Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11]O)=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].S(Cl)([Cl:18])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11][Cl:18])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1ccc(/C=C/CO)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(/C=C/CCl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.09 g of (E)-(4-methoxy-3-nitrophenyl)allyl alcohol was dissolved in 21 ml of methylene chloride. To the solution was added 1.79 g of thionyl chloride with ice-cooling. The mixture was stirred for 1 hour at room temperature. The solvent was removed by distillation under reduced pressure to obtain crystals of (E)-3-(4-methoxy-3-nitrophenyl)allyl chloride. The crystals were dissolved in 10 ml of methylene chloride.
Reaction SMILES: [CH2:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].C(C1C=CC2C3C(=CC=CC=3)CC=2C=1)C.[C:33](OC(=O)C)(=[O:35])[CH3:34].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:33]([C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:7](=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:17][CH:16]=3)[CH2:8][C:9]=2[CH:10]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1ccc2c(c1)Cc1ccccc1-2
Agent: CCc1ccc2c(c1)Cc1ccccc1-2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCCCc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2

Procedure:
2-Butylfluorene (6.1 g.) was acetylated exactly as described for 2-ethylfluorene in the preceding Example 21, using acetic anhydride (3.08 g.) and aluminium chloride (8.66 g.) in dichloroethane. The product was recrystallised from light petroleum to give 2-acetyl-7-butylfluorene, m.p. 102° 104.5°. This product (1.98 g.) was oxidised with sodium hypobromite (from 7.23 g. of bromine and 4.52 g. sodium hydroxide in 160 ml. water) exactly as described for 2-acetyl-7-ethylfluorene in the preceding Example. The 7-butylfluorenone-2-carboxylic acid thus isolated had m.p. > 300° and was homogeneous by thin layer chromatography.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24](O)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:68][C:69]1[S:73][N:72]=[C:71]([CH3:74])[N:70]=1>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:35])[CH3:36])[CH:29]=3)[C:24]([NH:68][C:69]3[S:73][N:72]=[C:71]([CH3:74])[N:70]=3)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)O)c1
Reactant: Cc1nsc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
DIPEA (0.5 mL, 3.0 mmol) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (485 mg, 1.0 mmol), HATU (4951 g, 1.3 mmol) and 5-amino-3-methyl-1,2,4 thiadiazole (345 mg, 3.0 mmol) in DMF (6 mL). The resulting mixture was stirred at ambient temperature for 16 hours, water (90 mL) was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (580 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[N:5]=[C:4]([C:13]([NH:15][C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[N:18]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:17]=2)=[O:14])[CH:3]=1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[N:40]1[C:44]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)=[CH:43][C:42]([C:52](O)=[O:53])=[N:41]1.[I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[N:40]1[C:44]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)=[CH:43][C:42]([C:52]([NH:1][C:2]2[N:6]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[N:5]=[C:4]([C:13](=[O:14])[NH:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[N:18]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:17]=3)[CH:3]=2)=[O:53])=[N:41]1
Reactant: Cc1ccc(-c2cc(C(=O)O)nn2C2CCCCO2)cc1
Reactant: Cc1ccc(-c2cc(NC(=O)c3cc(N)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(NC(=O)c3cc(NC(=O)c4cc(-c5ccc(C)cc5)n(C5CCCCO5)n4)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.4 %

Procedure:
5-Amino-1-(tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-yl)-1H-pyrazole-3-carboxamide (102 mg, 0.23 mmol) was added to a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazole-3-carboxylic acid (59 mg, 0.20 mmol), 2-chloro-1-methylpyridinium iodide (79 mg, 0.31 mmol) and N,N′-diisopropylethylamine (105 μL, 0.62 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried with Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE-EtOAc, 7:3) and gave 1-(tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-ylcarbamoyl)-1H-pyrazol-5-yl)-5-p-tolyl-1H-pyrazole-3-carboxamide (25 mg, 15%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[N:6]2[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24].[NH3:35].C(O)C>>[NH2:35][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[N:6]2[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24]
Reactant: N
Reactant: N#Cc1cccc(-n2c(-c3cccc(F)c3)nc3c(Cl)nc(C#CC4(O)CCCCC4)nc32)c1
Solvent: CCO
Product: CCCCCC(O)C#Cc1nc(N)c2nc(-c3cccc(F)c3)n(-c3cccc(C#N)c3)c2n1
Temperature: 25 °C
Yield: 73 %

Procedure:
3-{6-Chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}-9H-9-purinyl]benzonitrile (2.0 g) was suspended in 200 ml of a 20% ammonia/ethanol and reacted at 100° C. in an autoclave for 8 hours. The resulting mixture was cooled to room temperature, concentrated to dryness and purified by a silica gel column (40 g of silica gel). It was eluted with dichloromethane containing 5% of methanol. The fractions containing the aimed product were collected, concentrate to dryness, suspended in 100 ml of a mixed solvent of ethyl acetate and hexane (1:1) and the resulting product was collected by filtration and washed with hexane to give 1.4 g of the title compound. The yield was 73%.
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2=[O:18])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:24]([CH:25]=O)=[CH:23][N:22]=[CH:21]1.[O-:27][CH2:28][CH3:29].[Na+].C(O)C>C(OCC)(=O)CC>[CH3:19][N:20]1[C:24]([CH:25]2[C:28](=[O:27])[C:29]3[C:14]([C:13]([O:12][CH2:11][CH3:10])=[O:18])=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH:1]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:23][N:22]=[CH:21]1
Reactant: CC[O-]
Reactant: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Reactant: Cn1cncc1C=O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1cncn1C)C(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
A mixture of (E)-4-(benzylideneamino) isobenzofuran-1(3H)-one (474 mg, 2 mmol) and 1-methyl-1H-imidazole-5-carbaldehyde (220 mg, 2 mmol) in ethyl propionate (20 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol [sodium (184 mg, 8 mmol) in ethanol (10 mL)] was added dropwise. After the addition, the mixture was stirred at room temperature for 3 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=5:1 to 3:7) to give ethyl 3-(1-methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (170 mg, yield 23%). LC-MS (ESI) m/z: 376 (M+1)+.
Reaction SMILES: [C:1](Br)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O:19]=[C:20]([CH2:22][N:23]([C:25](=[NH:27])[NH2:26])[CH3:24])[OH:21].N1C=CC=CC=1.C(=O)=O>ClCCl.CC(C)=O>[CH3:24][N:23]([CH2:22][C:20]([OH:21])=[O:19])[C:25]([NH:27][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[NH:26]
Reactant: CN(CC(=O)O)C(=N)N
Reactant: CCCCCCCCCCCCCCCC(=O)Br
Agent: O=C=O
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NC(=N)N(C)CC(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the palmitoyl bromide solution, 10.99 g (60 mmol) of creatine is suspended, with stirring, in 100 ml of dry dichloromethane. To this suspension a catalytic amount (0.1 mmol) of pyridine is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of between to about −10° C. and 0° C. When the target temperature is reached the drop wise addition of palmitoyl bromide is commenced. Addition of palmitoyl bromide continues, with cooling and stirring, until all of the palmitoyl bromide is added, after which the reaction is allowed to warm to room temperature with constant stirring. The solution is then filtered to remove any remaining creatine and the volatile dichloromethane and pyridine are removed under reduced pressure yielding 2-(1-methyl-3-palmitoylguanidino)acetic acid.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([F:12])[CH:3]=1.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:9][C:6]1[CH:5]=[C:4]([F:12])[CH:3]=[C:2]([Br:1])[C:7]=1[NH2:8]
Reactant: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(F)cc(Br)c1N
Temperature: 25 °C

Procedure:
1,2-Diamino-3-bromo-5-fluorobenzene was prepared using an adaptation of the method of Bellamy et al., Tetrahedron Lett. 25:839 (1984). A mixture of 6-bromo-4-fluoro-2-nitroaniline (673 mg, 2.87 mmol) and SnCl2 2H2O (3.23 g, 14.3 mmol) dissolved in 6 mL ethyl acetate and 3 mL absolute ethanol was heated at 70° C. for 30 min. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient solid NaHCO3 was added to bring the pH to 7.5. The reaction mixture was then extracted with 3×20 mL ethyl acetate and the combined organic phases washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown liquid 510 mg (86.7%). 1H NMR (CDCl3) δ3.64 (br s, 4H, 2(NH2)), 6.44 (dd, 1H, H5, J4-5 =2.7, JH-F =9.8), 6.72 (dd, 1H, H4, J4-5 =2.7, JHF =8.4).
Reaction SMILES: [CH3:1][NH2:2].CO.[Cl:5][C:6]1[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:7]=1[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9]>CCO>[Cl:5][C:6]1[CH:19]=[C:18]([NH:2][CH3:1])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:7]=1[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9]
Reactant: CN
Reactant: O=C(NC1CCCC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: CCO
Solvent: CO
Product: CNc1cc(Cl)c(C(=O)NC2CCCC2)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
N-Methylamine in MeOH (2 M, 2.0 mL, 4.0 mmol) was added to 2-chloro-N-cyclopentyl-4-fluoro-5-nitrobenzamide (230 mg, 0.79 mmol) in EtOH. The mixture was heated at 50° C. for 12 h in a sealed vessel, cooled and concentrated. The residue was purified by chromatography to give the sub-title compound. Yield: 150 mg (64%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH3:22]>>[C:1]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC
Yield: 90 %

Procedure:
The filtered catalyst was added to oleic acid (1.41 g, 5 mmol) and ethanol (10 ml) and the procedure, above, was repeated. No loss in catalytic activity was observed and ethyl oleate (1.39 g, 90% yield) was obtained.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])(C)(C)C.[C:21](Cl)(=[O:23])[CH3:22].[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29](C(O)=O)=[C:28]([O:36][CH3:37])[CH:27]=1>>[C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6](=[O:7])[C:29]2[CH:33]=[C:34]([Cl:35])[C:26]([NH2:25])=[CH:27][C:28]=2[O:36][CH3:37])[CH2:11]1)(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)C1
Reactant: CC(=O)Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC(C)=O)C1

Procedure:
5-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentylamine (0.99 g) as starting compound was reacted and treated in the same manner as in Example 1 using acetyl chloride (0.25 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.71 g) to give N-(1-(5-acetylaminopentyl)pyrrolidin-3-ylmethyl)-4-amino-5-chloro-2-methoxybenzamide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)=[C:20]([CH3:25])[CH:19]=1
Reactant: Cc1cc(F)ccc1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(F)ccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 80.2 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 4-fluoro-2-methylphenol (20 μL, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(4-fluoro-2-methyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (28 mg, 80%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.01 (br. s., 1H), 7.92 (d, J=8.2 Hz, 2H), 7.54-7.63 (m, 3H), 6.91-7.08 (m, 3H), 5.16 (s, 2H), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:28])[C:7](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:8])([CH3:4])[CH3:3].[CH:29]1[CH:30]=[CH:31][C:32]([CH:37]=[O:38])=[C:33]([CH:35]=O)[CH:34]=1>>[CH3:1][C:2]([O:5][C:6](=[O:28])/[C:7](/[CH3:8])=[CH:35]/[C:33]1[CH:34]=[CH:29][CH:30]=[CH:31][C:32]=1[CH:37]=[O:38])([CH3:4])[CH3:3]
Reactant: CC(C(=O)OC(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1C=O
Product: C/C(=C\c1ccccc1C=O)C(=O)OC(C)(C)C

Procedure:
From 2-(triphenylphosphoranylidene)propanoic acid 1,1-dimethylethyl ester and ortho phthalaldehyde
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].N1C=CC=CC=1.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([O:1][CH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)CCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
To a solution of tert-butyl 3-hydroxypropanoate (2 g, 13.68 mmol) in dry DCM (50 ml), pyridine (3.32 ml, 41.0 mmol) was added. The solution was cooled to 5° C., and (chloromethanetriyl)tribenzene (3.81 g, 13.68 mmol) was added portion-wise; the ice cooling was removed and stirring was continued for 20 hours. The solvent was evaporated and the residue was portioned between EtOAc and water; the organic layer was washed with a 3% aqueous solution of citric acid, with brine and dried over Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel column (petroleum ether:EtOAc=95:5) affording tert-butyl 3-(trityloxy)propanoate (3.5 g, 9.01 mmol, 65.8% yield, MS/ESI+ 411.3 [MNa]+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-:13].[Na+].Cl>CS(C)=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([OH:13])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(O)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 95.1 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1 N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80° C. for 20 h. The mixture was cooled to room temperature, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O-:7])[CH:2]=1.[K+].[NH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]=1>CC(N(C)C)=O>[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:12][N:11]=1
Reactant: [O-]c1cccnc1
Reactant: Nc1ccc(I)cn1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2cccnc2)cn1

Procedure:
3.3 G. of potassium 3-pyridinolate, 5.47 g. of 2-amino 5-iodopyridine and 1.78 g. of cuprous oxide in 150 ml. of dimethylacetamide are heated at reflux under a nitrogen atmosphere for 24 hours. The solvent is removed in vacuo and the residue is extracted with chloroform. Chromatography of the methylene chloride soluble portion with silica gel and elution with ethyl acetate yields 2-amino-5-(3-pyridyloxy) pyridine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[C:9](=[O:12])([O-:11])[O-].[Na+].[Na+].[CH2:15](Cl)Cl.BrBr>CO>[CH3:1][O:2][CH2:3][C:4]1([O:5][CH3:6])[CH:8]=[CH:7][CH:9]([O:12][CH3:15])[O:11]1
Reactant: O=C([O-])[O-]
Reactant: COCc1ccco1
Reactant: ClCCl
Agent: BrBr
Agent: [Na+]
Solvent: CO
Product: COCC1(OC)C=CC(OC)O1
Temperature: -12.5 °C
Yield: 65 %

Procedure:
2-Methoxymethyl furan (120.4 g, 1.07 moles), anhydrous methanol (250 ml, 6.18 moles), anhydrous sodium carbonate (190 g), and methylene chloride (250 ml) were placed in a 3L three-necked flask equipped with a mechanical stirrer and an addition funnel. The mixture was cooled to -10 to -15° C. and an ice-cold solution of bromine (53 ml, 1.04 moles) in 500 ml anhydrous methanol was added dropwise with stirring. Four hours after the addition of the bromine solution, the mixture was filtered by suction. The excess solvent was removed on a rotatory evaporator and the crude product was distilled under reduced pressure to give colorless 2-methoxymethyl-2,5-dimethoxy-2,5dihydrofuran (118.3 g, 65%), bp. 57°-58° C. (0.2 mm Hg), nD =1.4414.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:19])=[C:11]([Cl:20])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:40][CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[NH:36][C:35]2=[O:45])[CH2:30][CH2:29]1.CN([CH:49]=[O:50])C>O>[NH2:19][C:12]1[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([CH2:8][CH:2]([NH:1][C:49]([N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:40][CH2:39][C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[NH:36][C:35]3=[O:45])[CH2:32][CH2:33]2)=[O:50])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][C:11]=1[Cl:20]
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(N)Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(Cc1cc(Cl)c(N)c(C(F)(F)F)c1)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4.15 g (23.04 mmol) CDT was added to a suspension of 8.00 g (23.04 mmol) ethyl 2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionate (Intermediate product 58) and 16.0 mL (115.00 mmol) triethylamine in 100 mL DMF at 0° C. and the mixture was stirred for 1.5 hours at 0° C. A solution of 5.64 g (23.00 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one in 200 mL DMF was added and the mixture was heated to 100° C. for 2 hours. The reaction mixture was cooled to RT, diluted with 1.5 L water and stirred for a further 10 minutes. The precipitate formed was filtered off, washed with water and dried i. vac.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7](Cl)=[O:8].[CH3:23][N:24]([CH3:37])[S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH2:32][CH2:31]2)(=[O:27])=[O:26]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7]([N:33]1[C:34]2[C:30](=[CH:29][C:28]([S:25]([N:24]([CH3:37])[CH3:23])(=[O:26])=[O:27])=[CH:36][CH:35]=2)[CH2:31][CH2:32]1)=[O:8]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CCN2
Reactant: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)Cl)c2)c1
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CCN2C(=O)COc1cc(Cl)cc(Oc2cc(Cl)cc(C#N)c2)c1

Procedure:
41 mg (0.115 mmol) of [3-chloro-5-(3-chloro-5-cyanophenoxy)phenoxy]acetyl chloride (5-4) and 26 mg (0.115 mmol) of N,N-dimethylindoline-5-sulfonamide (23-1) were refluxed in benzene. When the reaction was complete the benzene was evaporated off and the residue was purified on a silica column eluted with EtOAc:hexanes (3:97 to 1:1). Recovered the desired compound 23-2. HRMS: measured 546.0665; theoretical 546.0652. 1H NMR (CDCl3): 2.70 (s, 6H), 3.35 (t, 2H), 4.23 (t, 2H), 4.78 (bs, 2H), 6.59 (t, 1H), 6.68 (t, 1H), 6.83 (m, 1H), 7.15 (m, 1H), 7.24 (m, 1H), 7.39 (m, 1H), 7.63 (bs, 1H), 7.66 (bd, 1H), 8.34 (bd, 1H).