Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([Li])C=CC=CC=1.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH:10]=1.I[CH2:24][CH:25]([CH3:27])[CH3:26].[I-]>C(OCC)C.C1CCCCC1.C(OCC)C>[CH3:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:24][CH:25]([CH3:27])[CH3:26])[N:12]=[C:11]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH:10]=1
Reactant: CC(C)CI
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Agent: [I-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: Cc1cc(CCC(C)C)nc(-n2c(C)ccc2C)c1
Temperature: -10 °C
Yield: 51.5 %

Procedure:
A solution prepared by the addition of 1.58 mL (2.85 mmol) of 1.8 M phenyllithium in 70:30 cyclohexane/diethyl ether to 4.0 mL of diethyl ether was stirred at -10° C. 4,6-Dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (500 mg, 2.5 mmol) was added as a solution in 1.7 mL of diethyl ether and the mixture was stirred 1h at -5 to -10° C. The red solution was then cooled to -45° C. and 0.354 mL (566 mg, 3.08 mmol) of 1-iodo-2-methylpropane was added in one portion. The reaction was warmed slowly to 10° C., stirring a total 2 h after addition of the iodide. The reaction was then quenched with 10 mL of saturated aqueous ammonium chloride and extracted with 30 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated aqueous sodium chloride, dried over sodium sulfate and concentrated to give a yellow oil. Purification by flash column chromatography on silica gel, eluting with dichloromethane/hexane yielded 330 mg (52% yield) of 4-methyl-6-(3-methylbutyl)-2-(2,5-dimethylpyrrol-1-yl)pyridine as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([NH2:12])[C:5]=2[CH:4]=1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25][C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1>CN1C(=O)CCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([N:12]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:25][CH2:24][CH2:23][O:22][CH3:21])[CH2:31]3)[C:5]=2[CH:4]=1
Reactant: COCCC[C@H]1CNCCN1
Reactant: NC1=Nc2ccccc2Nc2ccc(C(F)(F)F)cc21
Solvent: CN1CCCC1=O
Product: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Temperature: 200 °C
Reaction time: 2 h

Procedure:
Add 2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine-11-ylamine (0.438 g, 1.58 mmol), (S)-2-(3-methoxy-propyl)-piperazine (0.25 g, 1.58 mmol) in NMP (2.8 mL). Heat at 200° C. with stirring. After 2 hours, stop heating and allow the reaction mixture cool down to ambient temperature. Add brine and extract with ethyl acetate. Wash the organic solution with brine three times, dry over sodium sulfate, filter, and concentrate under reduced pressure to give crude residue. Purify the residue by flash chromatography, eluting with 2M ammonia in methanol:dichloromethane (5:95) to give the title compound: mass spectrum (m/e):419.05 (M+1).
Reaction SMILES: [OH-:1].[Na+].CS([C:7]1[N:12]=[CH:11][C:10]2=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:9]2[N:8]=1)(=O)=O.Cl>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]1[N:9]2[C:10]([CH:11]=[N:12][C:7]([OH:1])=[N:8]2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)c1ncc2ccc(-c3ccccn3)n2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Oc1ncc2ccc(-c3ccccn3)n2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
5M NaOH (2 mL, 10 mmol) was added to 2-Methanesulfonyl-7-pyridin-2-yl-pyrrolo[2,1-f][1,2,4]triazine and the reaction was stirred and heated at 80° C. overnight. The reaction was let cool to room temperature and HCl was then added dropwise to the reaction mixture to precipitate the product (pH 1), which was filtered immediately and washed with water and left on vacuum overnight to give 7-Pyridin-2-yl-pyrrolo[2,1-f][1,2,4]triazin-2-ol (100 mg, 66% over two steps). 1H-NMR (DMSO-d6): 11.89 (s, 1H), 9.05 (s, 1H), 8.83 (d, 1H, J=7.91 Hz), 8.69 (d, 1H, J=4.74 Hz), 7.96 (t, 1H, J=7.69 Hz), 7.53 (d, 1H, J=4.86 Hz), 7.35 (t, 1H, J=4.86 Hz), 7.04 (d, 1H, J=4.86 Hz).
Reaction SMILES: [Na+].[I-].C[Si](Cl)(C)C.[C:8]([C:12]([S:14][C:15]1[C:26]2[O:25][C:24]([CH3:28])([CH3:27])[O:23][C:22]=2[C:21]([C:29]([C:54]2[C:64]3[O:65][C:66]([CH3:69])([CH3:68])[O:67][C:63]=3[C:62]([S:70][C:71]([C:73]([CH3:76])([CH3:75])[CH3:74])=[O:72])=[C:56]3[O:57][C:58]([CH3:61])([CH3:60])[O:59][C:55]=23)([C:31]2[C:41]3[O:42][C:43]([CH3:46])([CH3:45])[O:44][C:40]=3[C:39]([S:47][C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])=[O:49])=[C:33]3[O:34][C:35]([CH3:38])([CH3:37])[O:36][C:32]=23)O)=[C:20]2[C:16]=1[O:17][C:18]([CH3:78])([CH3:77])[O:19]2)=[O:13])([CH3:11])([CH3:10])[CH3:9].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(#N)C>[C:73]([C:71]([S:70][C:62]1[C:63]2[O:67][C:66]([CH3:68])([CH3:69])[O:65][C:64]=2[C:54]([CH:29]([C:21]2[C:22]3[O:23][C:24]([CH3:28])([CH3:27])[O:25][C:26]=3[C:15]([S:14][C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:13])=[C:16]3[O:17][C:18]([CH3:78])([CH3:77])[O:19][C:20]=23)[C:31]2[C:41]3[O:42][C:43]([CH3:45])([CH3:46])[O:44][C:40]=3[C:39]([S:47][C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])=[O:49])=[C:33]3[O:34][C:35]([CH3:37])([CH3:38])[O:36][C:32]=23)=[C:55]2[C:56]=1[O:57][C:58]([CH3:61])([CH3:60])[O:59]2)=[O:72])([CH3:74])([CH3:75])[CH3:76]
Reactant: CC1(C)Oc2c(c(C(O)(c3c4c(c(SC(=O)C(C)(C)C)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SC(=O)C(C)(C)C)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c(c2SC(=O)C(C)(C)C)OC(C)(C)O3)O1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Solvent: CC#N
Product: CC1(C)Oc2c(c(C(c3c4c(c(SC(=O)C(C)(C)C)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SC(=O)C(C)(C)C)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c(c2SC(=O)C(C)(C)C)OC(C)(C)O3)O1
Reaction time: 0.08 h
Yield: 56.8 %

Procedure:
NaI (0.185 g, 1.2342 mmol) and trimethylsilyl chloride (0.156 mL, 1.2336 mmol) were stirred in acetonitrile (50 mL). Tris(8-tertbutylcarbonylthio-2,2,6,6-tetramethylbenzo-[1,2-d:4,5-d]bis(1,3)dioxole-4-yl)methanol (0.220 g, 0.2056 mmol, Example 47) was added in solid form and the color of the solution became brownish. Na2S2O4 (20 mL, sat.) was added after 60 minutes and the mixture was stirred 5 minutes before separation of the phases. The aqueous phase was extracted with diethyl ether (50 mL), and the combined organic phase was dried (MgSO4) and evaporated, yielding 0.105 g (0.1168 mmol, 83%) of the title compound. Tris(8-tertbutylcarbonylthio-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methane (0.205 g, 0.200 mmol, 97.3%).
Reaction SMILES: [Br-:1].[Na+].N[C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][C:6]([OH:8])=[O:7].N([O-])=O.[Na+].NC(N)=O>S(=O)(=O)(O)O.O>[Br:1][C@@H:4]([CH2:5][C:6]([OH:8])=[O:7])[C:9]([OH:11])=[O:10]
Reactant: [Br-]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C[C@H](Br)C(=O)O
Temperature: 5 °C
Yield: 63.3 %

Procedure:
To a solution of 1,000 g (9.72 mol) sodium bromide in 2.1 liters 6N sulfuric acid under nitrogen was added 323.1 g (2.43 mol) L-aspartic acid and the resulting solution cooled to 5° C. To this was added in portions over 1.5 hours, 201.4 g (2.92 mol) sodium nitrite while keeping the temperature below 10° C. After the addition was completed, one liter of distilled water was added, followed by 73.07 g (1.22 mol) urea. The resulting mixture was poured into a separatory funnel and extracted with 2.5 liters ethyl ether. To the aqueous layer was added 500 g sodium chloride, and the mixture extracted three times with ether (3×1.25 liters). The combined ether layers were washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo to yield 303 g (63%) of the desired compound; [alpha]D =-73.5° (c=0.6 in ethyl acetate); m.p. 185° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](=[O:29])[NH:27][N:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[C:28](=[O:29])[N:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:31])[F:30])=[CH:23][CH:22]=2)[N:25]=[N:26]1)[CH3:13]
Reactant: O=c1[nH]nnn1-c1ccc(OC(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1nnn(-c2ccc(OC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 66.5 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.54 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.52 g of 1-(4-trifluoromethoxyphenyl)-5(1H,4H)-tetrazolone, 1.76 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-trifluoromethoxyphenyl)-5(1H,4H)-tetrazolone was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:21])=[C:15]([OH:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[CH3:24][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:21])=[C:15]([O:20][CH2:31][C:30]4[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:22])[CH3:23])=[CH:5][CH:4]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(N(C)C)cc1)C(C)(C)O2
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(N(C)C)cc2)C(C)(C)O3)cc1
Yield: 42 %

Procedure:
Using 3-[4-(dimethylamino)phenyl]-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10]Br.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21].O>CC(CC)=O>[C:20]([C:19]1([C:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C:4]2[C:3](=[CH:8][CH:7]=[C:6]([F:9])[CH:5]=2)[CH2:2]1)(=[O:21])[CH3:22]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Fc1ccc(CBr)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)C1(C(=O)OC(C)(C)C)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 10 g of 1,2-bis-(bromomethyl)-4-fluoro-benzene in 200 ml of methylethylketone were added 29.4 g of potassium carbonate followed by 6.7 g of tert-butyl acetoacetate. The mixture was stirred for 16 h at ambient temperature. 200 ml of water were added. The phases were separated and the aqueous phase was extracted once with 100 ml of methylethylketone. The combined organic phases were washed once with 100 ml of water. The solvent was evaporated and to the resulting oil were added 20 ml of methanol. After 1 h stirring at ambient temperature the product was filtered off, washed with 2×5 ml of methanol and dried. Yield: 6.2 g. Melt.p. 73° C. 1HNMR: δ=1.48 ppm (s, 9H); 2.25 ppm (s, 3H); 3.44 ppm (AB, 2H); 3.47 (AB, 2H); 6.87 ppm (m, 2H); 7.12 ppm (dd, 1H)
Reaction SMILES: [I:1][C:2]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([I:16])=[CH:10][C:3]=1[O:4][C:5](=[CH:8]C)[C:6]#[N:7].Cl.NC1C=CC=CC=1.O(C)[Na].Cl.[NH2:29][C:30]([NH2:32])=[NH:31]>C(O)C.CO>[I:1][C:2]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([I:16])=[CH:10][C:3]=1[O:4][C:5]1[C:6]([NH2:7])=[N:29][C:30]([NH2:32])=[N:31][CH:8]=1
Reactant: N=C(N)N
Reactant: CC=C(C#N)Oc1cc(I)c(OC)cc1I
Agent: CO[Na]
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: Nc1ccccc1
Product: COc1cc(I)c(Oc2cnc(N)nc2N)cc1I
Temperature: 85 °C
Reaction time: 18 h
Yield: 36.7 %

Procedure:
2-(2,5-Diiodo-4-methoxy-phenoxy)-but-2-enenitrile (3.47 g, 6.75 mmol) and aniline hydrochloride (3.5 g, 27 mmol) were dissolved in 27 mL ethanol. The reaction mixture was heated to 85° C. and stirred under nitrogen for 18 hours. The reaction mixture was cooled and 25% NaOCH3 in methanol (7.3 mL) was added, followed by guanidine hydrochloride (3.2 g), and ethanol (10 mL). The reaction mixture was heated to 100° C. for 21 hours, then cooled and concentrated under reduced pressure. The residue was poured into water and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.2 g of 5-(2,5-Diiodo-4-methoxy-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=485.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[S:10][C:9]([C:11]#[N:12])=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH2:12])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(Oc2cccc(F)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NCc1ccc(Oc2cccc(F)c2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a solution of 5-(3-fluorophenoxy)thiophene-2-carbonitrile described in Preparation Example 22 (670 mg, 3 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (460 mg, 12 mmol), and the solution was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was filtered with NH silica gel, the filtrate was evaporated in vacuo, and the title compound (570 mg, 2.42 mmol, 80.7%) was obtained as a brown oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([OH:24])(=[O:23])[C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([OH:19])=O)[CH:15]=1.[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl.CN(C=O)C>[F:25][C:26]([F:34])([F:35])[C:27]1[CH:28]=[C:29]([NH:33][C:17]([C:16]2[CH:15]=[C:14]([CH:22]=[CH:21][CH:20]=2)[C:13]([OH:24])=[O:23])=[O:19])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(C(=O)Nc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) was added to a stirring solution of isophthalic acid (1.66 g, 10 mmol) and 3-(trifluoromethyl)benzenamine (0.8 g, 5 mmol) in anhydrous CH2Cl2 (10 mL) and DMF (10 mL). The mixture was stirred at room temperature under argon for 2 h. The solvent was removed under reduced pressure and recrystalized from water to afford the title compound as a white solid after washed by CHCl3 (1.5 g, 49%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH2:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.[CH:24]1([C:27]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:28]=2[C:29](O)=[O:30])[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:28]=2[C:29]([NH:23][C:13]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:30])[CH2:26][CH2:25]1
Reactant: NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Product: O=C(NC1(c2ccccc2)CCCNC1)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
In analogy to the procedure described for the synthesis of example 29, the title compound was prepared from rac-3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (Example B.3). MS (m/e): 389.1 (MH+).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[Ba:12].[OH-].[Ba+2].[OH-].C(OC(=O)C(NC(=O)C)C(OCC)=O)C>O>[C:1]([NH:4][CH:5]([C:9]([O-:11])=[O:10])[C:6]([O-:8])=[O:7])(=[O:3])[CH3:2].[Ba+2:12]
Reactant: [Ba]
Reactant: CC(=O)NC(C(=O)O)C(=O)O
Agent: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(C(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
Preparation of Barium acetamidomalonic acid--To 14.5 g (46.0 mmol) of barium hydroxide in 750 ml of water is added 10.0 g (46 mmol) of acetamidomalonic acid diethyl ester. The solution is refluxed for one hour and suction filtered while still hot. The filtrate is allowed to cool to room temperature to give barium acetamidomalonate in quantitative yield as white crystals. IR (KBr) 3366.8, 1654, 1640, 1599, 1578,1530, 1427, 1344 cm-1. Elemental analysis for BaC5H
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[CH2:31][S:32](Cl)(=[O:34])=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][S:32]([CH2:31][C:30]4[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=4[Cl:28])(=[O:33])=[O:34])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NS(=O)(=O)Cc4ccccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-chlorobenzylsulfonyl chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:20][CH2:21]OC(C)=O>CN(C=O)C.[Cu]I>[C:20]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1)#[CH:21]
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(C)n1
Reactant: CCOC(C)=O
Agent: [Cu]I
Solvent: CN(C)C=O
Product: C#Cc1cc(Oc2ccc(NC(C)=O)nc2C)ccn1
Temperature: 75 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of Example A3 (0.35 g, 1.260 mmol) in DMF (5 mL) was sparged with argon, treated with TEA (1 mL) trimethylsilylacetylene (0.531 mL, 3.78 mmol), copper(I) iodide (0.024 g, 0.126 mmol) and trans-dichlorobis(triphenylphosphine)palladium(0) (0.088 g, 0.126 mmol) and heated at 75° C. under argon for 16 h. The mixture was cooled to RT, treated with EtOAc, solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and H2O and the layers of the filtrate separated. The aqueous layer was extracted with EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The resulting material was dissolved in MeOH (20 mL), treated with K2CO3 (300 mg) and stirred at RT for 1 h. The mixture was concentrated to dryness, treated with EtOAc, sonicated, the solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (102 mg, 30%) as a light red solid. 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1 H); 8.40 (d, J=5.8 Hz, 1 H); 8.01 (d, J=8.8 Hz, 1 H); 7.60 (d, J=6.0 Hz, 1 H); 7.04 (d, J=2.5 Hz, 1 H); 6.89 (dd, J=5.8, 2.6 Hz, 1 H); 4.34 (s, 1 H); 2.22 (s, 3 H); 2.07 (s, 3 H); MS (ESI) m/z: 268.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O>CN(C=O)C>[C:22]1([S:28]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:17]([O:18][CH3:19])[CH:16]=3)[CH:12]=[CH:13]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of 5-benzyloxy-6-methoxyindole (990 mg, 3.9 mmol) in DMF (3 mL) was added to a solution of NaH (234 mg, 5.9 mmol, 60% in oil) in DMF (1 mL) at 0° C. The ice bath was removed, and the reaction mixture allowed to stir at RT for 30 min. The reaction flask was cooled to 0° C. and PhSO2Cl (0.6 mL, 4.7 mmol) was added via syringe. The ice bath was removed and the reaction mixture stirred at RT for 24 h. Water (25 mL) was added and the aqueous layer extracted with Et2O (4×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give an oil. The residue was purified by column chromatography (25% then 40% EtOAc/hex) to furnish N-phenylsulfonyl 5-benzyloxy-6-methoxyindole as a crystalline solid (1.38 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22]CC(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:60]=[CH:59][C:51]([C:52]([O:54]C(C)(C)C)=[O:53])=[C:50]([OH:61])[CH:49]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C:60]2[CH:48]=[CH:49][C:50]([OH:61])=[C:51]([CH:59]=2)[C:52]([OH:54])=[O:53])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1O
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, tert-butyl 4-amino-2-hydroxybenzoate was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: CC1CC(OCC(O)CO)C(C(C)C)CC1.[C:17]([O:20][CH2:21][CH:22]([O:35]C(=O)C)[CH2:23][O:24][C:25]1([CH3:34])[CH2:30][CH2:29][CH:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]1)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:21][CH:22]([OH:35])[CH2:23][O:24][C:25]1([CH3:34])[CH2:30][CH2:29][CH:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCC(COC1(C)CCC(C(C)C)CC1)OC(C)=O
Agent: CC1CCC(C(C)C)C(OCC(O)CO)C1
Product: CC(=O)OCC(O)COC1(C)CCC(C(C)C)CC1
Yield: 92.38 %

Procedure:
The reaction mixture obtained in (1) was mixed with 30 ml of water and 50 ml of heptane to effect separation, the organic layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was recovered to obtain an oily substance. By distilling this oily substance under a reduced pressure, partially purified 1-acetoxy-3-l-menthoxypropan-2-ol was obtained at a boiling point of from 111 to 120° C./25 Pa (0.19 mmHg). Composition of this product when analyzed by the gas chromatography was composed of 5.53% by mass of 3-l-menthoxypropane-1,2-diol, 86.04% by mass of 1-acetoxy-3-l-menthoxypropan-2-ol (yield 92.38% based on 1-chloro-3-l-menthoxypropan-2-ol) and 5.13% by mass of 1,2-diacetoxy-3-l-menthoxypropane.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[N+:15]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:13])[F:14])=[N:4]2)([O-:17])=[O:16]
Reactant: FC(F)(F)c1ccc2ccccc2n1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2nc(C(F)(F)F)ccc12
Reaction time: 20 h

Procedure:
1.52 g (7.7 mmol) of 2-(trifluoromethyl)quinoline is dissolved in 7.90 ml of concentrated sulfuric acid, and 1.47 g of potassium nitrate is added in portions at 0° C. After 20 hours at room temperature, the reaction solution is poured onto ice/water. It is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium bicarbonate solution and dried on sodium sulfate. After removal of the solvent and chromatography on silica gel with hexane-ethyl acetate (10–100%), 390 mg (21% of theory) of the product is obtained.