Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[F:9][CH:10]([F:18])[C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CO>O>[F:9][CH:10]([F:18])[C:11]1[CH:12]=[C:13]([NH:14][C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(C(F)F)c1
Reactant: O=C1CCCC(=O)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CO
Product: O=C1C=C(Nc2cccc(C(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of cyclohexane-1,3-dione (2.00 g, 17.84 mmol), 3-(difluoromethyl)aniline (2.55 g, 17.82 mmol) and Ytterbium(III) trifluormethanesulfonate (111 mg, 178 μmol, 1.0 mol %) is stirred at room temperature for 2 h. Methanol and water are added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate). Yield: 2.76 g; ESI mass spectrum [M+H]+=237, Retention time HPLC: 0.40 min (X012_S01).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc(Cl)cc1Cl

Procedure:
AMR01045 A mixture of 2,4-dichlorophenol (2.00 g, 12.27 mmol), 2-fluorobenzonitrile (1.49 g, 12.27 mmol) and potassium carbonate (1.7 g, 12.27 mmol) in DMF (10 mL) was stirred under reflux for 1.5 h. After removal of DMF, the residue was dissolved in DCM and washed with NaOH (5%, 3×20 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated and 2-(2,4-dichlorophenoxy)benzonitrile was obtained as an oil (2.73 g, 84%), which was used in the next step without further purification. Rf: 0.64 (DCM) 1H NMR (300 MHz, CDCl3) δ 6.73 (1H, dd, J=8.4 Hz), 7.13 (1H, d, J=8.7 Hz), 7.22 (1H, td, J=8.7, 1.0 Hz), 7.35 (1H, dd, J=8.7, 2.4 Hz), 7.56 (1H, d, J=2.4 Hz) and 7.73 (1H, dd, J=7.5, 2.7 Hz).
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:31]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3cccc(N4CCN(C)CC4)c3)nc12

Procedure:
[8-(2-methoxy-5-trifloromethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.5 mmol), and 3-(4-methylpiperazin-1-yl)phenylamine (0.096 g, 0.5 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.19 g, 86%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.45 (d, J=6.4 Hz, 1H), 7.91 (s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.53 (d, J=6.4 Hz, 1H), 7.26-7.19 (m, 2H), 7.12 (d, J=7.7 Hz, 1H), 7.04 (d. J=7.7 Hz, 1H), 6.95 (t, J=7.7 Hz, 1H), 6.83 (s, 1H), 6.58 (d, J=7.7 Hz, 1H), 3.88 (s, 3H), 3.28-3.22 (m, 4H), 2.64-2.55 (m, 4H), 2.37 (s, 3H). MS=483 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][CH:33]([C:36]#[N:37])[C:34]#[N:35]>O1CCCC1>[NH2:37][C:36]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[C:8]([OH:9])=[N:32][C:33]=1[C:34]#[N:35]
Reactant: O=C=NCc1ccc(F)cc1
Reactant: N#CC(N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1nc(O)n(Cc2ccc(F)cc2)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
4-Fluorobenzylisocyanate (1.37 g, 10 mmol) and N,N-diisopropylethylamine (1.29 g, 10 mmol) were added to aminomalononitrile p-toluenesulfonate (2.53 g, 10 mmol) suspended in tetrahydrofuran (50 ml). The mixture was stirred at room temperature for 24 hours and then the solvent was removed in vacuo. To the residue was added ethyl acetate and the solution was washed and the organic layer was extracted with 1N aqueous sodium hydroxide. The extract was neutralized with 10% aqueous potassium hydrogen sulfide and extracted with ethyl acetate. The organic layer was dried on sodium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (1.93 g, yield 89%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([O:9][CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)=[O:8])=[CH:5][CH:4]=1.[NH2:22][OH:23]>>[CH3:16][C:14]1([CH3:17])[CH2:15][CH:10]([O:9][C:7]([C:6]2[CH:20]=[CH:21][C:3]([CH2:2][N:22]([CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:7]([O:9][CH:10]4[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]4)=[O:8])=[CH:20][CH:21]=3)[OH:23])=[CH:4][CH:5]=2)=[O:8])[CH2:11][C:12]([CH3:19])([CH3:18])[NH:13]1
Reactant: NO
Reactant: CC1(C)CC(OC(=O)c2ccc(CCl)cc2)CC(C)(C)N1
Product: CC1(C)CC(OC(=O)c2ccc(CN(O)Cc3ccc(C(=O)OC4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1

Procedure:
from 2,2,6,6-tetramethylpiperidin-4-yl 4-chloromethylbenzoate and hydroxylamine
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:12][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:11])=[CH:6][CH:5]=1
Reactant: Clc1ncccn1
Reactant: CC(O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ncccn1)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
NaH (300 mg, 60%, 7.5 mmol) was suspended in N,N-dimethylformamide. 1-(4-bromophenyl)ethanol was added to the above mixture and stirred at 40° C. for 0.5 hour. Then 2-chloropyrimidine was added to the above mixture and stirred at 100° C. for 12 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=3:1) to give 2-(1-(4-bromophenyl)ethoxy)pyrimidine as a white solid (2.6 g, 94%). LRMS (M+H+) m/z: calcd 278.01. found 278.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.[CH2:12]([C:14]1[S:15][C:16]([CH2:19][CH3:20])=[N:17][N:18]=1)[CH3:13]>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:12]([C:14]1[S:15][C:16]([C:19]([CH3:20])=[CH:10][C:3]2[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=2)=[N:17][N:18]=1)[CH3:13]
Reactant: CCc1nnc(CC)s1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCc1nnc(C(C)=Cc2ncc([N+](=O)[O-])n2C)s1
Yield: 34.6 %

Procedure:
4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde, which has been dissolved in 80 ml of acetic acid and 35 ml of acetic anhydride, is dripped into 17.1 g of 2,5-diethyl-1,3,4thiadiazole, which has been dissolved in a mixture of 60 ml of acetic acid, 25 ml of acetic anhydride and 0.5 g of zinc chloride, over a period of 5 hours at reflux temperature. After being heated for a further 24 hours at reflux temperature the reaction mixture is concentrated by removing the solvent and water is added. The precipitated reaction product is then subjected to sublimation and recrystallized from propanol. 2.9 g of product, corresponding to 35% of the theory, is obtained. The compound melts at 125° C.
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:12]>C1COCC1>[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]([OH:8])[CH3:1])[C:5]=1[OH:12]
Reactant: O=Cc1cccc(F)c1O
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(O)c1cccc(F)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
Methyl lithium (25.5 mL, 35.7 mmol, 1.4M in ether) was added to a cooled −78° C. solution of 3-fluorosalicylaldehyde (2 g, 14.3 mmol) dissolved in THF (50 mL). The reaction mixture was stirred for 3 hours and then warmed up to room temperature. After 3 hours the reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with 1N HCl, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 20% EtOAc in hexanes) to give the title compound as a clear oil (2.2 g, 99%). 1H NMR (400 MHz, CDCl3): δ 1.58 (d, J=6.6 Hz, 3H), 2.68 (s, 1H), 5.13 (m, 1H), 6.78 (td, J=7.8, 4.8 Hz, 1H), 6.87 (d, J=7.6, 1H), 6.99 (m, 1H), 7.33 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:19])=[CH:9][C:10]=2[Cl:18])[N:5]=1)([OH:3])=[O:2].[H][H]>CO.[Pt]=O>[C:1]([C@H:4]1[CH2:13][C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:19])=[CH:9][C:10]=2[Cl:18])[NH:5]1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)c1cc(C(=O)O)nc2cc(Cl)cc(Cl)c12
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Yield: 26.7 %

Procedure:
2-Carboxy-5,7-dichloro-4-methoxycarbonylquinoline (4.8 g) was dissolved in methanol (300 ml) and platinum oxide (0.48 g) was suspended in the solution. Rapid stirring under one atmosphere of hydrogen at room temperature for 75 minutes, followed by filtration and evaporation gave a crude product which was purified by chromatography on silica gel with 2.5% methanol, 0.5% acetic acid and 97% dichloromethane as eluent to give the title compound as a colourless solid (1.3 g, m.p. 154°-156° C.); δ (360 MHz, DMSO) 2.23 (1H, ddd, J=13.9, 7.1 and 5.3 Hz, CHACHBHCCHD), 2.66 (1H, dt, J=13.9 and 4.0 Hz, CHACHBHCCHD), 3.57 (3H, s, CH3), 3.86 (1H, dd, J=7.1 and 4.0 Hz, CHACHBHCCHD), 3.91 (1H, broad multiplet, CHACHBHCCHD), 5.74 (1H, broad s, NH), 6.56 (1H, d, J=1.9 Hz, 6-H or 8-H), 6.58 (1H, d, J=1.9 Hz, 6-H or 8-H); m/e 303 (M+) 198 (100%, M-H, CO2H and CO2Me); Found: C, 47.62; H, 3.60; N, 4.66. C12H11Cl2NO4 requires C, 47.39; H, 3.65; N, 4.61%.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrBr.C(Cl)(Cl)[Cl:14]>>[Cl:14][C:6]1[C:1]2[N:7]=[C:8]([NH2:10])[S:9][C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: ClC(Cl)Cl
Agent: BrBr
Product: Nc1nc2c(Cl)cccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The phenylthiourea (6.00 g, 32.16 mmol) was dissolved in CHCl3 (150 mL) and cooled to 0° C. with an ice bath. To this mixture was added a solution of Br2 (1.6 mL, 32.2 mmol) in CHCl3 (100 mL) dropwise over 30 min. After the addition, the mixture was stirred at 0° C. for 1 h, then allowed to warm to rt. the reaction was refluxed for 3 h to 4 h than allowed to cool to room temperature. The organic solvent was removed and the residue was washed with sulfurous acid. The residue was then neutralized with liquid ammonia. The solid was filtered off, washed with watyer and recrystallized from EtOH.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:31]C(=O)C)[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:17]=1.[ClH:35]>CO>[ClH:35].[NH2:31][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:17]=2)=[C:9]([F:8])[CH:10]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1

Procedure:
A mixture of N-(3-fluoro-4-(2-(2-morpholinoethylamino)pyridin-4-yloxy)phenyl)acetamide trifluoroacetate (40 mg), MeOH (1 mL), and 6 M HCl (0.2 mL) was heated at reflux for 3 h. The mixture was concentrated on a rotary evaporator and the residue was lyophilized to give the title compound (30 mg) as a white solid. 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 8.85 (s, 1H), 7.95 (d, 1H, J=7 Hz), 7.08 (dd, 1H, J=9, 9 Hz), 6.65-6.63 (m, 2H), 6.54 (d, 1H, J=8 Hz), 6.31 (s, 1H), 3.90-3.75 (m 6H), 3.37-3.21 (m, 6H); MS (ESI−): m/z 373.14 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].CCN(C(C)C)C(C)C.[Cl:14][S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[F:27])[C:21](Cl)=[O:22])(=[O:17])=[O:16]>C(Cl)Cl>[F:27][C:26]1[CH:25]=[CH:24][C:20]([C:21](=[O:22])[NH:4][CH2:1][C:2]#[CH:3])=[CH:19][C:18]=1[S:15]([Cl:14])(=[O:17])=[O:16]
Reactant: C#CCN
Reactant: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCNC(=O)c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Propargylamine (0.67 mL, 10.5 mmol) and DIEA (1.83 mL, 10.5 mmol) in DCM (10 mL) were added dropwise to 3-(chlorosulfonyl)-4-fluorobenzoyl chloride (2) in DCM (10 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 15 minutes. The reaction was washed with 2N HCl and brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep) to give product as an oil (2.52 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:44][N:45]1[C:49]2[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=3[O:56][C:57]3([CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)[C:48]=2[CH:47]=[N:46]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:60]2[CH2:61][CH2:62][C:57]3([C:48]4[CH:47]=[N:46][N:45]([CH3:44])[C:49]=4[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=4[O:56]3)[CH2:58][CH2:59]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Br
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1Br
Reaction time: 0.17 h

Procedure:
To a 100 mL round bottom flask was added 4-bromo-3-methoxy-benzoic acid (860 mg, 3.7 mmol), HATU (1.4 g, 3.7 mmol), DMF (6 mL) and triethylamine (1.4 mL, 10 mmol). The reaction mixture was allowed to stir for 10 minutes. 1-Methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (860 mg, 3.4 mmol) dissolved in DMF (6 mL) was added, and the mixture was allowed to stir at 25° C. After 2 h, the reaction was quenched with brine and was extracted with ethyl acetate. The combined organic layers were washed with brine 3 times. The combined organic layer were dried over sodium sulfate and evaporated. The residue was purified via silica gel chromatography (5-90% EtOAc:hexanes) to give (4-bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone as white foam. ESI-MS m/z calc. 467.1. found 468.2 (M+1)+. Retention time: 3.04 minutes (4 min run).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(O)c1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(Oc2ccc([N+](=O)[O-])cc2C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.13 g (0.050 moles) of 2-chloro-5-nitrobenzonitrile, 6.39 g (0.0515 moles) of 3-methoxyphenol, 7.10 g (0.0515 moles) of anhydrous potassium carbonate (K2CO3) and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from approximately 200 ml of absolute ethanol to give 7.15 g (53% yield) of purified 2-(3-methoxyphenoxy)-5-nitrobenzonitrile, mp 102°-103.5° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][C:8]3[C:12]4[NH:13][C:14]([C:21]([O:23]C)=[O:22])=[CH:15][C:16](=[O:20])[C:17]=4[CH:18]=[CH:19][C:7]=3[C:6]=2[NH:5][C:4]([C:25]([O:27]C)=[O:26])=[CH:3]1.[OH-].[Na+:30]>O.CO>[O:20]=[C:16]1[C:17]2[CH:18]=[CH:19][C:7]3[C:6]4[NH:5][C:4]([C:25]([O-:27])=[O:26])=[CH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][C:8]=3[C:12]=2[NH:13][C:14]([C:21]([O-:23])=[O:22])=[CH:15]1.[Na+:30].[Na+:30]
Reactant: COC(=O)c1cc(=O)c2ccc3c(ccc4c(=O)cc(C(=O)OC)[nH]c43)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])c1cc(=O)c2ccc3c(ccc4c(=O)cc(C(=O)[O-])[nH]c43)c2[nH]1

Procedure:
1.0 gram of the diester prepared in Example 1 is heated in 50 ml. of 1.0N NaOH for 30 minutes. The mixture is cooled, diluted with water, and methanol added. The precipitate is filtered and collected.
Reaction SMILES: [CH:1]1([N:4]([CH3:20])[C:5]2[C:6](=[O:19])[NH:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.N1C=CC=CC=1.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>ClCCl>[CH:1]1([N:4]([CH3:20])[C:5]2[C:6]([O:19][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:2][CH2:3]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C3CC3)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (126.0 mg, 0.46 mmol) in dichloromethane (34 mL) was added pyridine (145.0 mg, 1.84 mmol) and then Tf2O (259 mg, 0.92 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature and then quenched by the addition of ice-water (50 mL), extracted with dichloromethane (2×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 3-(cyclopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (180 mg, crude).
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=O)=[C:5]([OH:18])[CH:4]=1)[CH3:2].Cl.[NH2:20][OH:21]>>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7](=[N:20][OH:21])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:5]([OH:18])[CH:4]=1)[CH3:2]
Reactant: NO
Reactant: CCc1ccc(C(=O)c2ccc(F)cc2)c(O)c1
Agent: Cl
Product: CCc1ccc(C(=NO)c2ccc(F)cc2)c(O)c1

Procedure:
4-Ethyl-4'-fluoro-2-hydroxybenzophenone (21.0g, 80% pure) was treated with hydroxylamine hydrochloride (24.0g) similarly to Example 12, to give, after recrystallisation from benzene, the title compound as a white crystalline solid (10.7g), m.p. 130°-2°C.
Reaction SMILES: Cl[C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH3:12]>>[CH3:5][C:2]([N:11]([CH2:10][CH2:9][O:8][CH3:7])[CH3:12])([CH3:6])[C:3]#[CH:4]
Reactant: CNCCOC
Reactant: C#CC(C)(C)Cl
Product: C#CC(C)(C)N(C)CCOC

Procedure:
In analogy to example 37.1, 3-Chloro-3-methyl-1-butyne and N-(2-Methoxyethyl) methylamine were converted to yield (1,1-Dimethyl-prop-2-ynyl)-(2-methoxy-ethyl)-methyl-amine as colorless oil, MS: 155 (M).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[C:5]([F:9])=[CH:4][N:3]=1.C(O)(=[O:12])C.O>>[F:9][C:5]1[C:6]([I:8])=[CH:7][C:2](=[O:12])[NH:3][CH:4]=1
Reactant: Fc1cc(I)c(F)cn1
Reactant: CC(=O)O
Solvent: O
Product: O=c1cc(I)c(F)c[nH]1
Reaction time: 8 h
Yield: 99 %

Procedure:
2,5-Difluoro-4-iodopyridine (500 mg, 2.08 mmol) was suspended in acetic acid:water (2:1, 30 mL). The mixture was heated to reflux and stirred at this temperature overnight. The reaction was concentrated to dryness to afford the title compound as a yellow solid (491 mg, 99.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, J=5.07 Hz, 1 H) 7.69 (d, J=2.34 Hz, 1 H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([OH:26])[C:16]=1[CH3:27])(=[O:3])[CH3:2].[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29].N1C=CN=C1>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([O:26][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: COc1c(O)c(C)c(CCCCCCCCCCOC(C)=O)c(O)c1OC
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1c(O)c(CCCCCCCCCCOC(C)=O)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Temperature: 43 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
6-(10-Acetoxydecyl)-2,3-dimethoxy-5-methylhydroquinone (38.0 g) and tert-butylchlorodiphenylsilane (55.0 g) were dissolved in dichloromethane (50 ml). Imidazole (13.6 g) was added under a stream of nitrogen at room temperature. The mixture was stirred at 43° C. for 16 hours. The reaction mixture was washed with water (50 ml) and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (7:3) to obtain the desired compound (58.0 g).
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[N:5]2[C:9]([C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=1)=[CH:8][CH:7]=[CH:6]2.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[CH:19]=1>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[N:5]4[C:9]([C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=3)=[CH:8][CH:7]=[CH:6]4)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[CH:19]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(/C=N/O)n2cccc12
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Temperature: 68 °C
Yield: 6.6 %

Procedure:
A solution of crude (E)-methyl 5-((hydroxyimino)methyl)indolizine-8-carboxylate (1.0 mmol) in THF (10 mL) was added to a stirred solution of DIB (644 mg, 2.0 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (480 mg, 2.0 mmol) in THF (15 mL) at rt. Then the mixture was heated at 68° C. for 2 h. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and Combiflash to give methyl 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylate (30 mg; yield 7% over 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J=2.0 Hz, 1H), 7.77 (t, J=1.6 Hz, 1H), 7.57-7.62 (m, 3H), 7.23-7.27 (m, 2H), 7.06 (m, 1H), 4.57 (d, J=18.0 Hz, 1H), 4.46 (d, J=18.0 Hz, 1H), 3.87 (s, 3H) ppm; MS: m/z=456.7 (M+1, ESI+).