Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:32][C@H:33]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[CH:36](OC(=O)C)[O:35][C@@H:34]1[C:46]1[N:47]=[N:48][N:49]([CH2:51][CH3:52])[N:50]=1)(=[O:31])[CH3:30].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClC(Cl)(Cl)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:39]([O:38][C@@H:37]1[C@H:33]([O:32][C:29](=[O:31])[CH3:30])[C@@H:34]([C:46]2[N:47]=[N:48][N:49]([CH2:51][CH3:52])[N:50]=2)[O:35][C@H:36]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:41])[CH3:40]
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CCn1nnc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)OC)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A suspension of methyl 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 29) (0.4 g, 1.07 mmol) in 1,1,1-trichloroethane (25 ml) was treated with N,O-bis(trimethylsilylacetamide) (1.6 ml, 6.54 mmol) and the mixture was heated under reflux for one hour. The solvent was removed under reduced pressure and the residue was twice azeotroped with toluene. The residue was dissolved in toluene (5 ml) and treated sequentially with a solution of (2R,3R,4R)-4,5-bis(acetyloxy)-2-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (WO-A-9967265) (0.45 g, 1.31 mmol) in toluene (20 ml) and then trimethylsilyltriflate (0.25 ml, 1.37 mmol). The mixture was heated under reflux for 3 hours and then allowed to stand at room temperature overnight. The solution was diluted with ethyl acetate (40 ml), washed sequentially with saturated aqueous sodium hydrogen carbonate solution (20 ml) and brine (20 ml), dried (anhydrous magnesium sulphate) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (80:20 by volume) gradually changing to dichloromethane:ethyl acetate (60:40 by volume) to afford the title compound (0.44 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:23](=[O:25])[CH3:24]>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:23]([OH:25])[CH3:24])[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(CN2CCOCC2)n1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C(c1cccc(Br)n1)N1CCOCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
4-[(6-Bromopyridin-2-yl)methyl]morpholine (Example 45, step 1) (200 mg, 0.78 mmol) was placed under argon and then taken up in tetrahydrofuran (8 mL). The solution was cooled to −78° C. followed by the addition of LDA (0.65 mL of 1.8 M, 1.17 mmol) over 30 minutes. The reaction was maintained at −78° C. for one hour. Acetaldehyde (0.1 mL, 7.8 mmol) was then added and the reaction was then stirred at −78° C. for 2 hours. An additional portion of acetaldehyde (0.1 mL, 7.8 mmol) was then added and the reaction was then stirred an additional 2 hrs at −78° C. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification of the crude mixture via flash chromatography (silica, 0-5% methanol/ethyl acetate) afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=1.[C:17](OC)(OC)(OC)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO.C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:17]([CH3:18])[N:9]([C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:16])[N:15]=3)[C:3]=2[CH:4]=1
Reactant: COC(C)(OC)OC
Reactant: Nc1ncnc(Nc2cc(Br)ccc2N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To a solution of 2-N-(2-amino-5-bromophenyl)-1,3,5-triazine-2,4-diamine (2.50 g, 8.89 mmol) in methanol (25 mL) and THF (100 mL) was added trimethyl orthoacetate (16.77 ml, 133.4 mmol) and TsOH (153.14 mg, 0.89 mmol). The reaction mixture was stirred at 70° C. for 1 hr then allowed to cool to RT overnight. Saturated aqueous sodium bicarbonate (30 mL) was introduced and the resulting precipitous solution filtered. The filtrate was extracted into DCM (3×100 mL extractions). The combined organic extracts were washed with brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The orange/yellow solid residue was then triturated from a mixture of DCM and MeOH to give the title compound as a pale yellow powder (400 mg): 1H NMR (500 MHz, DMSO) delta 2.89 (3H, s), 7.46 (1H, dd, J=8.5, 1.9 Hz), 7.57 (1H, d, J=8.4 Hz), 8.02 (1 H, s), 8.10 (1H, s), 8.61 (1H, d, J=1.8 Hz), 8.64 (1H, s); LC-MS: m/z=+306.7 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O.O>[CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=2)[O:3]1
Reactant: CC1(C)CCc2ccccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g (30.82 mmol) of 2,2-dimethylchroman (Compound 56) in 50 ml of nitromethane was treated, under nitrogen, with 2.53 g (32.35 mmol) of acetyl chloride followed by 4.4 g (33 mmol) of aluminum chloride. The reaction mixture was stirred at room temperature for 3 hours and then cooled in an ice-bath and treated slowly with 50 ml of 6M HC1. The mixture was diluted with water and extracted with ether. The ether extracts were washed successively with saturated NaHCO3 solution, water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in-vacuo and the resultant residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a white solid. PMR (CDCl3) : & 1.36 (6H, s), 1.84 (2H, t, J~6.8 Hz), 2.54 (3H, s), 2.82 (2H, t, J~6.8 Hz), 6.80 (1H, d, J~8.4 Hz), 7.69-7.76 (2H, m). MS exact mass, m/e 204.1140 (calcd. for C13H16O2, 204.1150).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=[C:14]([NH2:21])[C:13]=2[N:12]=[C:11]1[CH3:22]>>[NH2:21][C:14]1[C:13]2[N:12]=[C:11]([CH3:22])[N:10]([CH2:9][CH2:8][NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[C:18]=2[C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCNC(=O)N(C)C)c2c1C

Procedure:
Using the method of Examples 118-133, dimethylcarbamyl chloride was reacted with 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 291.1929.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].[O:19]([CH2:26][CH2:27][CH2:28][CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)C>[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCCCOc1ccccc1
Reactant: COC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)Cc1ccccc1OCCCCOc1ccccc1

Procedure:
28.2 g (0.17 mole) of methyl 2-hydroxyphenylacetate, 25.8 g (0.19 mole) of potassium carbonate and 38.9 g (0.17 mole) of 4-phenoxybutyl bromide in 400 ml of dimethylformamide are stirred for 24 hours at 70° C. Thereafter, the solvent is stripped off and the residue is taken up in diethyl ether. The solution is extracted several times with water and saturated sodium carbonate solution and the organic phase is dried over MgSO4. The oil obtained after removal of the solvent is purified by chromatography over silica gel (cyclohexane/ethyl acetate). Yield: 31 g (58%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:57][C:58]2[S:59][CH:60]=[CH:61][N:62]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: CN(C)CC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 19.4 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-propionic acid (150 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.86 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 methylene chloride/methanol) afforded 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (37 mg, 19.3%) as a white solid: mp 164-167° C.; EI-HRMS m/e calcd for C22H27N3OS (M+) 381.1874, found 381.1879.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[C:7]3[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:6]=23)[CH2:3][CH2:2]1.Cl.[CH3:20][NH:21][O:22][CH3:23].OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH:1]1([NH:4][C:5]2[C:10]([C:11]([N:21]([O:22][CH3:23])[CH3:20])=[O:13])=[CH:9][N:8]=[C:7]3[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:6]=23)[CH2:2][CH2:3]1
Reactant: CCn1ncc2c(NC3CC3)c(C(=O)O)cnc21
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CC3)c(C(=O)N(C)OC)cnc21
Reaction time: 1 h

Procedure:
4-cyclopropylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (500 mg, 0.0020 mole) and N,O-dimethylhydroxylamine hydrochloride (298 mg, 0.0030 mole) were taken in dimethylformamide. At 0° C., hydroxybenzotriazole (550 mg, 0.0040 mole) and N-methylmorpholine (1.34 ml, 0.012 mole) were added and the reaction mixture was stirred for about 1 hour. 1-(3-dimethylaminopropyl) 3-ethyl carbodiimide hydrochloride (780 mg, 0.0040 mole) was added and the reaction mixture was stirred for about 14 hours. Water was added and extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give an oily compound. Yield: 500 mg. m/z: (M++1) 290.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[CH2:18][O:19]CC2C=CC=CC=2)=[CH:12][CH:11]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][OH:19])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCOc1ccc(NC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCOc1ccc(NC(=O)CO)cc1
Reaction time: 5 h
Yield: 65.1 %

Procedure:
6-[4-(2-Benzyloxyacetylamino)-phenoxy]-hexanoic acid methyl ester 53 (1 grams, 2.6 mmol) was dissolved in methanol (10 ml) in a pressure vessel. Palladium on carbon (5%, 250 mg) was added and the mixture stirred under a hydrogen atmosphere (2 kg) for 5 hrs. Catalyst was removed by filtration and methanol distilled off. Crude 54 was recrystallised in chloroform:hexane (1:6) to get pure 54 (0.5 g, 65.3%) as a white powder with an m.p. between 91.5-94° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:16].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CC(C)=O>[CH3:22][O:21][C:19](=[O:20])[CH2:18][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][OH:15])[C:8]=1[Cl:7]
Reactant: COC(=O)CBr
Reactant: OCc1cccc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1cccc(CO)c1Cl
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
Cesium carbonate (3.42 g, 10.5 mmol) was added to a solution of 2-chloro-3-hydroxymethylphenol (1.59 g, 10 mmol) in acetone at room temperature, and the reaction mixture allowed to stir for 30 minutes. Methyl bromoacetate (1.68 g, 11 mmol) was then added. The mixture was stirred overnight, filtered, and the filtrate was concentrated in vacuo. Purification of the residue by silica gel flash chromatography, eluting with dichloromethane/methanol, gave (2-chloro-3-hydroxymethylphenoxy)acetic acid methyl ester as a white crystalline solid (1.94 g, 84.1%).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4C([CH:20]=3)=CC=CC=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]2)[CH:3]=1.C[N:36]1C=C(C2C=NN3C(N)=CC(C4CCNCC4)=NC=23)C=N1.N1CCC(C2C=C(N)N3N=CC(C4C=NC5C(C=4)=CC=CC=5)=C3N=2)CC1>>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:20]=[N:36][N:13]([CH3:14])[CH:12]=3)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23][CH2:22]2)[CH:3]=1
Reactant: Cn1cc(-c2cnn3c(N)cc(C4CCNCC4)nc23)cn1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Agent: Nc1cc(C2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Product: Cn1cc(-c2cnn3c(N)cc(C4CCN(CC(=O)OC(C)(C)C)CC4)nc23)cn1

Procedure:
tert-Butyl 2-(4-(7-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetate was synthesized in a manner similar to the synthesis of tert-butyl 2-(4-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl)acetate, but with 3-(1-methyl-1H-pyrazol-4-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine substituted for 5-(piperidin-4-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[N:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:40]2[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=2)=[O:47])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Product: Cc1ccc(C(=O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(F)c2F)cn1

Procedure:
Starting materials (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3 and N-methoxy-N,6-dimethylnicotinamide.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]([NH:16][C:17](=[O:45])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[N:27][C:28]([O:34]CC4C=CC(OC)=CC=4)=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=3)=[CH:21][C:20]=2[F:44])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[C:6]1[CH:7]=[C:8]([NH:16][C:17](=[O:45])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[C:28](=[O:34])[NH:27][CH:26]=3)=[CH:21][C:20]=2[F:44])[CH:9]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:11]=1
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4nn[nH]n4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4nn[nH]n4)cc(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a mixture of N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (30 mg, 0.048 mmol) in DCM (5 mL) was added TFA (7.42 μL, 0.096 mmol). The mixture was stirred at 20° C. for 1 h. LCMS showed the reaction was finished. The mixture was concentrated to give crude product, which was purified by preparative HPLC (Column: ASB C18 150*25 mm; Mobile phase A: Water+0.1% HCl; Mobile phaseB: MeCN; Flowrate: 25 mLl/min; Gradient Profile Description: 30-66 (B %)) to give N-(3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (5.12 mg, 10.01 μmol, 20.8% yield): 1H NMR (400 MHz, DMSO-d6) δ 11.83 (br. s., 1H), 11.33 (s, 1H), 10.85 (s, 1H), 8.69-8.57 (m, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.47 (d, J=11.7 Hz, 1H), 7.42-7.27 (m, 3H), 7.12 (br. s., 1H), 4.03 (d, J=6.8 Hz, 2H), 3.79 (s, 2H), 1.31 (t, J=6.8 Hz, 3H). ES-LCMS m/z 503 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH2:11].C(N(CC)CC)C.[F:26][C:27]([F:40])([F:39])[O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH:11][S:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:39])[F:40])=[CH:34][CH:33]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(OC(F)(F)F)cc1
Yield: 59.6 %

Procedure:
To a solution of 0.20 g of 3,5-dichloro-4-(2-aminoethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene and 0.10 g of triethylamine dissolved in 5 ml of dichloromethane was added dropwise a solution of 0.16 g of 4-trifluoromethoxybenzenesulfonyl chloride dissolved in 5 ml of dichloromethane, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.20 g of 3,5-dichloro-4-(2-(4-trifluoromethoxybenzenesulfonamido)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (60% yield), nD23.0 1.5470.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[O:14])=[CH:8][CH:7]=1.[C:25]([N:32]1[CH:36]=[CH:35]N=[CH:33]1)(N1C=CN=C1)=[S:26].C(N([CH2:42][CH3:43])CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:23][C:25]([N:32]([C:36]1[CH:35]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:43]1[CH:42]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:33])=[S:26])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([C:15]2[C:16]([Cl:22])=[CH:17][N:18]=[CH:19][C:20]=2[Cl:21])=[O:14])=[CH:10][CH:11]=1
Reactant: CCN(CC)CC
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC(=S)N(C)c1ccccc1Cc1ccccc1
Reaction time: 2 h
Yield: 122.1 %

Procedure:
(S)-2-Amino-3-{4-[(3,5-dichloropyridine-4-carbonyl)amino]phenyl}propionic acid methyl ester (0.25 g, 0.62 mmol) was added at room temperature to a tetrahydrofuran solution (3 ml) of thiocarbonyidiimidazol (0.12, 0.68 mmol) and triethylamine (0.062, 0.62 mmol) and stirred for 2 h. Next, the solvent was removed under reduced pressure and compound from Preparation 11 was added in acetonitrile (3 ml) and stirred at 80° C. for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (Hexane:AcOEt, 1:1) to yield the title compound(0.23 g, 62%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[C:14]([C:16]([O:18]CC2C=CC=CC=2Cl)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:27])[CH:12]=2)[N:7]=1.[OH-].[Na+].CO.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:27])[CH:12]=2)[N:7]=1
Reactant: Cc1ccc2nc(OCc3ccccc3Cl)cc(C(=O)OCc3ccccc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc2nc(OCc3ccccc3Cl)cc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To 2-(2-chlorobenzyloxy)-4-(2-chlorobenzyloxycarbonyl)-6-methylquinoline (Method 11; 0.980 g, 2.173 mmol) in THF (100 ml) was added a solution of sodium hydroxide (261 mg, 6.519 mmol) in water (2.6 ml) followed by water (60 ml) and methanol (10 ml). The reaction mixture was stirred at ambient temperature for 2 hrs 30 min and then adjusted to pH 4–5 with 1M HCl. It was then concentrated in vacuo and the resulting solid filtered, washed with water, and dried to give the title compound as a colourless solid (0.704 g, 99%). NMR: 2.45 (3H, s), 5.60 (2H, s), 7.35 (3H, m), 7.50 (1H, m), 7.55 (1H, dd), 7.65 (1H, m), 7.75 (1H, d), 8.30 (1H, s); m/z 328 (M+H)+, 326 (M−H)−.
Reaction SMILES: [P:1]([O:19][CH2:20][C:21](=[O:46])[C@@H:22]([NH:30][C:31](=[O:45])[C@H:32]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].CO>C(OCC)(=O)C.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[P:1]([O:19][CH2:20][C:21](=[O:46])[C@@H:22]([NH:30][C:31](=[O:45])[C@H:32]([CH2:41][CH:42]([CH3:43])[CH3:44])[NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:3])([OH:11])=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)COP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)COP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
A suspension of 30 mg of 20% Pd(OH)2 in a solution of dibenzyl (3S)-[3-[(N-t-Butoxycarbonyl-L-leucyl)amino]-2-oxo-4-phenylbutyl] phosphate (30 mg, 0.046 mmol) in 1.0 mL of ethyl acetate was stirred under H2 (1 atm) at room temperature for 4 hours. The catalyst was filtered through Celite™ and the filtrate was concentrated to give the crude product. Flash chromatography (10% MeOH in CH2Cl2) gave 8 mg of pure product. MS: 471 m/z (M-1).