Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].[CH:9]1[C:19]2[CH:18]=[CH:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH:14]([C:24]3[C:25](=[O:38])[NH:26][C:27](=[O:37])[N:28]([C:30]4[N:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=4)[CH:29]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH:20]1[C:16]2[CH:17]=[CH:18][C:19]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]([C:24]3[C:25](=[O:38])[NH:26][C:27](=[O:37])[N:28]([C:30]4[N:31]=[N:32][C:33]([S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[CH:34][CH:35]=4)[CH:29]=3)[C:15]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CS
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)nn2)cc1C1c2ccccc2C=Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1ccc(-n2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl thioglycolate (0.97 ml) was added dropwise to a stirred suspension of sodium hydride (0.434 g, 60% dispersion in oil) in dimethylformamide (30 ml). The mixture was stirred at room temperature for 1 hour. 13 ml of this solution was added to a solution of the product from step (i) (0.9 g) in dimethylformamide (20 ml). The mixture was stirred for 2 hours then quenched with aqueous arnmonium chloride and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.0 g.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[C:30]([O:29][CH3:28])[CH:31]=3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: COc1cccc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cccc(Nc2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Yield: 59 %

Procedure:
A solution of 408 (700 mg, 1.68 mmol), Cs2CO3 (1.12 g, 3.43 mmol), 3-methoxyaniline (190 μL, 206 mg, 1.68 mmol), Pd(OAc)2 (70 mg, 0.17 mmol) and Xantphos (1.43 g, 2.52 mmol) (J. Org. Chem. 1999, 64, 6019-6022) in dioxane (15 mL) was heated to reflux for 5 hrs. The reaction mixture was then concentrated and purified by flash chromatography using 80% EtOAc in hexanes as an eluent yielding 448 of (408 mg, 59% yield). LCMS: (M+H) 412.0.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:23](=[O:29])[C:24]([O:26]CC)=[O:25])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:23](=[O:29])[C:24]([OH:26])=[O:25])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccccc3)cc12
Yield: 62.3 %

Procedure:
{1-Benzyl-5-phenyl-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-phenyl-1H-indol-3-yl}(oxo)acetate (0.680 g, 1.77 mmol), and potassium hydroxide (0.322 g, 5.74 mmol) in THF (10 mL) and water (10 mL), following the procedure described in Step 4 of Example 5. Crystallization from acetonitrile, and drying for 3.5 hours at 70° C., yielded the title compound as a yellow solid (0.392 g, 62%), mp: 193-195° C. (dec.). Mass spectrum (+ES, [M+H]+) m/z 356; 1HNMR (500 MHz, DMSO-d6): δ 13.7-14.2 (br s, 1H), 8.7 (s, 1H), 8.45 (d, 1H, J=0.61 Hz), 7.65 (m, 3H), 7.55 (dd, 1H, J=8.7 Hz and 1.1 Hz), 7.45 (t, 2H, J=7.6 Hz), 7.25-7.35 (m, 6H), and 5.65 ppm (s, 2H). Elemental Analysis for C23H17NO3: Calculated: C, 77.73; H, 4.82; N, 3.94. Found: C, 77.52; H, 4.81; N, 3.95.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Br)[CH:10]=[CH2:11]>>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:11][CH:10]=[CH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: Oc1cccc(F)c1
Product: C=CCOc1cccc(F)c1

Procedure:
3-fluoro-phenol was reacted with allyl bromide to form 3-fluoro-allyloxy-benzene with a refractive index of nD23 =1.4985 which was reacted with nitric acid to obtain 2-allyloxy-4-fluoro-nitro-benzene with a refractive index of nD23 =1.5432 which was reacted as in Example 1 to obtain 0-(4-nitro-3-allyloxy-phenyl)-hydroxylamine melting at 94°-95° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(O)(=O)C(O)=O.OC[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19](CO)[C:18]=1[OH:26]>O>[CH:17]1[C:18]([OH:26])=[CH:19][CH:20]=[C:21]([CH3:23])[CH:22]=1.[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2]
Reactant: Cc1cc(CO)c(O)c(CO)c1
Agent: O=C(O)C(=O)O
Agent: Oc1ccccc1O
Solvent: O
Product: Cc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a 1 liter, 3 necked round bottomed flask equipped with a paddle stirrer, condenser, thermometer and heating source, were added 159 g (1.45 moles) of catechol, 10 g (0.11 moles) of oxalic acid and 100 g of water. The mixture was stirred and heated to 60° C. Complete solution was obtained. 147 g (0.874 moles) of 2,6-bis(hydroxymethyl)-4-methylphenol were added, in eight equal portions. After the first portion was added, the temperature dropped several degrees. The temperature of the reaction mixture was raised to 70° C. and four more portions were added at 15 minute intervals. After five portions were added, the temperature of the reaction was raised to 80° C. and the remaining three portions were added at 15 minute intervals. The reaction product phase separated, with the water layer on top. The temperature was then raised to 110° C. and held for 10 minutes. The temperature was then raised to 185° C. and held for 15 minutes. Vacuum was gradually applied and ultimately brought to 30 mm Hg. The reaction mixture was held under these conditions for 30 minutes. The vacuum was broken and the hot product drained into an aluminum dish. After cooling, a dark brown, brittle solid was obtained. 13C NMR shows an average molecular weight of 994 and approximately 5.3%, by weight, of free catechol. Differential scanning calorimetry shows a Tg of 97° C.
Reaction SMILES: [H-].[Na+].[C:3]([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([CH3:21])[NH:15][C:14]=2[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]1=2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[I-].[K+]>C1COCC1>[CH2:26]([N:15]1[C:14]2[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[N:11]([C:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:10])[CH2:20][CH2:19][C:18]=2[N:17]=[C:16]1[CH3:21])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccccc1)CC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccccc1)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 905 mg, 22.5 mmol) was placed in anhydrous THF (200 ml) and cooled down to 0° C. 6-Benzoyl-2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E5.8 (4.9 g, 16.1 mmol) was added dropwise and the mixture was stirred for 1 h at room temperature. Benzyl bromide (2.31 ml, 19.3 mmol) and potassium iodide (1.34 g, 8.0 mmol) were added and the mixture was stirred for 16 h. The solution was diluted with EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (5.73 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: ClCCN1CCCC1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cn[nH]c3)nn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCN4CCCC4)c3)nn12
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 7-fluoro-6-[6-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 251, 50 mg, 0.145 mmol), 1-(2-chlorethyl)pyrrolidine hydrochloride (25 mg, 0.145 mmol) and Cs2CO3 (99 mg, 0.305 mmol) in DMF (1 mL) was stirred at 95° C. for 18 h. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) to afford the title compound as a foam (tR 3.06 min (conditions 3), MH+=442.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.44 (s, 1H); 8.34 (d, 1H); 8.08 (m, 2H); 8.03 (d, 1H); 7.76 (d, 1H); 7.61 (s, 1H); 7.52 (d, 1H); 7.46 (dd, 1H); 4.54 (s, 2H); 4.26 (t, 2H); 2.83 (m, 2H); 2.44 (m, 4H); 1.62 (m, 4H)).
Reaction SMILES: C(S([C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21]CC)=[O:20])=[CH:12][N:13]2[CH2:16][CH2:17][F:18])=[CH:8][C:7]=1[F:25])(=O)=O)C.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][N:30]([C:6]2[N:15]=[C:14]3[C:9]([C:10](=[O:24])[C:11]([C:19]([OH:21])=[O:20])=[CH:12][N:13]3[CH2:16][CH2:17][F:18])=[CH:8][C:7]=2[F:25])[CH2:29]1
Reactant: CCOC(=O)c1cn(CCF)c2nc(S(=O)(=O)CC)c(F)cc2c1=O
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)C1

Procedure:
The same reaction as in Example 4 was carried out using ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 3-dimethylaminopyrrolidine as starting materials. There was obtained the compound 5, m.p. 247°-249° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH2:8]([O:24][P:25](OCC[N+](C)(C)C)([OH:27])=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(OCC)C.C(Cl)(Cl)Cl.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C([O-])(=O)C.[Cl-].[Cl-].[Ca+2]>[CH2:8]([O:24][P:25]([O:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])([OH:27])=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCOP(=O)(O)OCC[N+](C)(C)C
Reactant: N[C@@H](CO)C(=O)O
Agent: CC(=O)[O-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOP(=O)(O)OC[C@H](N)C(=O)O
Temperature: 45 °C
Reaction time: 2.2 h
Yield: 16.3 %

Procedure:
0.8 g of L-serine (7.6 mmol) is dissolved in 1.52 ml of 0.1M acetate buffer (pH 5.6), which is 0.09M in CaCl2, at 45° C. 31 mg (0.075 mmol) of n-hexadecylphosphonocholine, 1.6 ml of diethyl ether/chloroform (9:1, v/v, ethanol-free) and 200 mg of a phospholipase D enzyme preparation which has been prepared from white cabbage and has an activity of 0.9 U/ml (1 unit (U) converts 1 μmol of substrate per minute at 27° C.) in the reaction mixture, are added to this solution. The mixture is stirred at 45° C. for 2.2 hours. After cooling to room temperature, 3.31 ml of 0.1M EDTA solution are added and the organic solvents are removed by passing in nitrogen. The aqueous phase which remains is stirred with 4.3 times its volume of chloroform/methanol (5:8, v/v) for 30 minutes and the undissolved material (L-serine) is filtered off with suction. 1 volume of water and 3.7 volumes of chloroform are added to the filtrate, the mixture is shaken for 10 minutes, the organic phase is separated off and concentrated in vacuo, and the residue obtained is separated by column chromatography on carboxymethyl cellulose (CM 52 Whatman, Na+ form) Elution is carried out successively with 75 ml of chloroform, 300 ml each of chloroform/methanol 9:1, 8:2 and 7:3, then 1,750 ml of chloroform/methanol 1:1 (in each case v/v). The fraction size is 50 ml. 5 mg of pure n-hexadecylphosphono-L-serine (I, R=C16H33) are obtained from fractions 20-39.
Reaction SMILES: [C:1]([O:10]C1C=CC=CC=1)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([NH:17][C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:4])=[CH:19][CH:20]=1)#[N:23]
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
The 4′-cyano-salicylanilide was prepared by condensing phenyl salicylate with 4-amino-benzonitrile then purified as described in Example 2a. The ligand mixture was then prepared from 4′-cyano-salicylanilide and 1,1′-bi-2-naphthol using the procedure described in Example 5a. 31P NMR (121.77 MHz): several peaks between 116.4-117.7 ppm.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[O:16])([O:3][CH2:4][CH3:5])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[Cl-:18].[C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[O:16])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: CCOC(=O)c1ccc2c(c1)C(=O)C(=O)N2
Product: [Cl-]

Procedure:
By reacting 5-carboethoxyisatin with phosphorous pentachloride, there is obtained 5-carboethoxyisatin chloride which, on reaction with 3(2H)-thianaphthenone, yields 5'-carboethoxy-2'-indole-2-thianaphthenone indigo, which also is useful as a dyestuff.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([C:17]#[C:18][Si:19]([CH3:20])([CH3:21])[CH3:22])=[C:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(N)c(F)cc1C#C[Si](C)(C)C
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
To a stirring suspension of ethyl 2-(4-fluoro-5-nitro-2-(2-(trimethylsilyl)ethynyl)phenyl)acetate (0.66 g, 2.04 mmol) in MeOH/THF (1:1, 20 mL) was added NH4Cl (1.09 g, 20.4 mmol), followed by Zn dust (1.33 g, 20.4 mmol). After stirring 1.5 h, the mixture was filtered through C elite, and rinsed forward with MeOH. The combined filtrates were concentrated, diluted with brine and extracted with THF (2×). The combined organic layers were washed with brine (1×), dried (MgSO4), filtered and concentrated to afford ethyl 2-(5-amino-4-fluoro-2-(2-(trimethylsilyl)ethynyl)phenyl)acetate (0.54 g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.86 (d, J=12.0 Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 5.47 (brs, 2H), 3.88 (d, J= 6.8 Hz, 2H), 3.43 (s, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.00 (s, 9H); MS (ESI) m/z: 294.0 (M+H+).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].O.CCOC(C)=O>CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)#[CH:5]
Reactant: COC(=O)CCc1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1ccc(CCC(=O)OC)cc1
Temperature: 25 °C

Procedure:
Methyl 3-(4-((trimethylsilyl)ethynyl)phenyl)propanoate (225 mg, 0.86 mmol) and potassium carbonate (234 mg, 1.69 mmol) was dissolved in MeOH (9 mL) and stirred vigorously for 2½ hours at room temperature. The reaction was added water and extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4 before concentrated under vacuum to give 138 mg (90%) of a brown, oily product. Rf: 0.31 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.43-7.40 (m, 2H), 7.17-7.14 (m, 2H), 3.66 (s, 3H), 3.04 (s, 1H), 2.97-2.92 (t, 2H, J=7.7 Hz), 2.65-2.59 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 141.4, 132.3, 128.3, 120.2, 83.5, 76.8, 51.6, 35.3, 30.8; ESI-MS m/z 287.1 (MNa+).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: NC(Cc1cccnc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1cccnc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloro-quinoline-3-carboxylic acid is reacted with 2-amino-3-pyridin-3-yl-propionic acid in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)[CH:8]=[C:7]([C:16]([F:19])([F:18])[F:17])[N:6]=1)([CH3:3])[CH3:2].[OH-:20].[Na+]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:15]=[CH:14][N:13](/[CH:9]=[CH:10]\[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:20])[N:12]=2)[CH:8]=[C:7]([C:16]([F:18])([F:17])[F:19])[N:6]=1)([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)Oc1cc(-c2nc[nH]n2)cc(C(F)(F)F)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)/C=C\n1cnc(-c2cc(OC(C)C)nc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 12 h
Yield: 70.8 %

Procedure:
In a 50 ml capacity 3-neck round-bottomed flask attached with nitrogen bubbler, & magnetic stirrer 2-isopropoxy-4-(1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyridine (1 g), dissolved in 10 ml DMF at RT. Ethyl iodo acrylate (1.310 g) in DMF (1 ml) dropwise added in the reaction mixture. Then NaOH (0.291 g) added and stirred the reaction mixture for 12 h at 0° C. Completion of the reaction confirmed on TLC in 30% ethyl acetate/hexane mobile phase. Reaction gives two isomeric compounds (cis/trans). The reaction mixture was poured in ice water solution & extract with ethylacetate (3×50 mL). Organic layer dried over Na2SO4 & concentrate to give crude product (1.1 g). The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions) from 1% to 5% ethyl acetate in hexane. Compound started eluting with 5% ethyl acetate in hexane. Fractions containing such TLC profile was collected together to obtain pure (Z)-isopropyl 3-(3-(2-isopropoxy-6-(trifluoromethyl)pyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylate (500 mg).
Reaction SMILES: [CH3:1][C:2](=[O:4])[CH3:3].Cl[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[O-]CC.[Na+]>C(OCC)C>[CH3:1][C:2]1([CH3:3])[O:4][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCl
Reactant: CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C1OC1(C)C
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a stirred solution of propan-2-one (11.52 ml, 157 mmol) and ethyl 2-chloroacetate (25.04 ml, 235 mmol) in dry diethyl ether (125 ml) at −10° C. under nitrogen was added sodium ethoxide (10.66 g, 157 mmol) portionwise, keeping the temperature below 5° C. After addition was complete, the mixture was stirred for two hours at −10° C., whereafter the reaction was continued at room temperature for three hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, the phases were separated, and the aqueous layer was extracted with diethyl ether (100 ml). The combined organic phases were dried over Na2SO4 and evaporated in vacuo). The resulting residue was purified by vacuum distillation. The major fraction (−25 mbar, 82° C.-85° C., 14.3 g) consisted of the desired product, containing 6.4 mol % ethyl chloroacetate. This was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23](F)([F:31])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:27]5[S:28][C:24]([CH:23]([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1ccc(C(F)(F)F)s1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)F)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (78 mg), (5-(trifluoromethyl)-2-thienyl)methanol (77 mg) and tributylphosphine (168 mg) in THF (3 ml) was added 1,1′-(azodicarbonyl)dipiperidine (210 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (48.5 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C@@H:23]([OH:26])[CH2:24][OH:25])[CH:16]=1.C(N(CC)CC)C.[C:35](Cl)(Cl)=[O:36].Cl>C1COCC1.C(OCC)(=O)C.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C@@H:23]2[CH2:24][O:25][C:35](=[O:36])[O:26]2)[CH:16]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(C(=O)c2cccc(OC[C@@H](O)CO)c2)cnn1-c1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)c2cccc(OC[C@@H]3COC(=O)O3)c2)cnn1-c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 15.0 g (40.4 mmol) of 5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-dihydroxypropoxy}benzoyl]pyrazole in 150 ml THF was added 17 ml (168 mmol) of triethylamine. The mixture was cooled to −5° C. and 18 ml of phosgene (20% in toluene) was added over a 30 minute period keeping the reaction temperature below 0° C. Once addition was complete, the reaction was stirred for an additional hour at 0° C. Then, 20 ml of distilled water was added along with 5% HCl until the pH of the solution was 5 to 6. After 30 minutes, ethyl acetate was added and the organic layer was separated, washed with brine, and dried over MgSO4. Filtration and concentration in vacuo gave a yellow oil which was purified by flash column chromatography using 1:1-1:2 hexanes/ethyl acetate as eluent. The desired carbonate precipitated upon concentrating the column fractions to give 7.38 g of desired product.