Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[CH2:4]([O:6][C:7]([C:9]1[NH:13][N:12]=[C:11]([CH3:14])[CH:10]=1)=[O:8])[CH3:5].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:4]([O:6][C:7]([C:9]1[N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[C:11]([CH3:14])[CH:10]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc(C)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
An acetonitrile (8.0 mL) mixture of ethyl-3-methyl-1H-pyrazole-5-carboxylate (15) (0.50 g. 3.2 mmol), benzyl bromide (0.48 mL, 4.0 mmol), and K2CO3 (0.90 g, 6.5 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After removal of solvent under reduced pressure, the residue was purified by flash column chromatography [silica gel, eluting with mixtures of ethyl acetate and hexanes (0% ramped to 15% EtOAc/hexanes)] to yield 0.30 g of ethyl-1-benzyl-3-methylpyrazole-5-carboxylate (16). 1H NMR (CDCl3): δ 7.30-7.22 (m, 5H), 6.65 (s, 1H), 5.71(s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.32 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); LCMS: purity: 99%; MS (m/z): 345(MH+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([CH2:17]Br)[C:13]=2[CH:19]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[C:13]=2[CH:19]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc2onc(CBr)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc2onc(Cn3ccnc3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 276.6 g, 6.92 moles) is added in portions to a solution of imidazole (471 g, 6.92 moles) in dimethylformamide (4 L) over a period of 1 hour. After the addition is complete, the resulting suspension is stirred for 1 hour at ambient temperature. A solution of 5-chloro-3-bromomethyl-1,2-benzisoxazole (1.57 kg, 6.37 moles) in dimethylformamide (3 L) is then added over a period of 30 minutes, during which time there is an exotherm from 24° C. to 68° C. On completion of this addition, the reaction mixture is stirred and heated at 90° C. for 2 hours. The solvent is then removed in vacuo and the residue is taken up in methylene chloride (4 L). The resulting suspension is washed with water (2×2 L), which dissolves the solid material, and the organic solution is then dried over anhydrous sodium sulfate (1 kg), filtered and evaporated to give 5-chloro-3-[(1H-imidazol-1-yl)methyl]-1,2-benzisoxazole, m.p. 100°-102° C.; hydrochloride salt, m.p. 201°-203° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[N:7]#[C:8][C:9]#N.Cl>>[CH3:1][N:2]1[C:6]([CH2:9][C:8]#[N:7])=[CH:5][CH:4]=[CH:3]1
Reactant: N#CC#N
Reactant: Cn1cccc1
Agent: Cl
Product: Cn1cccc1CC#N
Temperature: 25 °C
Yield: 14.3 %

Procedure:
N-methylpyrrole (4 g, 0.049 mole) is dissolved in 40 ml of dry (ethanol-free) chloroform in a dry, 200 ml, 3-necked round-bottomed flask and flushed with a stream of dry nitrogen. The temperature of the solution is lowered to 0° C and cyanogen (3.25 g, 0.063 mole) is added. Hydrogen chloride (dried through sulfuric acid) is introduced in a slow steady stream with mechanical stirring at 0° C for 4 hrs at which time all the N-methylpyrrole has been consumed. The hydrogen chloride flow is stopped; the chloroform is evaporated to 1/2 its volume at reduced pressure and room temperature; and the temperature is then lowered to -40° C. Dry pyridine (25 ml) is added dropwise with rapid stirring. The rest of the chloroform is evaporated at reduced pressure and then 25 mls of additional pyridine is added. The reaction mixture is allowed to warm to room temperature and hydrogen sulfide is introduced in a slow stream for 20 minutes. Chloroform (200 ml) is added and the reaction solution is washed with 35% aqueous potassium carbonate solution, followed by a 3N hydrochloric acid wash which is backwashed with chloroform. The combined chloroform extracts are washed with 5% aqueous sodium bicarbonate solution and dried over anhydrous MgSO4 powder. The mixture is filtered and the filtrate evaporated in vacuo to a brown oil. The oil is distilled under high vacuum to give 840 mg of N-methylpyrrole-2-acetonitrile, bp 61°-65° C at 0.04 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O.[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)ccc1O
Reaction time: 5 h

Procedure:
0.125 mol (16 g) of 4-chlorophenol, 25 ml of water and 35 ml of acetic acid are introduced into a 125 ml three-necked flask equipped with a stirring system and a thermometer; the mixture is brought to 40° C. and 14.2 ml of nitric acid (d=1.38) are then added drop by drop; the reactants are left in contact for 5 hours. The product is separated by filtration and is crystallized in the minimum of absolute alcohol.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6](O)[CH:5]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[Cl:17][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1cc(O)nc2ccccc12
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Cl)nc2ccccc12
Yield: 84 %

Procedure:
4-Isopropylquinolin-2-ol (1.95 g, 10.43 mmol) and 1.14 mL (1.2 eq) of POCl3 in toluene were reacted as outlined in Scheme 1 above to yield 1.8 g (84%) of the desired title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.40 (d, J=6.74 Hz, 6 H) 3.71 (quin, J=6.81 Hz, 1 H) 7.28 (s, 1 H) 7.48-7.63 (m, 1 H) 7.65-7.78 (m, 1 H) 7.98-8.10 (m, 2 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(F)C=CC=1S(O)(=O)=O)(C)(C)C.P(Cl)(Cl)(Cl)(Cl)[Cl:32]>ClC(Cl)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:32])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)O)c(F)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: CC(C)(C)c1cc(F)ccc1S(=O)(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)Cl)c(F)c1

Procedure:
Synthesized as described for 2 using a 3:1 regioisomeric mixture of 107 (23.68 g; 0.10 mol) and 2-tert-butyl-4-fluorobenzenesulfonic acid, phosphorus pentachloride (23.13 g; 0.11 mol) and dichloroethane (700 mL). The title compound was obtained as a white solid which was a 1:1 regioisomeric ratio of itself and 2-tert-butyl-4-fluorobenzene-1-sulfonyl chloride (10.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:19][O:20]C1C=C([N+]([O-])=O)C=CC=1S(NC1C=CC(C)=CC=1)(=O)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])(=[O:10])=[O:9])=[C:4]([O:20][CH3:19])[CH:3]=1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc(C)cc1
Product: COc1cc(N)ccc1S(=O)(=O)Nc1ccccc1C
Yield: 93 %

Procedure:
(RK2-065-01) I This compound was prepared according to the procedure described for compound 12a except using 11j to obtain the required product as a yellow solid (63 mg, 93%). Mp=189-191° C.; 1H NMR (400 MHz, CD3OD) δ 7.30 (d, J=8.8 Hz, 1H), 7.10-7.06 (m, 2H), 7.01-6.97 (m, 2H), 6.31 (d, J=1.6 Hz, 1H), 6.12 (dd, J=8.8, 2.0 Hz, 1H), 3.30 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[O:26][C:25]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])=[CH:24][CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:25]4[O:26][C:22]([C:20](=[O:21])[C:19]([F:18])([F:36])[F:37])=[CH:23][CH:24]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)o2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2ccc(C(=O)C(F)(F)F)o2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 6 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2,2-trifluoroacetyl)furan-2-yl)benzoic acid as described in example 8 step 6 (20 mg, yield 6%). 1H NMR (400 MHz, DMSO-d6) δ 8.52-8.49 (t, J=6.2 Hz, 1H), 8.30-8.29 (t, J=1.6 Hz, 1H), 8.09-8.06 (dt, J=8.1 Hz, 1.2 Hz, 1H), 8.01-7.98 (m, 4H), 7.94-7.92 (dt, J=8.1 Hz, 1.2 Hz, 1H), 7.66-7.62 (t, J=7.8 Hz, 1H), 7.51-7.50 (d, J=4.0 Hz, 1H), 7.35-7.31 (t, J=9.0 Hz, 2H), 3.52-3.50 (d, J=6.4 Hz, 2H), 1.29 (s, 6H). MS (ESI) m/z: Calculated for C26H20F4N2O4: 500.14. found: 499.4 (M−H)−.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: CN1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 3 h

Procedure:
A solution of 4-nitrophenyl chloroformate, 5.04 g (25 mMole) in 25 ml of dry ethyl acetate was added dropwise to an ice bath cooled, stirred solution of N-methylpiperazine, 5.55 ml (50 mMole), and N,N-diisopropylethylamine, 5.23 ml (30 mMole), in 50 ml of dry ethyl acetate. The ice bath was removed and stirring was continued at 22° C. for three hours. The thick reaction mixture was diluted with ethyl acetate, extracted with aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate and evaporated under reduced pressure. The solid residue was recrystallized from methylene chloride hexane furnishing 3.67 g of 1-(4-nitro-phenoxycarbonyl)-4-methylpiperazine, m.p. 134°-135° C., which was characterized by nuclear magnetic resonance, mass spectra, infrared spectra and elemental analyses.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(=CC)C.P([O-])([O-])(O)=[O:23].[Na+].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:5][C:6]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]([OH:23])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1ccccc1C=O
Reactant: O=P([O-])([O-])O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
21.5 g (93.8 mmol) of 2-(tert-butoxycarbonyloxy)-benzaldehyde and 80 ml (750 mmol) of 2-methyl-2-butene are diluted in 250 ml of tert-butanol. A solution containing 28.1 g (234 mmol) of sodium hydrogenphosphate and 29.7 g (328 mmol) of sodium chlorite in 75 ml of water is added dropwise to the reaction medium, which is stirred at ambient temperature for 2 hours. The mixture is evaporated under reduced pressure and the residue is dissolved in dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated. The white solid obtained is precipitated from heptane at 0° C. The precipitate is filtered off and then rinsed with heptane and dried. 15.8 g of 2-(tert-butoxycarbonyloxy)benzoic acid are obtained in the form of a white powder with a yield of 70%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:17])=[CH:12][CH:11]=2)=[O:7].[OH-].[K+].[I:20]I>CN(C=O)C>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[I:20])=[CH:14][C:13]([F:17])=[CH:12][CH:11]=2)=[O:7]
Reactant: O=C(NCCCO)c1cc2cc(F)ccc2[nH]1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(NCCCO)c1[nH]c2ccc(F)cc2c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-fluoro-1H-indole-2-carboxylic acid (3-hydroxy-propyl)-amide, prepared as in reference 11, (4.89 g, 20.7 mmol) in DMF (100 mL) is added KOH (3.48 g, 62 mmol) and I2 (5.78 g, 22.8 mmol). It is stirred at room temperature for 1 hour and concentrated. Water is added to the residue and the mixture is acidified with HCl. The mixture is extracted with EtOAc (100 mL×2). The combined organic layers are washed with Na2S2O3 (1M, 50 mL), brine (100 mL), and dried with Na2SO4. Solvent is removed to give 5-fluoro-3-iodo-1H-indole-2-carboxylic acid (3-hydroxy-propyl)-amide; 1H NMR (DMSO-d6) δ 1.73 (quint, 2H, J=6.0 Hz), 3.39 (q, 2H, J=6.0 Hz), 3.54 (t, 2H, J=6.0 Hz), 4.54 (bs, 1H), 7.06-7.16 (m, 2H), 7.46 (dd, 1H, J1=4.4 Hz, J2=8.8 Hz), 8.00 (t, 1H, J=6.0 Hz), 12.10 (s, 1H); m/z [M++1] 363.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]1=[O:21])[C:5]([OH:7])=O.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]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>CN(C)C=O>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:5](=[O:7])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[CH3:20])=[CH:10][C:9]3=[O:21])[CH2:3][CH:2]([CH3:1])[CH3:22])=[N:31]2)[CH2:26][O:25]1
Reactant: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C1
Temperature: 0 °C
Yield: 48.4 %

Procedure:
To a solution of (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (prepared as in Example 120, 0.228 g, 0.75 mmol) in N,N-dimethylformamide (4 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.192 g, 0.97 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.663 g, 1.50 mmol). The mixture was stirred at 0° C. and triethylamine (0.153 g, 1.51 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 30% to 70% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.175 g, 48%) as a pink solid: HR-ES-MS m/z calculated for C26H34N4O5 [M+H]+ 483.2602, observed 483.2603, 1H NMR (200 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.36-1.66 (m, 2H), 1.68-1.81 (m, 1H), 2.19 (s, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.11 (t, J=5.7 Hz, 2H), 4.20 (d, J=18.4 Hz, 1H), 4.28-4.42 (m, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.63 (s, 1H), 4.88 (dd, J=10.6, 4.8 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 7.16-7.33 (m, 3H), 7.36 (d, J=7.5 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]#[N:29].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH2:27][C:28]#[N:29])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(OCC#N)c2ccccc12
Yield: 98.3 %

Procedure:
N-tertbutyloxycarbonyl-4-amino-1-naphthol (1.0 g, 3.86 mmol), potassium carbonate (1.06 g, 7.7 mmol) and bromoacetonitrile (0.4 ml, 5.8 mmol) in anhydrous dimethylformamide (10 ml) are stirred at room temperature for 5 hours. The mixture is poured into ethyl acetate (100 ml) and washed with water (2×100 ml). The organic layer is then dried over anhydrous sodium sulfate and evaporated to dryness to give (4-cyanomethoxynaphthalen-1-yl)-carbamic acid tert-butyl ester as a red brown solid (1.132 g). 1H NMR 300 MHz (CDCl3) 8.2(d, 1H, J=11.5 Hz), 7.85(d, 1H, J=11.5 Hz), 7.55-7.75(m, 3H), 6.9(d, 1H, J=14 Hz), 6.62(s, 1H), 4.95(s, 2H), 1.5(s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)=[CH:10][C:9]=1[CH3:20])([CH3:21])[CH3:6])[CH3:2]
Reactant: Clc1ccc(I)cc1
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(Cl)cc2)cc1C

Procedure:
In analogy to the procedure described in example 13B], 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid ethyl ester (example 13A]) and 1-chloro-4-iodo-benzene gave the title compound as a yellow viscous oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Br[C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[C:25]1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.BrCC1CCCCC1.BrCC1OC(C(F)(F)F)=CC=1>>[CH:24]1([CH2:25][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:23]1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(CC2CCCCC2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and bromomethyl cyclohexane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (74%) as a white solid: mp 153-154° C.; 1H NMR (300 MHz, CDCl3) δ 7.30 (td, 1H), 7.16 (d, 1H), 7.04 (t, 1H), 6.90 (d, 1H), 6.51 (s, 1H), 6.14 (s, 1H), 5.90-5.84 (m, 2H), 4.91 (d, 1H), 4.65 (d, 1H), 3.72-3.44 (m, 2H), 1.94-1.60 (m, 6H), 1.32-0.99 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 177.8, 156.1, 148.9, 143.0, 142.4, 132.5, 128.9, 124.0, 123.2, 119.7, 109.0, 103.2, 101.6, 93.7, 80.8, 58.3, 46.8, 36.3, 31.1, 31.0, 26.4, 25.9, 25.8; MS (ES+) m/z 378 (M+1), 400 (M+23).
Reaction SMILES: [Si](O[C@@:9]1([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[S:32][CH:33]=[C:34]([C:36]5[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=5)[N:35]=4)=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][CH:16]=2)[N:10]1C([O-])=O)(C(C)(C)C)(C)C.Cl.C[OH:58]>>[OH:58][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C@@H:9]1[NH:10][C@H:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[S:32][CH:33]=[C:34]([C:36]5[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:45])[F:44])=[CH:40][CH:41]=5)[N:35]=4)=[CH:27][CH:26]=3)(=[O:23])=[O:24])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@]1(Cc2ccccc2)CCC(Cc2ccc(NS(=O)(=O)c3ccc(-c4nc(-c5ccc(C(F)(F)F)cc5)cs4)cc3)cc2)N1C(=O)[O-]
Reactant: CO
Agent: Cl
Product: O=S(=O)(Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 16 mg (0.02 mmol) of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl-5-(4-{[(4-{4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}phenyl)sulfonyl]amino}benzyl)pyrrolidine-1-carboxylate (from Step A) in 0.25 mL methanol was added 0.25 mL conc. HCl and the reaction mixture stirred at room temperature for 30 min. Azeotrop with toluene (2×) to remove water. The residue was taken up in acetonitrile/water/MeOH (9:1:1) and purified on the Gilson HPLC eluting with a 0-50% gradient of acetonitrile/water with 0.05% TFA buffer. The fractions containing the product were combined, frozen, and lyophilized to give a white foam (7.3 mg, 61%). m/z (ES) 650 (MH)+. 1HNMR (500 MHz, CD3OD) δ: 8.22 (br d, J=7.8 Hz, 2H), 8.15-8.10 (m, 3H), 7.86 (d, J=7.8 Hz, 2H), 7.72 (d, J=7.8 Hz, 2H), 7.38-7.30 (m, 4H), 7.16 (br d, J=7.8 Hz, 2H), 7.09 (br d, J=7.8 Hz, 2H), 4.56 (d, J=8.1 Hz, 1H), 3.54-3.45 (m, 2H), 2.93 (dd, J=6.4, 13.0 Hz, 1H), 2.82 (dd, J=7.7, 13.0 Hz, 1H), 1.90-1.82 (m, 1H), 1.68-1.53 (m, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[O:10].[OH:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1>CC(C)=O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9](=[O:10])[CH2:8][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1cccc(O)c1)c1ccccn1
Reactant: COc1ccccc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1C(=O)COc1cccc(NC(=O)c2ccccn2)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 55.3 %

Procedure:
According to Scheme 2: K2CO3 (2.33 mmol, 323 mg) and 2-bromo-1-(2-methoxyphenyl)ethanone (0.47 mmol, 107 mg) were added sequentially to a solution of N-(3-hydroxyphenyl)picolinamide (0.47 mmol, 100 mg) in acetone (3 mL). The reaction mixture was stirred at 50° C. for 14 hours. After filtration and evaporation, the crude product was diluted with water and with DCM. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was triturated with Et2O to obtain N-(3-(2-(2-methoxyphenyl)-2-oxoethoxy)phenyl)picolinamide (0.26 mmol, 94 mg, 55%) as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:4]=[CH:5][C:6]([C:13]([CH:15]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18](=[O:24])[C:17]([CH3:26])([CH3:25])[C:16]2=O)=[O:14])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.C(Cl)(=O)C([Cl:32])=O>ClCCl.CN(C)C=O>[F:1][CH:2]([F:28])[C:3]1[CH:4]=[CH:5][C:6]([C:13]([C:15]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18](=[O:24])[C:17]([CH3:26])([CH3:25])[C:16]=2[Cl:32])=[O:14])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CC1(C)C(=O)C(C(=O)c2ccc(C(F)F)c3ncccc23)C(=O)C(C)(C)C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)C(=O)C(C(=O)c2ccc(C(F)F)c3ncccc23)=C(Cl)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.25 g (0.65 mmol) of 2-(8-difluoromethylquinolin-5-yl)carbonyl-4,4,6,6-tetramethyl-cyclohexane-1,3,5-trione was dissolved in 15 ml of dichloromethane and 0.25 g (1.95 mmol) of oxalyl chloride and 7 drops of dimethylformamide were added. The mixture was stirred at 25° C. for 17 hours, after which the solvent was removed. This gave 0.2 g of colorless crystals.