Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][C:4]12[C:10]([CH3:12])([CH3:11])[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2.[BrH:13].S(=O)(=O)(O)O>O>[Br:13][CH2:2][CH2:3][C:4]12[C:10]([CH3:12])([CH3:11])[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2
Reactant: CC1(C)C2CCC1(CCO)CC2
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)C2CCC1(CCBr)CC2

Procedure:
A stirred mixture of 1-(2-hydroxyethyl)-7,7-dimethyl-norbornane (42.0 g, 0.25 mole), 48% hydrobromic acid (63.0 ml) and concentrated sulphuric acid (14 ml) was heated under reflux for 4 hours, cooled, poured into water (500 ml) was extracted with ether. The combined extracts were washed with water, sodium bicarbonate solution and water. After drying (MgSO4) the solvent was evaporated in vacuo to yield the title product (50.9 g), m.p. 68°-71° [from light-petroleum (b.p. 40-60°)] (Found: C, 57.0: H, 8.1; Br, 34.2. C11H19Br requires C, 57.0; H, 8.3; Br, 34.5%).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([F:20])[F:19])=[CH:14][CH:13]=2)[C:7]1=[O:21])(=O)=O.Cl.[F:23][C@H:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][NH:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:19][CH:18]([F:20])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][CH:6]([N:26]3[CH2:27][CH2:28][C@@H:29]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[C@H:24]([F:23])[CH2:25]3)[C:7]2=[O:21])=[CH:13][CH:14]=1
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccc(C(F)F)cc2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1C(N2CC[C@@H](c3ccc(O)cc3)[C@H](F)C2)CCN1Cc1ccc(C(F)F)cc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
A solution of (S)-1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl methanesulfonate (500 mg, 1.57 mmol) in 5.0 mL of acetonitrile was added dropwise over 1.5 h to a stirred mixture of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol, hydrochloride (363 mg, 1.57 mmol, from example 46, step M) and N,N-diisopropylethylamine (1.09 mL, 6.26 mmol) in 5.0 mL of acetonitrile maintained at 85° C. After complete addition, the reaction mixture was stirred at 85° C. for 16 h. The resulting mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (0-100% EtOAc/hexanes) to afford a diasteromeric mixture of 1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (235 mg, 35% yield) due to partial epimerization. A sample of the diastereomeric mixture (780 mg) was separated by preparative chiral SFC (column=Lux Cellulose-2 (21×250 mm, 5 μm); isocratic solvent=20% methanol (with 15 mM ammonia)/80% CO2; temp=35° C.; flow rate=60 mL/min; injection volumn=1.0 mL (˜20 mg/mL in MeOH) stacked @ 13 min intervals; λ=210 nM; Peak 1=19.6 min, Peak 2=24.5 min) to afford 389 mg of Example 114, P-1 and 242 mg of Example 114, P-2. Data for Example 114, P-1: LC-MS m/z 419.3 (M+H+); 1H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.91-6.80 (m, 2H), 6.65 (t, J=56.4 Hz, 1H), 4.96 (s, 1H), 4.77-4.43 (m, 3H), 3.68 (t, J=8.8 Hz, 1H), 3.42-3.33 (m, 1H), 3.29-3.14 (m, 2H), 2.85 (d, J=10.4 Hz, 1H), 2.78-2.69 (m, 1H), 2.69-2.57 (m, 1H), 2.48 (td, J=9.9, 4.9 Hz, 1H), 2.21-2.11 (m, 1H), 2.04 (dq, J=13.0, 8.6 Hz, 1H), 1.94-1.82 (m, 2H)). The relative and absolute configuration of Example 114, P-1 was confirmed by single crystal X-ray analysis. Data for Example 114, P-2: LC-MS m/z 419.3 (M+H+); 1H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9 Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.87-6.81 (m, 2H), 6.65 (t, J=56.5 Hz, 1H), 4.95 (s, 1H), 4.74-4.42 (m, 3H), 3.66 (t, J=8.9 Hz, 1H), 3.28-3.15 (m, 3H), 3.07-2.99 (m, 1H), 2.72-2.58 (m, 2H), 2.49-2.40 (m, 1H), 2.20-2.12 (m, 1H), 2.04 (dq, J=13.0, 8.7 Hz, 1H), 1.93-1.87 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][O:9][CH2:8]2)=[CH:4][C:3]=1[CH2:15]Br.[C:17]([O-:20])(=[O:19])[CH3:18].[K+].O>CN(C)C=O>[C:17]([O:20][CH2:15][C:3]1[CH:4]=[C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][O:9][CH2:8]2)[CH:12]=[C:13]([CH3:14])[C:2]=1[Br:1])(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(CBr)c1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1cc(O[C@@H]2CCOC2)cc(C)c1Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
(R)-3-(4-Bromo-3-(bromomethyl)-5-methylphenoxy)tetrahydrofuran 35b (700 mg, 2 mmol) was dissolved in 15 mL of N,N-dimethylformamide, followed by addition of potassium acetate (197 mg, 2 mmol). The reaction solution was heated to 50° C. and stirred for 1 hour. The resulting solution was cooled down to room temperature, mixed with 100 mL of water and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (R)-2-bromo-3-methyl-5-((tetrahydrofuran-3-yl)oxy)benzyl acetate 35c (658 mg) as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH3:13])[CH2:11]Cl)=[C:5]([CH:14]([CH3:16])[CH3:15])[CH:4]=1.[CH3:17][C@H:18]1[O:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH3:13])[CH2:11][N:20]2[CH2:19][C@H:18]([CH3:17])[O:23][C@H:22]([CH3:24])[CH2:21]2)=[C:5]([CH:14]([CH3:16])[CH3:15])[CH:4]=1
Reactant: CC(CCl)Cc1ccc(CCl)cc1C(C)C
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc(CCl)cc1C(C)C)CN1C[C@@H](C)O[C@@H](C)C1
Temperature: 150 °C
Yield: 67.1 %

Procedure:
A mixture of 24 g of 3-(p-1-chloromethyl-1-methylethylphenyl)-2-methylpropyl chloride and 32 g of cis-2,6-dimethylmorpholine is heated for 4 hours at 150° C. The crude product is dissolved in chloroform, washed several times with water, and dried over Na2SO4, the solvent is evaporated and the residue is distilled. There is obtained 21 g of N-[3-(p-1-chloromethyl-1-methylethylphenyl)-2-methylpropyl]-2,6-cis-dimethylmorpholine (active ingredient no. 1); b.p. (0.1 mm) 165°-166° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:24]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
1-(4-Fluorophenyl) piperazine (2.8 mmol) was dissolved in 10 mL of CH2Cl2. Triethylamine (5.5 mmol) was added to it and the reaction was cooled to 0° C. Chloroacetylchloride (4.2 mmol) was added to it slowly, and the reaction was warmed to room temperature overnight. After completion, the reaction was quenched with brine solution and reaction mixture was extracted with methylene chloride. The combined organic phases were washed with brine and water and dried over magnesium sulfate. The solvent was evaporated and the compound purified by column chromatography (hexane/ethyl acetate=1.5/1) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.9–7.2 (m, 2H), 6.82–6.92 (m, 2H), 4.1 (s, 2H), 6.62–3.8 (m, 4H), 3.46–3.6 (m, 4H). 13C NMR (400 MHz, CDCl3): 164, 158, 156.2, 148.5, 118.2, 116.8, 52.6, 52.2, 48, 46, 42.1, 40.6.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]1)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1.[C:27]([C@@H:31]1[CH2:36][CH2:35][C@H:34](O)[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:27]([C@H:31]1[CH2:36][CH2:35][C@H:34]([O:14][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]=[C:4]([CH:3]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]2)[C:2]([F:1])([F:25])[F:26])[CH:13]=[CH:12]3)[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)C1CCN(C(c2ccc3cc(O)ccc3c2)C(F)(F)F)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(C(c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirring mixture of methyl 1-(2,2,2-trifluoro-1-(6-hydroxynaphthalen-2-yl)ethyl)piperidine-4-carboxylate (300 mg, 0.8 mmol), cis-4-(t-butyl)cyclohexanol (245 mg, 1.6 mmol, 2 eq) and PPh3 (420 mg, 1.6 mmol, 2 eq) in THF (3 mL) was added DIAD (323 g, 1.6 mmol, 2 eq) at room temperate under N2 atmosphere. The mixture was stirred at 80° C. for 2 h, diluted with ethyl acetate (10 mL) and washed with water (5 mL*3). The organic solvent was removed in vacuum and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give methyl 1-(1-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-2,2,2-trifluoroethyl)piperidine-4-carboxylate (130 mg, yield: 31%) as a yellow solid. ESI-MS (M+1)+: 506.1. 1HNMR (400 MHz, CDCl3) δ: 7.86˜7.80 (m, 3H), 7.46 (d, J=8.8 Hz, 1H), 7.27 (s, 1H), 7.16 (d, J=8.8 Hz, 1H), 4.68˜4.66 (m, 1H), 4.39˜4.36 (m, 1H), 3.56 (s, 3H), 3.32˜3.30 (m, 2H), 2.65˜2.64 (m, 1H), 2.44-2.43 (m, 1H), 2.30-2.27 (m, 3H), 1.93-1.90 (m, 3H), 1.80-1.79 (m, 2H), 1.44˜1.41 (m, 2H), 1.29˜1.27 (m, 3H), 1.14˜1.13 (m, 1H), 0.90 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[CH3:32])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:41])[N:13]2[C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[CH3:32])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:41])[N:13]2[C:33]1[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CNCCN1Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}-3-methylpiperazine-1-carboxylate (186 mg, 0.30 mmol) in methylene chloride (1 mL) at 0° C. was added trifluoroacetic acid (0.92 mL) dropwise. Then the reaction was stirred at rt for 1 h. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 8% of 2N ammonium in methanol/methylene chloride as eluent provided the 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(2-methylpiperazin-1-yl)methyl]-3,4-dihydroquinazolin-2(1H)-one compound. 1H NMR (CDCl3, 500 MHz): δ 0.98 (m, 3H), 2.06 (m, 2H), 2.32 (s, 1H), 2.48 (m, 1H), 2.63 (m, 1H), 2.72 (t, 1H, J=10.2 Hz), 2.84 (m, 2H), 3.15 (dd, 1H, J1=14.0 Hz, J2=6.0 Hz), 3.86 (t, 1H, J=13.2 Hz), 4.34 (abq, 2H, J=14.2 Hz), 5.23 (s, 1H), 6.15 (d, 1H, J=9.4 Hz), 6.88 (s, 1H), 7.20-7.60 (m, 7H). MS (API-ES+): 517 (M+H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>CO>[NH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: N#CCCN(CCC#N)Cc1ccccc1
Reactant: [H][H]
Solvent: CO
Product: NCCCN(CCCN)Cc1ccccc1
Yield: 98.2 %

Procedure:
8.53 g of N,N-bis(2-cyanoethyl)benzylamine, 0.72 g of Raney Co and 100 mL of methanol were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 100° C. for 1 hour. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 8.69 g of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[C:13]([N+:25]([O-])=O)[C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:4].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:25][C:13]1[C:14](=[O:24])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12]=1[CH2:11][CH2:10][C@@H:9]1[C@@H:19]2[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:8]1[CH2:7][CH2:6][C@@H:5]2[CH:3]([CH2:2][OH:1])[CH3:4]
Reactant: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 70 °C

Procedure:
A solution of 20-hydroxymethyl-4-nitropregn-4-en-3-one (0.52 g, 1.38 ml) in absolute ethanol (4.8 mL) is combined with stannous chloride (2.1 g) added in one portion and then heated to 70° C. for 6 hours. The reaction vessel is then cooled to room temperature and the solution is carefully neutralized with sodium bicarbonate (9 g) over a 10 minute period. The resulting slurry is then filtered, removing a brown solid which is then stirred in 10% hydrofluoric acid (25 mL) and ethyl acetate (25 mL). The HF/EtOAc treatment is repeated. The organic phases from each filtration are combined, dried over magnesium sulphate, filtered and concentrated. The resulting residue is purified by flash chromatography to give 4-amino-20-hydroxymethylpregn-4-en-3-one as a white solid identical to the material described in U.S. Pat. No. 5,218,110 to Weintraub and U.S. Pat. No. 5,120,840 to Weintraub et al., which are both herein incorporated by reference. The compound has the following formula: ##STR32##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](=O)[CH2:6]Br)[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][N:12]=1>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][N:12]2[CH:6]=1)=[O:9])[CH3:2]
Reactant: Nc1ccc(I)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC#N
Product: CCOC(=O)c1cn2cc(I)ccc2n1
Yield: 55.7 %

Procedure:
Add 3-bromo-2-oxo-propionic acid ethyl ester (1.75 g, 9.09 mmol) to a solution of 2-amino-5-iodo pyridine (Tetrahedron 2002, 58, 2885-2890; 1.0 g, 4.54 mmol) in acetonitrile (100 ml). Reflux for 12 h, concentrate to ˜30 ml, and dilute with saturated aqueous sodium bicarbonate. Extract into dichloromethane, combine organic extracts, dry over anhydrous magnesium sulfate, and concentrate. Titurate the residue in diethyl ether and filter to give 0.8 g (56%) of the subtitled compound as an off-white solid. TOF MS ES+ exact mass calculated for C10H91N2O2 (p+1): m/z=316.9787; Found: 316.9784. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (m, 1H), 8.46 (s, 1H), 7.57-7.49 (m, 2H), 4.32 (q, T 7.0 Hz, 2 Hz), 1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1>C(N)(C)C>[Cl:1][C:2]1[C:11]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:10]([NH:3][CH:4]([CH3:9])[CH3:5])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3cccnc3c2Cl)c(F)c1
Solvent: CC(C)N
Product: CC(C)Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2cccnc12
Temperature: 60 °C
Yield: 24.1 %

Procedure:
The product from Step 4 (0.070 g) was dissolved in isopropylamine (1.0 ml) and warmed in a sealed tube to 60° C. for 2 hours. The isopropylamine was evaporated and the residue was purified by flash column chromatography on silica gel (40-60) eluting with diethyl ether to give [2-chloro-3-(2,4,6-trifluorophenyl)-[1,5]naphthyridin-4-yl]-isopropylamine as a yellow gum (0.009 g).
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23](O)=[O:24])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][O:27][CH2:28][CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:33]([O:32][C:31]([NH:30][CH2:29][CH2:28][O:27][NH:26][C:23]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]([NH:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][N:14]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:24])=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1C(=O)O
Reactant: NOCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1C(=O)NOCCNC(=O)OCc1ccccc1
Yield: 100 %

Procedure:
(2S,5R)-5-((Benzyloxy)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1.879 g, 5.362 mmol) described in Example 99 or 100, benzyl 2-(aminooxy)ethylcarbamate (1.41 g, 6.707 mmol) of Reference Example 11 and 1-hydroxybenzotriazole.monohydrate (220 mg) were dissolved in methylene chloride (20 mL), followed by stirring under ice cold. To this was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.29 g), and a temperature was elevated to room temperature, followed by stirring overnight. The mixture was diluted with methylene chloride (20 mL), and washed with water, 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine sequentially, and then dried over magnesium sulfate. The solvent was concentrated under reduced pressure to afford 2.91 g of the title compound (quantitative).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(OCC)OCC)C>[C:2]1([C:1]2[O:8][CH:11]=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)c1ccccc1
Solvent: CCOC(OCC)OCC
Product: c1ccc(-c2nnco2)cc1
Temperature: 120 °C
Yield: 5695 %

Procedure:
A mixture of the benzoic hydrazide (22.5 g, 165 mmol), triethylorthoformate (150 mL) and p-toluenesulfonic acid (300 mg) was heated at 120° C. for 12 h. Excess triethylorthoformate was removed under vacuum and the residue was purified by silica gel column chromatography to produce 2-phenyl-[1.3.4]-oxadiazole (14.5 g).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C([N:10]([CH2:13][CH3:14])CC)C>C(O)C>[CH:14]1([C:13]2[C:3]([C:2](=[O:7])[CH3:1])=[C:4]([CH3:5])[O:6][N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: CC(=O)CC(C)=O
Reactant: CCN(CC)CC
Solvent: CCO
Product: CC(=O)c1c(C2CCCCC2)noc1C
Temperature: 70 °C
Yield: 67.2 %

Procedure:
To a solution of 2 and 2,4-pentanedione (0.932 ml, 9.08 mmol) in ethanol (10 ml) was added triethylamine (1.26 ml, 9.08 mmol). The resulting mixture was heated at 70° C. overnight. The reaction was partitioned between EtOAc and water and the layers were separated. The organic layer was dried over sodium sulfate then concentrated in vacuo. The crude product was purified by silica column chromatography (5% to 10% EtOAC:hexanes gradient elution) to afford compound 3 (0.633 g, 3.05 mmol) in 37% yield for 2 steps. 1H NMR (CDCl3) δ 0.8-2.0 (m, 10H), 2.5 (s, 3H), 2.7 (s, 3H), 3.2 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Nitrophenylhydrazine (32.0 g, 0.21 mole) was slurried in acetonitrile (500 ml) and the mixture was cooled to 0° C. A solution of 4-chlorobenzoyl chloride (17.5 g, 0.10 mole) in acetonitrile (25 ml) was added dropwise to the cooled slurry. The reaction mixture was allowed to stand overnight. The mixture was filtered and the solid was washed with acetonitrile, then thoroughly with water. The product was recrystallized from acetonitrile and decolorized with charcoal to give a pale yellow solid. Yield 24.8 g (85%) m.p. 245.5°-248.5° C.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([CH:14]1[CH2:16][CH2:15]1)([OH:13])[CH3:12])=[O:8].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[CH:14]1([C:11]([OH:13])([CH3:12])[CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[C:34]([Cl:35])[CH:33]=3)[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]=2[C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15]1
Reactant: CC(O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CC(O)(CNC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-(2-cyclopropyl-2-hydroxy-propyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 3,4-dichlorophenylboronic acid as starting materials, MS (ISP) 531.0, 533.0 (M)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([NH:12][C:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+]>C(O)C>[C:6]1([CH2:5][CH:4]([NH:12][C:13]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)=[O:14])[C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)c1nc(-c2ccccc2)cs1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 3-Phenyl-2-[(4-phenyl-thiazole-2-carbonyl)-amino]-propionic acid methyl ester (74 mg, 0.2 mmol) dissolved in ethanol (4 mL) was added 1N—KOH (0.5 mL, 0.5 mmol) and the mixture was stirred at room temperature for 2 hours. After the solvent was evaporated from the reaction mixture, the residue was dissolved by adding water and acidified (H=2) with 2N—HCl under ice cooling. The produced precipitates were filtered with suction, washed with water to afford 59 mg (yield 80%) of the desired 3-Phenyl-2-[(4-phenyl-thiazole-2-carbonyl)-amino]-propionic acid as white solids.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl.P([O-])([O-])([O-])=O>CN(C=O)C.C(OCC)(=O)C>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([N:14]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])(=[O:12])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: NS(=O)(=O)c1cccc(CO)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CO)c1
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% oil dispersion, 0.315 g) was added to 3-hydroxymethylbenzenesulfonamide (0.67 g) with stirring in DMF (20 ml) under nitrogen at 20°. After 15 min, 2-(trimethylsilyl)ethoxymethyl chloride (1.27 ml) was added and stirring was continued for 1.5 h. pH 6.4 Phosphate buffer and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed twice with brine, dried (MgSO4) and evaporated to an oil. This oil in dichloromethane was loaded onto a column of silica gel (75 g) set up in 10% ethyl acetate in 40-60 petroleum ether. The column was run with this, then 20%, 30% and 50% ethyl acetate in 40-60 petroleum ether to give the title compound (0.74 g) LCMS RT=4.00 min.