Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[C:27]=1[CH3:33]>ClCCl>[Br:25][C:26]1[C:27]([CH3:33])=[C:28]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(Br)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Temperature: 150 °C
Yield: 63.9 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (150 mg, 0.789 mmol), cuprous iodide (30 mg, 0.16 mmol) and potassium carbonate (109 mg, 0.789 mmol) were deposited in a sealed vessel. 3 mL DMSO and 2,6-dibromotoluene (395 mg, 1.58 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (30 mg, 0.16 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was washed with brine. The combined aqueous layers were washed with dichloromethane. The combined dichloromethane layers were dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (181 mg, 0.504 mmol). MS (ESI) 361.1 (M+H)+.
Reaction SMILES: O.O.O.[O-:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: [O-]c1ccccc1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccccc2)c([N+](=O)[O-])c1

Procedure:
A solution of sodium phenoxide trihydrate (5.0 g, 30 mmol) and 4-chloro-3-nitrotoluene (2.65 mL, 30 mmol) was heated in 60 mL of DMF at 100° C. for 5 days with stirring following the procedure from Example 1c. The product was purified by silica gel column chromatography eluting with CH2Cl2 giving the title compound as an orange solid (1.36 g, 30%).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([NH2:18])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:20]([C:22]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23]1)#[CH:21]>>[F:19][C:3]1[C:2]([C:21]#[C:20][C:22]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:7][C:6]2[C:8]3[N:9]=[C:10]([C:16]([NH2:18])=[O:17])[S:11][C:12]=3[CH2:13][CH2:14][O:15][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC1(O)CCCC1
Product: NC(=O)c1nc2c(s1)CCOc1cc(F)c(C#CC3(O)CCCC3)cc1-2

Procedure:
9-Bromo-8-fluoro-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide (0.25 g) was reacted with 1-ethynylcyclopentanol similar to as described in Procedure E to afford 157 mg of 8-fluoro-9-[2-(1-hydroxycyclopentyl)ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide following reverse phase hplc purification. MS (Q1) 338 (M)+. 1H NMR (400 MHz, DMSO) δ 8.65 (d, J=8.6 Hz, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.03 (t, J=25.1 Hz, 1H), 5.29 (d, J=38.1 Hz, 1H), 4.38 (t, J=4.8 Hz, 2H), 3.40 (t, J=4.8 Hz, 2H), 2.02-1.86 (m, 4H), 1.85-1.57 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[CH2:13][C:14]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:15]=1[O:16][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:13][C:14]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:15]=1[O:16][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc([N+](=O)[O-])c(F)c1
Yield: 97.7 %

Procedure:
By the method of Example 1, Step I, 1.71 g (0.010 mole) of 3-fluoro-4-nitrophenol and 2.85 g (0.011 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate were reacted in the presence of 1.66 g (0.012 mole) of anhydrous potassium carbonate in 100 mL of N,N-dimethylformamide, yielding 3.55 g of methyl 2-[2-(3-fluoro-4-nitrophenoxymethyl)-5-methylphenoxy]propionate as a yellowish solid, m.p. 92°-94° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[ClH:43]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:43][C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[CH:24]=[CH:23][CH:22]=[CH:21][C:14]=1[O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h

Procedure:
A mixture of 11.02 g of isoamyl nitrite and 45 ml of acetonitrile was added dropwise to a mixture of 15.16 g of methyl [2-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate, 6.21 g of copper (I) chloride, 12.65 g of copper (II) chloride, and 250 ml of acetonitrile at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was poured into 2% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 13 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate (compound a-5).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: Fc1ccccc1Br
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1ccccc1F)CC2

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 2-bromofluoro benzene. White solid. MS (ESI): 409.2 (MH+)
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1.O>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1ccc(F)c(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ccc3F)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.9 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-4-fluorophenyl)propanoate (400 mg) in methanol (5.0 mL) and THF (10 mL) was added a solution of sodium hydroxide (305 mg) in water (10 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (350 mg) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][CH2:4]1.Cl[CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][N:9]=1.O>C1COCC1.[H-].[Na+]>[CH:3]1([CH2:2][O:1][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH2:4]1
Reactant: Nc1ccnc(CCl)n1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccnc(COCC2CC2)n1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
Hydroxymethylcyclopropane (0.17 g) was dissolved in THF (2 mL) and at 0° C. sodium hydride dispersion (55% in oil, 0.1 g) was added. The mixture was allowed to stir for 30 minutes and subsequently, a solution of 2-chloromethyl-pyrimidin-4-ylamine (0.2 g, Eur. Pat. Appl. EP 61318 A2, 1982; Eur. Pat. Appl. 60094 A2, 1982) in THF (7 mL) was added dropwise. The resulting mixture was heated to reflux for 2 hours, cooled and water was added. The mixture was extracted with ethyl acetate and the organic layers were combined, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (ethyl acetate/methanol 9:1) to give 2-cyclopropylmethoxymethyl-pyrimidin-4-ylamine as colorless solid (54 mg). 1H NMR (δ, CDCl3): 8.22 (d, 1H), 6.32 (d, 1H), 4.98 (br s, 2H), 4.58 (s, 2H), 3.46 (d, 2H), 1.21-1.12 (m, 1H), 0.59-0.53 (m, 2H), 0.27-0.24 (m, 2H). MS (ESI): 180.3 (MH+).
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[O:9]=[C:7]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1
Reactant: CCCOc1ccc(/C=C(\CSC(C)=O)C(=O)O)cc1
Reactant: NCCC(=O)OCc1ccccc1
Product: CCCOc1ccc(/C=C(\CSC(C)=O)C(=O)NCCC(=O)OCc2ccccc2)cc1

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-propoxyphenyl)propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C@H:23]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1)[CH3:21].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:31](=[O:32])[CH2:30][O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:24][C@H:23]([O:22][CH2:20][CH3:21])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:35][CH:34]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CC(C)c1ccc(CNCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(Cl)cc2)Cc2ccc(C(C)C)cc2)cc1)OCC
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a solution of N-(4-chlorobenzyl)-N-(4-isopropylbenzyl)amine (1.64 g, 6.0 mmol) in methylene chloride (50 mL) at 0° C. were added {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) and N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight. The mixture was diluted with methylene chloride (100 mL) and the organic phase was washed with 2 M HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL, some emulsions), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Twice repeated purification on silica gel with methanol (0-5% gradient) in methylene chloride as the eluent and collection of pure fractions afforded 1.28 g (46%) of a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O.[H][H]>[Ni].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccccc1C1(O)CCCCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1C1(O)CCCCC1

Procedure:
A suspension of 5.20 g (16.45 mmol) 1-(2-nitro-phenyl)-cyclohexanol and 500 mg Raney nickel in EtOH (70 mL) is hydrogenated at RT and under 3 bar hydrogen pressure for 4 h. The catalyst is filtered off through Celite and the filtrate is evaporated down in vacuo. The residue is recrystallised from hexane. Yield: 1.53 g (49%); Rf=0.38 (silica gel, hexane/EtOAc 4:1); ESI-MS: [M+H—H2O]+=174.
Reaction SMILES: C([O:8][C:9]([C:11]1([N:17]([CH:35]=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.O>[CH2:40]([O:39][C:37]([CH2:36][CH2:35][N:17]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:11]1([C:9]([OH:10])=[O:8])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:38])[CH3:41]
Reactant: [H][H]
Reactant: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCN(C1(C(=O)O)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of (4.4 mmol) of the product of step D in 25 mL of ethanol is treated with 2.5 g of 50% water wet 10% palladium on carbon catalyst and shaken under 53 psi of hydrogen for 21 hours. The catalyst is removed by filtration and washed with ethanol (4×25 mL). The filtrate and washings are combined and concentrated under vacuum to crude product.
Reaction SMILES: [CH3:1][CH2:2]N=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:29][N:30]1[C:38]2[CH:37]=[CH:36][C:35]([CH3:39])=[C:34]([C:40]([OH:42])=O)[C:33]=2[CH:32]=[CH:31]1.[C:43]1(C)[CH:48]=[CH:47][C:46]([NH:49][CH:50]2[CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:51]2)=[CH:45][CH:44]=1>ClCCl.ClCCCl>[CH2:58]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][CH:50]1[N:49]([CH2:46][C:45]1[CH:44]=[CH:43][C:48]([CH3:47])=[CH:2][CH:1]=1)[C:40]([C:34]1[C:33]2[CH:32]=[CH:31][N:30]([CH3:29])[C:38]=2[CH:37]=[CH:36][C:35]=1[CH3:39])=[O:42]
Reactant: Cc1ccc2c(ccn2C)c1C(=O)O
Reactant: Cc1ccc(NC2Cc3ccccc3C2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(CN(C(=O)c2c(C)ccc3c2ccn3C)C2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
EDCI (2 equivalents), HOBT (1 equivalent), and 2.0 equivalents of triethylamine are added to a solution of 1,5-Dimethyl-1H-indole-4-carboxylic acid (23) (189 mg, 1.0 mmol) and (4-tolyl)-indan-2-ylamine (237 mg, 1.0 mmol, 1.0 eq.) (24) in 10 nml of anhydrous 1,2-dichloroethane. The resulting solution is stirred at room temperature for 5 hours and heated at reflux overnight. The reaction mixture is diluted with dichloromethane (20 ml), extracted with saturated sodium bicarbonate solution (10 ml×2), water (10 ml×2), and brine (10 ml). The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure, and purified by reverse-phase preparative HPLC to obtain 1,5-dimethyl-1H-indole-4–Carboxylic acid indan-2-yl-(4-methyl-benzyl)-amide (25).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].C=O.S(Cl)(Cl)=O.Cl.S(=O)=O.[CH:23](Cl)(Cl)[Cl:24]>>[CH3:1][N:2]([CH3:12])[C:3]([N:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:23][Cl:24])=[O:4]
Reactant: CCOC(=O)CNC(=O)N(C)C
Reactant: ClC(Cl)Cl
Agent: C=O
Agent: Cl
Agent: O=S=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN(CCl)C(=O)N(C)C
Temperature: 25 °C

Procedure:
A reaction flask was charged with 100 cubic centimeters (cc) of chloroform, 45.4 grams (g) (0.26 mole) of N,N-dimethyl-N'-carboethoxymethylurea, and 9.0 g (0.3 mole) of paraformaldehyde. While the mixture was stirred continuously at room temperature, 35.4 g (21.4 cc, 0.3 mole) of thionyl chloride in a concentrated chloroform solution was added dropwise. A rise in temperature to 34° C. was observed. Hydrogen chloride and sulfur dioxide gases evolving from the reaction mixture were trapped in a caustic solution. The product was isolated by evaporation of the solvent, to provide 53.4 g, representing essentially full conversion. The structure as shown above was confirmed by proton resonance and mass spectrometry. The refractive index of the product was nD30 =1.4782.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][CH2:7][CH2:8][CH:9]=O)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[CH3:17][O:18][C:19](=[O:40])[CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:40])[CH:20]=[CH:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]2[C:1]1=[O:16]
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C=CCCCN1C(=O)c2ccccc2C1=O
Yield: 95.8 %

Procedure:
4-Phthalimidobutanal (120.9 g, 556 mmol) was then dissolved in 600 ml of CH2Cl2 and treated with methyl(triphenylphosphoranylidene)acetate (186 g, 556 mmol) in 600 ml of CH2Cl2. After 1 h the mixture was concentrated in vacuo and chromatographed in seven equal portions (Merck Kieselgel 60; 7×14 cm column; eluent 30% ethyl acetate in hexane) to give 145.6 g (96%) of methyl-6-phtalimidohex-2-enoate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(C(Cl)=O)=O.[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=1[NH2:21]>C1COCC1.C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:21][C:20]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=1[F:18])=[O:9]
Reactant: O=C(O)c1cc(Br)cnc1F
Reactant: Nc1ccc(F)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(F)cc1F)c1cc(Br)cnc1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 5-bromo-2-fluoronicotinic acid (55 mg, 0.25 mmol) in a mixture of 2.0 mL of THF and 5.0 mL of DCM was added (COCl)2 (0.13 mL, 1.5 mmol). The mixture was stirred at room temperature for 1 h and at 40° C. overnight. After cooling, the solvent was removed under reduced pressure. The residue was dissolved in 2.0 mL of DCM and to it were added 2,4-difluoroaniline (0.05 mL, 0.5 mmol) and 0.1 mL of TEA. The mixture was stirred at room temperature for 2 h and diluted with H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified on preparative (RP) HPLC to give the desired product (60 mg, 73% yield). MS(ESI+) m/z 331.18, 333.18 (M+H)+.
Reaction SMILES: [Mg].Br[CH:3](Br)[CH3:4].[CH2:6](Br)C#C.[CH2:10]=[C:11]([CH2:15][CH2:16][CH3:17])[C:12](=[O:14])[CH3:13].[Cl-].[NH4+]>CCOCC>[OH:14][C:12]([CH3:6])([C:11](=[CH2:10])[CH2:15][CH2:16][CH3:17])[CH2:13][C:3]#[CH:4]
Reactant: CC(Br)Br
Reactant: C#CCBr
Reactant: C=C(CCC)C(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCC(C)(O)C(=C)CCC
Temperature: 0 °C

Procedure:
To a mixture of 5.0 g. of magnesium and 100 mg. of mercuric chloride in 10 ml. of ether is added with stirring, one ml. of dibromoethane. The mixture is stirred for 10 minutes and 0.5 ml. of propargyl bromide is added. An additional 50 ml. of ether is added, followed by a solution of 17.5 g. of 3-methylene-2-hexanone and 27.8 g. of propargyl bromide in 60 ml. of ether, dropwise at a rate to maintain vigorous reflux. The mixture is refluxed for 1/2 hour, cooled at 0° C. and saturated ammonium chloride solution is added dropwise. The mixture is filtered through Celite and the solids are washed with ether. The ether solution is dried over magnesium sulfate and the ether is removed giving the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[C:8]([Cl:11])([Cl:10])=[O:9]>C1COCC1>[Cl:11][C:8]([O-:9])=[O:1].[Cl-:10].[OH:1][CH2:2][CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[OH:1][CH2:2][CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)Cl
Agent: C[N+](C)(C)CCO
Solvent: C1CCOC1
Product: O=C([O-])Cl
Product: [Cl-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of choline (2.235 mg, 16 mmol) and phosgene (32 ml, 1.93M in toluene) in THF (90 ml) was stirred at room temperature for 72 hours. The precipitate was filtered, washed with hexane, and dried in vacuo to yield choline chloride chloroformate (3.0 g).
Reaction SMILES: [C:1]([C:7]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:8]=1[C:9](N(C)OC)=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:1]([C:7]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:8]=1[C:9](=[O:10])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCCCC#Cc1cc(OC)ccc1C(=O)N(C)OC
Solvent: C1CCOC1
Product: CCCCC#Cc1cc(OC)ccc1C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
2-(1-Hexyn-1-yl)-N-methyl-N,4-bis(methyloxy)benzamide (79) (0.42 g, 1.51 mmol) was dissolved in THF (10 mL). Cooled to 0° C. in an ice bath, benzylmagnesium chloride (2 M in THF, 1.50 mL, 3.0 mmol) was added. The mixture was stirred at 0° C. for 3 h, quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography over SiO2 eluted with a gradient from hexanes to 15% EtOAc in hexanes to give 0.37 g (80%) of the title compound (80) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.93 (t, J=7.3 Hz, 3H), 1.40-1.55 (m, 2H), 1.55-1.65 (m, 2H), 2.46 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 4.44 (s, 2H), 6.82 (dd, J1=8.8 Hz, J2=2.7 Hz, 1H), 6.96 (d, J=2.5 Hz, 1H), 7.20-7.34 (m, 5H), 7.65 (d, J=8.7 Hz, 1H). LCMS (ESI): m/z 307 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[CH2:13][NH2:14])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[CH2:13][NH:14][C:22](=[O:24])[CH3:23])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)/C(=C/CN)CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)/C(=C/CNC(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
To a solution of (E)-2-(6-methoxyindan-1-ylidene)-ethylamine (736 mg, 3.89 mmol) and triethylamine (0.59 g, 5.84 mmol) in tetrahydrofuran (20 ml) was added acetyl chloride (0.37 g, 4.70 mmol) gradually dropwise on an ice bath and the mixture was stirred at room temperature for 2 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed serially with saturated saline and water and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to provide (E)-N-[2-(6-methoxyindan-1-ylidene)ethyl]acetamide (yield 1.0 g, 90%).