu reaction as described above.