Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.CN(C)[CH:24]=[O:25]>C1COCC1>[Br:13][C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]([F:21])[C:15]=1[CH:24]=[O:25]
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cc(Br)cc1Br
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a flame-dried 250 mL round-bottomed flask equipped with an addition funnel and magnetic stirrer, a mixture of diisopropylamine (4.82 mL, 34.66 mmol) in 100 mL of anhydrous THF was cooled to −78° C. and treated with 2.5N n-butyllithium (13.86 mL, 34.66 mmol) in THF, dropwise. After stirring for 10 minutes a mixture of 3,5-dibromo-1-fluorobenzene (8.0 g, 31.51 mmol) in 16 mL of THF was added dropwise and stirring was continued for an additional 30 minutes. At this point, N,N-dimethylformamide (DMF) (2.68 mL, 34.66 mmol) was added dropwise and stirring continued another 10 minutes at −78° C. The reaction was quenched with saturated aqueous ammonium chloride and the solvent removed on a rotary evaporator. The residue was dissolved in ether, washed with saturated brine and dried over calcium sulfate, filtered and concentrated to an oil, 7.36 g. Purification by flash chromatography using ethyl acetate-hexanes (1:99) gave the title product as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21]CC)=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([OH:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CCO.O>[CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([OH:21])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([OH:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(OCc3ccccc3)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1OB(O)c2cc(O)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of ethyl 2-(4-(benzyloxy)-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (195 mg, 0.57 mmol) in EtOH (4 mL) was added dropwise an aqueous solution of lithium hydroxide (47.9 mg, 1.14 mmol) in water (4 mL). The reaction mixture was stirred at room temperature overnight and acidified with 1N HCl to pH=3. The resulting mixture was extracted with EtOAc (2×20 mL). Combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (41.2 mg, Yield: 23%). 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 9.14 (s, 1H), 7.44-7.33 (m, 5H), 6.66 (d, J=1.2 Hz, 1H), 6.54 (s, 1H), 5.36 (m, 1H), 5.12 (s, 2H), 3.15 (m, 1H), 2.07 (m, 1H). MS (ESI) m/z=315 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([S:24][CH3:25])[C:14](=[S:21](=[O:23])=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1.I[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:37]([CH3:40])([CH3:39])[CH3:38])=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1.[Cl-].[NH4+]>O.C(OCC)C.CN(C)C=O.O1CCCC1.CCCCCC>[C:37]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=2)([S:24][CH3:25])[C:14](=[S:21](=[O:22])=[O:23])[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:33][C:32]=1[N+:34]([O-:36])=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)c1ccc(CI)cc1[N+](=O)[O-]
Reactant: CCCCCCC(C(SC)c1ccc(C)cc1)=S(=O)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSC(Cc1ccc(C(C)(C)C)c([N+](=O)[O-])c1)(C(C1CCCCC1)=S(=O)=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3.45 ml (5.52 mmol) of a 1.6M hexane solution of butyllithium was added dropwise over a period of 5 minutes to 10 ml of a tetrahydrofuran solution containing 1.73 g (5.52 mmol) of 1-[2-(4-methylphenyl)-sulfonyl-2-methylthioethyl]hexane (prepared as described in Preparation 8), maintained at -78° C. After 15 minutes, 12 ml of a dimethylformamide solution containing 1.68 g (5.26 mmol) of 5-iodomethyl-2-t-butyl-1-nitrobenzene (prepared as described in Preparation 51) was added dropwise. The reaction mixture was allowed to return to room temperature, after which it was stirred for 1 hour and 20 minutes. At the end of this time, a dilute aqueous solution of ammonium chloride was added, to stop the reaction. Water and diethyl ether were added, and the product was distributed between the organic solvent and water. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, to obtain the title compound. Since this compound was unstable, however, it was used for the next step without purification.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][S:14][N:13]=2)=[CH:8][CH:7]=1.[CH2:20](O)[CH3:21]>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][S:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)c1csnc1-c1ccc(Cl)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1csnc1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethanol (10 mL), thionyl chloride (440 mg, 3.70 mmol, 1.00 equiv), 3-(4-chlorophenyl)-1,2-thiazole-4-carboxylic acid (860 mg, 3.69 mmol, 1.00 equiv). The resulting solution was stirred for 6 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum and taken up in 150 mL of dichloromethane, washed with 1×30 mL of brine. The solution was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.72 g (75%) of ethyl 3-(4-chlorophenyl)-1,2-thiazole-4-carboxylate as brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:52]=[CH:51][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[C:41](=[O:42])[NH:40][C:39](=[O:43])[NH:38][C:37]3=[O:44])=[O:33])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[CH2:53](Br)[C:54]#[CH:55]>>[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][N:48]([CH2:55][C:54]#[CH:53])[CH2:47][CH2:46]4)[C:37](=[O:44])[NH:38][C:39](=[O:43])[NH:40][C:41]3=[O:42])=[O:33])=[CH:51][CH:52]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(C4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: C#CCBr
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1CCC(C2(CNC(=O)c3ccc(OCc4cc(C)nc5ccccc45)cc3)C(=O)NC(=O)NC2=O)CC1
Yield: 40 %

Procedure:
Following the procedure analogous to that used in reaction (10), the compound from Example 29 was reacted with propargyl bromide to provide the title compound (8.5 mg, 40%). MS found: (M+H)+=554.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1>O>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([N:1]3[CH:9]=[CH:10][CH:2]=[CH:3]3)=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:27][CH:28]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(N)ccc2n1Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(-c2c(C(=O)O)n(Cc3ccccc3)c3ccc(-n4cccc4)cc23)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-(4-tert-butylphenyl)-1H-indole-2-carboxylate followed the procedures of Example 1 Step 3 and Step 4 as a beige solid: 1H NMR (DMSO-d6) δ 1.35 (s, 9 H), 5.86 (s, 2 H), 6.21 (s, 2 H), 7.05-7.85 (m, 14 H); MS (ESI) m/z 447 ([M-H]−); HRMS calcd for C30H29N2O2: 449.2230; found (ESI+) 449.2225; Anal. calcd for C30 H28N2O2.0.2 H2O: C, 79.69; H, 6.33; N, 6.20. Found: C, 79.70; H, 6.18; N, 6.20.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]([OH:29])[CH2:26][CH2:27][OH:28])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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>ClCCl.[O-2].[O-2].[Mn+4]>[OH:28][CH2:27][CH2:26][C:25]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)=[O:29]
Reactant: OCCC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(CCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 66 h
Yield: 95.6 %

Procedure:
1-(1-Trityl-1H-imidazol-4-yl)-1,3-propanediol (135.9 g) was dissolved in dichloromethane (1.76 L) and manganese dioxide (262 g) was added, which was followed by vigorous stirring at room temperature for 66 h. An insoluble material was filtered off by celite filtration and the filtrate was concentrated to dryness. The residue was suspended in ethyl acetate (1.5 L) and an aqueous solution (1 M; 3.5 L) of Rochelle salt was added, which was followed by stirring with a mechanical stirrer for 3 days. The reaction mixture was partitioned, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The aqueous layer was extracted again with ethyl acetate and treated in the same manner. The organic layer was combined and the solvent was evaporated to give the title compound (129.3 g) as a pale-brown caramel.
Reaction SMILES: C(=O)([O-])O.[K+].[I:6][C:7]1[CH:8]=[C:9]([C:14](=[NH:16])[NH2:15])[CH:10]=[CH:11][C:12]=1[CH3:13].Cl[CH2:18][C:19](=O)[CH3:20]>O1CCCC1.O>[I:6][C:7]1[CH:8]=[C:9]([C:14]2[NH:15][C:19]([CH3:20])=[CH:18][N:16]=2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: Cc1ccc(C(=N)N)cc1I
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc(C)c(I)c2)[nH]1
Yield: 80.8 %

Procedure:
Potassium hydrogen carbonate (0.204 g, 2.0 mmol) was added to a solution of 3-iodo-4-methylbenzenecarboximidamide (preparation 59a, 0.53 g, 0.54 mmol) in tetrahydrofuran (5 mL) and water (1 mL) and the mixture was heated to reflux. Then 1-chloropropan-2-one (0.16 mL, 2.1 mmol) in tetrahydrofuran (2.50 mL) was added dropwise over 20 min and the mixture was refluxed overnight. The mixture was evaporated and the residue purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (0.13 g, 22%) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@@:15]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)([CH2:18][CH2:19][CH2:20]O)[O:14][C:13]2=[O:29])[CH3:11])=[CH:6][CH:5]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:18][CH2:19][CH2:20][NH:35][S:32]([CH3:31])(=[O:34])=[O:33])([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[O:14][C:13]2=[O:29])[CH3:11])=[CH:6][CH:5]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccc(OC(F)F)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 34.9 %

Procedure:
To a solution of (R)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (0.0332 g, 0.0784 mmol) and methanesulfonamide (0.0549 g, 0.577 mmol) in dry toluene (2 mL) was added (cyanomethene)tributylphosphorane (CMBP, 0.1720 g, 0.713 mmol) at rt under N2. The mixture was stirred for 19 h at rt. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0137 g (35%) of N-(3-((R)-3-((S)-1-(4-(difluoromethoxy)phenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide. LC-MS Method 1 tR=1.64 min, m/z=523 (MNa+), 501 (MH+), 171; 1H NMR (400 MHz, CD3OD) δ 7.24-7.21 (m, 2H), 7.01 (t, J=8.6 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 6.65 (t, J=73.8 Hz, 1H), 5.45 (q, J=7.0 Hz, 1H), 3.04-3.00 (m, 1H), 2.93-2.86 (m, 2H), 2.77 (s, 3H), 2.38-2.34 (m, 1H), 2.22-2.09 (m, 2H), 1.92-1.82 (m, 2H), 1.58-1.50 (m, 1H), 1.44 (d, J=7.0 Hz, 3H), 1.26-1.18 (m, 1H); 19F NMR (376 MHz, CD3OD) δ −83.93 (d, J=75.0 Hz), −117.33 (m).
Reaction SMILES: CO.[Na].[CH3:4][SH:5].Br[C:7]([CH3:14])([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:8]>O>[CH3:4][S:5][C:7]([CH3:14])([C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:8]
Reactant: CC(C)C(=O)C(C)(C)Br
Reactant: CS
Agent: [Na]
Solvent: CO
Solvent: O
Product: CSC(C)(C)C(=O)C(C)C
Reaction time: 2 h

Procedure:
A solution of 200 ml. of methanol containing 9.2 g. (0.40 mole) sodium metal was colled in an ice-bath and saturated with gaseous methyl mercaptan. To this was added 77.2 g (0.40 mole) of 2-bromo-2,4-dimethylpentan-3-one at room temperature and the resulting mixture stirred for two hours. The reaction mixture was diluted with water, extracted with ethyl ether, the extracts washed with water, brine and dried over anhydrous sodium sulfate. The ether was evaporated and the residue distilled in vacuo to afford 50.4 g. of product, B.P. 76° (20 mm.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=O)[CH:20]([CH3:22])[CH3:21])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:24])[S:11]([C:14]2[CH:18]=[C:17]([C:19](=[N:26][OH:27])[CH:20]([CH3:22])[CH3:21])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)C(=O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)C(=NO)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Temperature: 25 °C

Procedure:
To a mixture solution of 5-isobutyrylthiophene-3-sulfonic acid [2-(4-fluorophenyl)-ethyl]-methyl-amide (the compound of Preparation Example 88) (30 mg) in ethanol (2 mL) and water (1 mL) was added hydroxylamine.hydrochloride (11 mg) and sodium acetate (13 mg). After heating and refluxing for 12 hours, the reaction solution was cooled to room temperature. The solution was diluted with water and extracted with ethyl acetate. This solution was washed with saturated sodium chloride water. The crude product that was obtained after drying with anhydrous sodium sulfate and removing the solvent by evaporation was purified by silica gel column chromatography (ethyl acetate/hexane), the title compound (a pale yellow viscous oily substance) (29 mg) was obtained as a mixture where (E):(Z)=1:1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:6][N:7](C)C)[CH3:2].C(OC(=O)C(C(=O)C1C=CC=CC=1)=CN(C)C)C>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][O:19][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(OC)cc1
Agent: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Product: CCOC(=O)c1cnoc1-c1ccc(OC)cc1
Yield: 61 %

Procedure:
The procedure of Example 15 was employed utilizing ethyl-2-(4'-methoxybenzoyl)-3-dimethylaminopropenoate in lieu of ethyl-2-benzoyl-3-dimethylaminopropenoate to yield ethyl-5-(4'-methoxyphenyl)-4-isoxazolecarboxylate (1.5 g.; 61% yield) having a melting point of 57°-59° C. and the following analysis:
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH2:15](Br)[CH:16]=[CH2:17]>>[CH2:17]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)[CH:16]=[CH2:15]
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: C=CCBr
Product: C=CCn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano [3,2-b]-indol-4(5H)-one is alkylated with allyl bromide to give 3.9 g of product, mp 67°-68° C., after recrystallization from methylene chloride-hexane.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[CH3:13].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(N(CC)C=O)C.O>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1)[CH3:13]
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(O)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Agent: CCN(C=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.14 g) was added portionwise to a stirred solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-hydroxypropanoate (1.20 g) in dry N,N-diethyl formamide (20 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes prior to the addition of benzyl bromide (0.6 mL). Stirring was continued at room temperature for 3 hrs, then at 80° C. for 17 hrs before the mixture was cooled, diluted with water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were washed with water (4×500 mL) and brine (500 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane to afford the title compound, a gum, which was used in the next stage without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:5][CH:4]=1)#[CH:2].S(=O)(=O)(O)O.[H][H]>[Pd].C1C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:5][CH:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: C#Cc1ccc(-c2ccccc2F)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCc1ccc(-c2ccccc2F)cc1
Reaction time: 0.25 h

Procedure:
1-Ethynyl-4-(2-fluorophenyl)benzene, 22 g, was reduced in a Parr Instrument Company Series 3910 Low Pressure Shaker-type Apparatus, using 100 ml of benzene, 2 g of five percent palladium on charcoal, and 0.5 ml of concentrated sulfuric acid. Reduction was carried out at room temperature and at an initial hydrogen pressure of 50 psig. Within 15 minutes, the hydrogen pressure had dropped to 32 psig. Hydrogen pressure was increased to 52 psig and agitation continued for two hours, with no additional hydrogen pressure drop. The reaction mixture was filtered and the filtrate was neutralized with two percent aqueous sodium carbonate. The resulting mixture was washed with water. The benzene phase was separated, dried over anhydrous sodium sulfate, and filtered. The benzene was evaporated and the residue was vacuum distilled to give 17 g of 1-ethyl-4-(2-fluorophenyl)benzene, bp 99°-101°/0.3 mm. The following elemental analysis was obtained:
Reaction SMILES: O.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([N+:14]([O-])=O)[CH:5]=1>C(O)C.[Fe]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([NH2:14])[CH:5]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(F)cc1N
Reaction time: 16 h
Yield: 96.5 %

Procedure:
5-Fluoro-2-methylsulfonylphenylamine can be obtained in the following way: 1.25 ml of water and 0.47 ml of an aqueous 12N hydrochloric acid solution are added to a solution of 1.2 g of 4-fluoro-1-methylsulfonyl-2-nitrobenzene in 80 ml of ethanol. The reaction mixture is then heated at the reflux of the solvent and 0.92 g of powdered iron are added portionwise. The reaction mixture is then stirred at the reflux of the solvent for 2 hours, then at a temperature in the region of 20° C. for 16 hours. It is then filtered through sintered glass and the solid is washed with ethanol. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of water and ethyl acetate and then basified with an aqueous sodium hydrogencarbonate solution, to a pH in the region of 10, and allowed to settle out. The aqueous phase is extracted with 4 times 50 ml of ethyl acetate. The organic extracts are pooled, washed with water, dried over magnesium sulfate, treated with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1 g of 5-fluoro-2-methylsulfonylphenylamine is thus obtained in the form of a beige oil which crystallizes (Rf=0.33, silica gel thin layer chromatography, eluent: dichloromethane).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:25][O:26][CH:27]([F:29])[F:28])[C:4]([NH:6][C@@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5].Cl.[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38](O)=[O:39])[CH2:33][CH2:32]1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:29][CH:27]([F:28])[O:26][CH2:25][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][N:34]1[CH2:35][CH2:36][O:31][CH2:32][CH2:33]1)[C:4]([NH:6][C@@H:7]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5]
Reactant: O=C(O)CN1CCOCC1
Reactant: N[C@@H](COC(F)F)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(CN1CCOCC1)N[C@@H](COC(F)F)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of benzyl (2S)-2-[[(2S)-2-amino-3-(difluoromethoxy)propanoyl]amino]-3-phenyl-propanoate hydrochloride (1.65 g, 3.84 mmol), 2-morpholinoacetic acid hydrochloride (768 mg, 4.23 mmol) and HOBt hydrate (648 mg, 4.23 mmol) in DCM (20 mL) was added EDC hydrochloride (811 mg, 4.23 mmol). The resulting mixture was cooled to 0° C. and treated with DIPEA (0.736 mL, 4.23 mmoL), dropwise, warmed to room temperature and stirred overnight. The mixture was diluted with DCM (30 mL) and washed with saturated sodium bicarbonate (2×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo then chromatographed on silica gel eluting with 0%-100% ethyl acetate in hexanes. The product-containing fractions were concentrated in vacuo giving the compound of Formula XVII(a) (1.54 g, 77%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.72 (m, 1H), 7.35-6.90 (m, 10H), 6.12 (t, J=74 Hz, 1H), 5.14-5.04 (m, 2H), 4.81-4.75 (m, 1H), 4.65-4.55 (m, 1H), 4.26-4.20 (m, 1H), 3.93-3.87 (m, 1H), 3.65-3.50 (m, 4H), 3.15-2.90 (m, 4H), 2.45-2.35 (m, 4H).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.N[C:34]1C=C(C)C=CN=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]2[CH:8]=[C:9]([CH3:34])[CH:4]=[CH:5][N:6]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Reactant: Cc1ccnc(N)c1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2cc(C)ccn2)cc1

Procedure:
The product from Example 1, Part C (0.3 g, 0.93 mmol) and 2-amino-4-picoline (0.151 g, 1.4 mmol) were converted to the title compound by the method described in Part B of Example 16 (0.223 g, 58%). 1H NMR (300 MHz, CDCl3) δ 8.28 (broad s, 1H); 7.92 (d, J=8 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H); 7.23 (d, J=8.6 Hz, 2H); 6.88 (d, J=7.4 Hz, 1H); 6.84 (d, J=8.5 Hz, 2H); 5.11 (d, J=15 Hz, 1H), 4.61 (s, 1H); 4.16 (d, 15 Hz, 1H); 3.76 (s, 3H); 2.89 (s, 2H); 2.44 (s, 3H); 1.94 (s, 3H); 1.84 (s, 3H). MS: m/z (MH+) 412.