Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:55]([OH:57])=[O:56])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:63](=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:55]([O:57][CH3:63])=[O:56])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 84.4 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 25m (0.45 g, 0.57 mmol) in a methanol/tetrahydrofuran mixture (v/v=6/5, 22 mL) was added concentrated sulphuric acid (0.05 mL) at room temperature. The mixture was warmed up to 60° C. and stirred for 14 hours. The reaction mixture was adjusted with saturated aqueous sodium bicarbonate to pH 7 at room temperature and extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=6/1 to give the title compound 25n as a pale yellow solid (0.38 g, 84.4%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ(ppm): 7.48 (m, 1H), 7.47 (m, 2H), 7.41 (m, 4H), 7.33 (m, 7H), 7.25 (m, 3H), 7.21 (m, 4H), 7.16 (m, 2H), 7.08 (m, 2H), 6.87 (m, 2H), 5.01 (s, 2H), 4.81-4.75 (m, 3H), 4.78 (m, 1H), 4.63 (d, 1H), 4.52 (d, 1H), 4.26 (d, 1H), 4.19 (m, 2H), 4.09 (m, 1H), 4.01 (m, 2H), 3.87 (m, 1H), 3.74 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[S:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[CH:27][O:26][C:25]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:20][CH:19]=1)(=[O:17])(=[O:16])[NH2:15]>CC(N(C)C)=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]2[O:26][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:24]([C:21]3[CH:20]=[CH:19][C:18]([S:14](=[O:16])(=[O:17])[NH2:15])=[CH:23][CH:22]=3)[CH:28]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1occc1-c1ccc(S(N)(=O)=O)cc1
Reactant: Clc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 150 °C
Yield: 9.8 %

Procedure:
1-bromo-4-chlorobenzene (0.214 g, 1.11 mmol) and potassium acetate (0.199 g, 2.03 mmol) were added to a solution of ethyl 3-(4-sulfamoylphenyl)furan-2-carboxylate (60a, 0.3 g, 1.01 mmol) in dimethyl acetamide (5 ml) at 25° C. in a tube. A nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added palladium (II) acetate (0.023 gm, 0.102 mmol) under nitrogen atmosphere and the tube was sealed. The reaction mixture was then heated at 150° C. for 20 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and concentrated under reduced pressure. The residue so obtained was dissolved in ethyl acetate (30 ml). The solution so obtained was then washed with water (2×10 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (0.040 gm, 9.70%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CCOCC.Cl>[F:9][C:2]([F:1])([F:8])[C:3](=[C:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:25])[OH:5]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C1C(=C(O)C(F)(F)F)CCc2ccccc21
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A 250 mL one neck round bottomed flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in ether (50 mL) was added over about 5 minutes The reaction mixture was stirred at room temperature for 14 hours and was diluted with 100 mL of 3N HCl. The phases were separated, and the organic layer was washed with 3N HCl and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was taken up in 70 mL of boiling ethanol/water and cooled to room temperature, whereupon crystals of 3,4-dihydro-2-[2,2,2-trifluoro-1-hydroxyethylidene]-1(2H)-naphthalenone formed which were isolated by filtration and air dried to give 32 g (81%) of pure 3,4-dihydro-2-[2,2,2-trifluoro-1-hydroxyethylidene]-1(2H)-naphthalenone: mp 48°-49° C.; 1H NMR (CDCl3) δ 2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19F NMR (CDCl3) δ-72.0. EI GC-MS M+ =242.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (4.9 g; 21.4 mmol; 1 eq.), 2-methoxyphenylboronic acid (Aldrich 44,523-1; 3.6 g; 23.5 mmol; 1.1 eq.), potassium carbonate (14.8 g; 107 mmol; 5 eq.) and Pd(PPh3)4 (2.47 g; 2.14 mmol; 0.1 eq.) in toluene (24.5 mL) and water (24.5 mL) was refluxed for 6 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of CELITE which was further washed with toluene (500 mL). The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate (500 mL). The organic layer was washed with sat. aq. NaHCO3 (200 mL), water (200 mL) and brine (200 mL) then dried over magnesium sulfate and concentrated in vacuo. The crude was purified by column chromatography (c-hexane/ethyl acetate, 90/10) to afford the title compound (4.38 g, 80%) as a colorless oil. HPLC (Method A): Rt 4.85 min (purity 98.9%). LC/MS: 257.0 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8](=[O:16])[NH:7][C:6]1=[O:17])([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:22](O)[CH3:23]>S(=O)(=O)(O)O>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]2[CH2:4][C:1]([O:3][CH2:22][CH3:23])=[O:2])=[CH:10][CH:11]=1
Reactant: O=C(O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Yield: 75.8 %

Procedure:
To a suspension of 1-carboxymethyl-7-chloro-2,4(1H, 3H)-quinazolinedione (I) (0.5 g) in ethanol (10 ml) was added thionyl chloride (0.35 g) at 0° C. After one drop of concentrated sulfuric acid was added to the solution, the solution was refluxed for 7 hours, and cooled. The resulting crystal was collected by filtration, washed with ethanol and dried under vacuum to give 0.42 g of the desired compound (yield, 75.8%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1.Cl>O1CCCC1.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[OH:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Reactant: Brc1ccccn1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(O)c2ccccn2)C1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
2-Bromopyridine (6.50 g, 40 mmol) was added to isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 20 mL, 40 mmol) at room temperature. The mixture was stirred for 10 minutes then warmed to 30° C. and stirred for 105 minutes. The mixture was cooled to −10° C. and a solution of (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (5.5 g, 10 mmol) in tetrahydrofuran (9 mL) was added dropwise. The reaction mixture was stirred for 15 minutes at −10° C. followed by stirring at room temperature for 1 hour. The reaction mixture was cooled and treated with water (20 mL) followed by aqueous hydrochloric acid (1.0 M, 40 mL). The mixture was stirred for 10 minutes then extracted with dichloromethane (×2) and the combined organic phases dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (gradient: 20-80% ethyl acetate in cyclohexane) to afford the diastereoisomeric (2:1) mixture (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanol as an off-white foam (3.25 g). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J=4.8 Hz, 1 H); 8.00 (d, J=8.2 Hz, 2 H); 7.84-7.86 (m, 3 H); 7.44-7.46 (m, 1 H); 7.29-7.30 (m, 1.5 H); 7.09-7.10 (m, 3.5 H); 6.95-6.97 (m, 2.5 H); 6.41 (s, 0.5 H); 6.18 (s, 1 H); 5.11 (s, 0.5 H); 5.04 (s, 1 H); 4.87 (s, 1 H); 4.50 (d, J=11.8 Hz, 1 H); 4.10 (d, J=13.3 Hz, 2.5 H); 3.80 (d, J=12.1 Hz, 0.5 H); 3.69 (s, 0.5 H); 3.24 (d, J=16.6 Hz, 1 H); 3.09-3.13 (m, 1.5 H); 2.54-2.58 (m, 2.5 H); 2.25-2.27 (m, 1 H); 2.11 (d, J=16.6 Hz, 1 H); 1.43 (s, 0.5 H).
Reaction SMILES: [CH:1]1([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][C@H:8]2[NH:23][C:24](OC2C=CC([N+]([O-])=O)=CC=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:36][C:37]1[C:38]([F:57])=[C:39]([C@:43]([C@@H:51]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52]2)([OH:50])[CH2:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:40]=[CH:41][CH:42]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:36][C:37]1[C:38]([F:57])=[C:39]([C@:43]([C@@H:51]2[CH2:56][CH2:55][CH2:54][N:53]([C:24]([NH:23][C@H:8]3[C@H:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:14])[CH2:9]3)=[O:25])[CH2:52]2)([OH:50])[CH2:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:40]=[CH:41][CH:42]=1
Reactant: O=C(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CCCCC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)N[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]2C2CCCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Half of the crude (3S,4S)-benzyl 4-cyclohexyl-3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate from Step 1 was added to a solution of (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (29 mg, 2 equiv) and DIEA (15 μL, 3 equiv) in CH2Cl2 (2 mL). The mixture was stirred for 1 h at rt. LC-MS showed the reaction was complete. The mixture was concentrated and purified by preparative HPLC to afford (3S,4S)-benzyl 3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexylpiperidine-1-carboxylate (18.4 mg, 63%). LC-MS (3 min) tR=2.40 min., m/z 672 (M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[I:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[CH3:17]>ClC1C=CC=CC=1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>[I:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[CH2:17][Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1I
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: Clc1ccccc1
Product: BrCc1ccc(Br)cc1I
Yield: 24.2 %

Procedure:
N-Bromosuccinimide (NBS) (1.1 molar equivalents, 66.5 g, 373 mmol) and benzyl peroxide (0.006 molar equivalent, 450.7 mg, 1.9 mmol) are added to a solution of 2-iodo-4-bromotoluene 6 (1 molar equivalent, 100.3 g, 338 mmol) in chlorobenzene (1200 ml). The batch is then stirred under reflux overnight. After the solvent has been removed in a rotary evaporator, ethyl acetate and water are added. The aqueous phase is extracted by shaking with ethyl acetate. The organic phase is washed by shaking with water, dried and evaporated in a rotary evaporator. The product 7 (30.7 g, 24%) is obtained in the form of a white powder by recrystallisation from ethanol (50 ml).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][OH:26])=[NH:24])=[C:21]([O:29][CH3:30])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42](OC1C=CC=CC=1)=[O:43].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]2[NH:24][C:42](=[O:43])[O:26][N:25]=2)=[C:21]([O:29][CH3:30])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1C(=N)NO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)ccc1-c1noc(=O)[nH]1
Temperature: 150 °C

Procedure:
To a solution of 1.05 g of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-hydroxy-2-methoxy-benzamidine in 5 mL of tetrahydrofuran were added 254 μL of phenyl chloroformate and 607 μL of diisopropylethylamine. The resulting mixture was heated to 150° C. under microwave irradiation for 20 minutes. After allowing it to cool down to room temperature, the mixture was concentrated under reduced pressure and dichloromethane/water were added to the residue. The organic layer was separated and the aqueous layer extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Diisopropyl ether was added to the residue and the solid was collected by filtration and washed with diisopropyl ether to give 558 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>C(#N)C.O.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>[C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]([C:32]2[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:34][CH:33]=2)[CH:16]=[CH:17][CH:18]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)OC(C(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)OC(C(=O)OC(C)(C)C)c1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 130 °C

Procedure:
A mixture of compound 3 (811 mg, 2.46 mmol), Na2CO3 (650 mg, 6.13 mmol), Pd(PPh3)4 (207 mg, 0.18 mmol) and 4-trifluoromethoxy phenyl boronic acid (870 mg, 4.22 mmol) in acetonitrile (7.0 mL) and water (0.7 mL) was heated to 130° C. in the microwave for 30 minutes. The mixture was filtered through Celite® diatomaceous earth and washed with EtOAc. The filtrate was concentrated in vacuo and the resulting residue was purified by flash chromatography (80 g silica cartridge, 0-10% EtOAc/hexanes) to provide compound 4.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:31][CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: OC(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(F)(F)F)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.91 g), 3-bromo-1,1,1-trifluoropropan-2-ol (1.2 mL), cesium carbonate (3.8 g) and N,N-dimethylacetamide (20 mL) was stirred at 100° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 65%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH3:28]
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 68 %

Procedure:
Part A. To a solution of 4,5-diphenyl-2-imidazolethiol (25.2 g, 0.1 mol) in N,N-dimethylformamide (250 mL) was added, dropwise, a solution of ethyl 5-bromopentanoate (23.73 mL, 31.35 g, 0.15 mol) in N,N-dimethylformamide (80 mL), and the reaction mixture was stirred at reflux under nitrogen for 18 hours. The reaction mixture was cooled, poured into 5% sodium bicarbonate and ice, and then extracted with ethyl acetate. The combined organic extracts were washed sequentially with 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was chromatographed with 7:3 hexane-ethyl acetate, and the resulting solid was recrystallized from acetonitrile and triturated with hexane to give 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid ethyl ester (25.95 g, 0.068 mol) as a white solid, mp 87°-89°. 1H NMR (DMSO-d6) δ 7.55-7.15 (m,11H), 4.0(q,2H,J=8 Hz) , 2.9(t,2H,J= 7 Hz) , 2.3(t,2H,J=7 Hz), 1.9-1.6(m,4H), 1.2(t,3H,J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([F:13])[CH:3]=1.[C:14](Cl)(Cl)=[S:15].[OH-].[Na+]>O.Cl>[F:13][C:4]1[CH:3]=[C:2]([N:1]=[C:14]=[S:15])[C:11]([CH3:12])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: S=C(Cl)Cl
Reactant: Cc1c(N)cc(F)c2cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N=C=S)cc(F)c2cccnc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-amino-5-fluoro-8-methylquinoline (0.39 g) and thiophosgene (0.2 mL) in water (5 mL) and 1N hydrochloric acid (5 mL) is stirred at room temperature for 1.5 hours. An additional amount of thiophosgene (0.1 mL) is added and the mixture stirred another hour. The mixture is treated with 1N sodium hydroxide (25 mL) and extracted with methylene chloride (4×50 mL). The combined extracts are dried over sodium sulfate and rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 15% ethyl acetate/hexanes, to afford 5-fluoro-7-isothiocyanato-8-methylquinoline as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[OH-:17].[Na+]>O1CCOCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:17])[N:7]=2)=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: Clc1ccc(COc2ccnc(Cl)n2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1nc(OCc2ccc(Cl)cc2)cc[nH]1
Temperature: 0 °C
Yield: 5 %

Procedure:
To a stirred solution of 2-chloro-4-((4-chlorobenzyl)oxy)pyrimidine (2.8 g) in dioxane and water (1:4, 30 ml) was added NaOH (440 mg), and the mixture was heated at reflux for 3 h. The reaction mixture was then cooled to 0° C. and the product was precipitated out from the reaction medium. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound (130 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20](=[O:25])[NH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].I[CH3:36]>CN(C=O)C>[CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20](=[O:25])[N:21]([CH3:36])[CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc[nH]c3=O)cc2)C(=O)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cccn(C)c3=O)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (15.5 mg, 0.036 mmol) in dry DMF (1 mL) was cooled to 0° C. Sodium hydride (60% in mineral oil, 3 mg, 2 equiv) was added. After 20 min, iodomethane (4.54 μL, 2 equiv) was added. The mixture was stirred another 20 min before being warmed to rt slowly and stirred for 2 h. LC-MS found the reaction completed. The mixture was quenched with satd aq NH4Cl (1 mL) and purified by prep HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (13.3 mg, 83% yield). LC-MS Method 1 tR=1.63 min, m/z 447 (M+1).