Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc2c(c1)CCC2=O)c1ccccc1
Reaction time: 8 h

Procedure:
Benzoyl chloride (126.9 g, 0.900 mol) was added slowly to a stirred mixture of the product of Step A (121 g, 0.818 mol), triethylamine (99.1 g, 0.982 mol) and catalytic amount of DMAP (1 g, 8.18 mmol) in dichloromethane (1 L) at rt under nitrogen. The mixture was stirred overnight and diluted with dichloromethane (1 L). Then the solution was washed with water, hydrochloric acid (0.5 M, 2×1 L), and brine. The organic layer was dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was dried in vacuo to give the compound. 1H-NMR (400 MHz, CDCl3): δ 8.19-8.22 (m, 2H), 7.83 (d, J=8.1 Hz, 1H), 7.65-7.69 (m, 1H), 7.52-7.55 (m, 2H), 7.37 (s, 1H), 7.22 (dd, J=8.1 Hz, J=2.0 Hz, 1H), 3.17-3.20 (m, 2H), 2.73-2.76 (m, 2H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:19])[CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CN(C)CCCN
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NCCCN(C)C)n1
Temperature: 0 °C
Yield: 78.1 %

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 40 ml of ethanol and 5.33 ml (0.0424 mol) of 3-dimethylaminopropylamine are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 4.2 g of yellow powder are obtained, ie a yield of 78.1%.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([OH:41])[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([OH:41])[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:30])([CH3:28])[CH3:29])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: N#Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
Trimethylaluminium (2M in toluene) (6.21 mL, 12.42 mmol) was added to 6-aminonicotinonitrile (1.480 g, 12.42 mmol) in toluene (80 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes. (S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (2.5 g, 6.21 mmol) in toluene (20 mL) was added. The reaction was heated to 110° C. for 2 hours and cooled to RT. The reaction mixture was concentrated. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (1.780 g, 58.5%). 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 3.65-3.69 (3H, m), 3.81-3.91 (4H, m), 4.35 (1H, q), 7.35-7.45 (6H, m), 7.65-7.67 (4H, m), 7.92-7.95 (1H, m), 8.36-8.38 (1H, m), 8.55-8.56 (1H, m), 9.40 (1H, s); m/z (ES+) (M+H)+=490; HPLC tR=3.07 min.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][C:9]=1[N:10]=[CH:11][N:12](C)[CH3:13])=[O:4].NC1[CH:40]=[CH:39][C:38]([N:41]2[CH2:45][CH2:44][CH:43]([N:46]([CH3:48])[CH3:47])[CH2:42]2)=[CH:37][CH:36]=1>>[C:18]([SiH2:17][O:16][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]1[S:6][C:5]2[C:3](=[O:4])[N:12]([C:13]3[CH:40]=[CH:39][C:38]([N:41]4[CH2:45][CH2:44][CH:43]([N:46]([CH3:48])[CH3:47])[CH2:42]4)=[CH:37][CH:36]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: COC(=O)c1sc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)cc1N=CN(C)C
Product: CN(C)C1CCN(c2ccc(-n3cnc4cc(C(O[SiH2]C(C)(C)C)(c5ccccc5)c5ccccc5)sc4c3=O)cc2)C1

Procedure:
5-(tert-Butyl-diphenyl-silanyloxymethyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester was reacted with [1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amine by method A1. The product with the molecular weight of 608.87 (C35H40N4O2SSi) was obtained in this way; MS (ESI): 609 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:20][CH3:21])=[CH:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=O)[C:11]([C:16]#[N:17])=[CH:12][NH:13]3)=[CH:8][C:7]=2[CH:19]=1.P(Cl)(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:10]1[C:9]2[C:14](=[CH:15][C:6]3[CH:5]=[C:4]([O:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:19][C:7]=3[CH:8]=2)[N:13]=[CH:12][C:11]=1[C:16]#[N:17]
Reactant: COc1cc2cc3[nH]cc(C#N)c(=O)c3cc2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OC
Temperature: 105 °C
Yield: 49.4 %

Procedure:
A mixture of 356.2 mg (1.3 mmol) of 7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile in 5 mL of phosphorus oxychloride and 4 drops of DMF is heated at 100-110° C. for 4.5 hours. After cooling, the mixture is concentrated to dryness in vacuo to give a dark residue. The residue is partitioned between methylene chloride and ice-cooled saturated aqueous sodium carbonate solution. The organic layer is washed with cooled brine and dried over sodium sulfate. The organic solvent is passed through a short column of silica gel, and the column is first eluted with additional methylene chloride, then a 99:1 methylene chloride/ethyl acetate soltion. Removal of the solvent yields 187.0 mg (49.4%) of the product as a bright yellow solid, mp>265° C.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23](C(O)=O)=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CNC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:67][N:68]([CH:70]=[O:71])[CH3:69]>>[CH3:67][N:68]([CH3:69])[C:70]([C:23]1[CH:24]=[CH:25][C:19]2[O:18][C:17]([CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:11]([C:1]45[CH2:8][CH:7]6[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]6)[CH2:2]4)[CH2:10]5)=[CH:30][CH:29]=3)=[N:21][C:20]=2[CH:22]=1)=[O:71]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Yield: 59 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (60.4 mg, 0.15 mmol), dimethyl amine (0.030 ml, in 2M THF) in DMF 5.0 mL was added HBTU (113.8 mg, 0.30 mmol) and DIPEA (0.052 ml, 0.30 mmol). After sting at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc:MeOH=15:3:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid dimethylamide as a white solid (37.9 mg, 59% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[C:14](=[O:30])[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:18]([CH3:29])[CH2:17]2)=[CH:7][CH:6]=1)=O.[CH3:31][NH2:32]>CO>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3](=[O:2])[NH:32][CH3:31])[CH:13]=3)[CH2:9][CH2:10]2)=[O:30])[CH2:17][C@H:18]1[CH3:29])=[O:23])([CH3:27])([CH3:26])[CH3:28]
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Reactant: CN
Solvent: CO
Product: CNC(=O)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Temperature: 120 °C
Yield: 20 %

Procedure:
1-[2-((R)-4-tert-Butoxycarbonyl-3-methyl-piperazin-1-yl)-acetyl]-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (200 mg, 0.48 mmol) was dissolved in 2.0 M methylamine in MeOH (2.4 mL) and heated under microwave irradiation at 120° C. for 4 h. The solvent was removed in vacuo and the resulting oil was purified by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), to give the title compound (39 mg, 20%) as a colourless solid, 1H NMR (Me-d3-OD): 8.58 (1H, s), 7.51 (1H, d), 7.33 (1H, d), 4.39-4.28 (2H, m), 4.23 (1H, d), 3.88-3.77 (1H, m), 3.31-3.14 (3H, m), 2.92 (3H, s), 2.84 (1H, d), 2.39-2.30 (1H, m), 2.24-2.12 (1H, m), 1.48 (9H, s), 1.30 (3H, d).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[C:20]([CH3:35])=[N:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-].Cl>C1COCC1.CO>[CH3:35][C:20]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][N:8]3[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=2)=[CH:24][CH:23]=[C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)[N:21]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc2ccn(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 1 %

Procedure:
To a solution of {6-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester (20 mg, 0.04 4 μmol) in THF/methanol 2/1 (3 ml) was added a 1 N aqueous LiOH solution (1 ml). The reaction mixture was stirred for 14 h at ambient temperature, neutralized with 1 N aqueous HCl solution under ice cooling and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (18 mg, 0.04 μmol, quant.) as white solid.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](NCCCCCN)=[O:11])[C@H:3]2[NH:19][C:20]([NH:22][C@@H:2]12)=[O:21].CC1(C)C(/C=C/C=C/C=C2\C(C)(C)C3C(N\2CCCCCC(ON2C(=O)CCC2=O)=[O:53])=CC=CC=3)=[N+](C)C2C1=CC=CC=2.C(N(CC)CC)C>CS(C)=O>[OH:53][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:22][C:20]([NH:19]2)=[O:21])[CH2:1][S:5]1)=[O:11]
Reactant: C[N+]1=C(/C=C/C=C/C=C2/N(CCCCCC(=O)ON3C(=O)CCC3=O)c3ccccc3C2(C)C)C(C)(C)c2ccccc21
Reactant: NCCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Biotin Cadaverine (Sigma Aldrich) was conjugated to Cy5 NHS ester (Amersham Biosciences) in DMSO by adding triethylamine for one hour. The conjugate was purified on a Sephadex LH20 column (Amersham Biosciences) by collecting the first ˜500 μl of the coloured fraction. The concentration of the conjugate was determined by preparing a standard curve of Cy5 NHS Ester dye by diluting it in steps of five (resulting in 205, 41.1, 8.21, 1.64, 0.329 and 0 nM). An aliquot of the conjugate was diluted by a factor of 100. Based on the standard curve, we evaluated the concentration to be 11 mM. For biotin assay experiments the biotin conjugate was diluted to 2.2, 1.1, 0.22, 0.044 nM. In an assay experiment, the scanner was operated in line-scanning mode (˜2 sec/line) across the streptavidin line, resulting in data collection also from areas with no biotin. After a few seconds of scanning, 40 μl of biotin solution was dispensed on the chip and data was recorded for about 3.5 minutes. A new chip was used for each experiment.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[C:26]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Clc1nccnc1Cl
Product: O=S(=O)(CCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1

Procedure:
EXAMPLE 89 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2,3-dichloropyrazine (refluxing 2-butanol): MS (m+1)=396.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)N)=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH3:22][C:23]([CH3:33])([CH2:28][C:29](=O)[CH2:30][CH3:31])[C:24]([O:26]C)=[O:25]>C(O)(C)(C)C>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:14]3[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:30]([CH3:31])=[C:29]2[CH2:28][C:23]([CH3:33])([CH3:22])[C:24]([OH:26])=[O:25])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: COc1ccc(N(N)Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CCC(=O)CC(C)(C)C(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)(C)C(=O)O)n2Cc1ccc([N+](=O)[O-])cc1

Procedure:
Following the method of Example 2, but using 1-[(4-nitrophenyl)methyl-1-(4-methoxyphenyl) hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-hexanoate as the starting materials and tert-butanol as the solvent, the title compound was prepared.
Reaction SMILES: [C:1]1([Mg]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]1(=[O:17])[CH2:16][CH2:15][CH2:14]1.Cl>C(OCC)C>[OH:17][C:13]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Br[Mg]c1cccc2ccccc12
Reactant: O=C1CCC1
Agent: Cl
Solvent: CCOCC
Product: OC1(c2ccc3ccccc3c2)CCC1

Procedure:
To a mixture of 23.1 g. of naphthyl magnesium bromide and 250 ml. of diethyl ether, 7 g. of cyclobutanone are slowly added. After the addition, the mixture is refluxed for 1 hour, cooled, acidified with aqueous hydrochloric acid and filtered. The product is isolated by methylene chloride extraction to furnish 2-(1'-hydroxycyclobutyl)-naphthalene. The product is hydrogenated in 200 ml. of ethanol with a molar equivalent of hydrogen in the presence of 50 g. of Raney nickel; the reaction mixture is filtered after the hydrogenolysis and evaporated to furnish 2-cyclobutylnaphthalene.
Reaction SMILES: CS(C)=O.[C:5]([C:9]1[C:10](=[O:30])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[CH:28])[C:20]=3[CH:29]=2)[CH2:13][C:14]=1[OH:15])(=O)[CH2:6][CH3:7].Cl.[CH2:32]([O:34][NH2:35])[CH3:33].C([O-])(=O)C.[Na+]>Cl>[CH2:32]([O:34][N:35]=[C:5]([C:9]1[C:10](=[O:30])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[CH:28])[C:20]=3[CH:29]=2)[CH2:13][C:14]=1[OH:15])[CH2:6][CH3:7])[CH3:33]
Reactant: CCON
Reactant: C#CCN1C(=O)COc2ccc(C3CC(=O)C(C(=O)CC)=C(O)C3)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCN1C(=O)COc2ccc(C3CC(=O)C(C(CC)=NOCC)=C(O)C3)cc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 50 mL of methyl sulfoxide were added in sequence 2.2 g (6.2 mmol ) of 2-propionyl-3-hydroxy-5-(N-(2-propynyl)-3-oxo-(2H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one, 0.70 g (7.4 mmol) of ethoxyamine hydrochloride and 0.60 g (7.3 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 3.5 hours. The reaction mixture was then diluted with 400 mL of 0.2N HCl and extracted four times with 20 mL portions of dichloromethane. The extracts were combined, washed with aqueous NaCl, dried over MgSO4 and filtered through a short pad of silica gel. Evaporation off of the solvent gave the crude product as a light yellow glass, which solidified upon standing. The solid was triturated in ether and the product isolated by filtration which afforded the above-named product as a white solid which melted at 100°-102° C. in a yield of 1.3 g (53 percent of theoretical). 1H NMR (CDCl3): d1.08-1.47 (m, 6H, both --CH2CH3 's), 2.31 (t, J=2 Hz, 1H,--C--CH), 2.62-3.64 (m, 7H), 4.17 (q, J=7 Hz, 2H, OCH2CH3), 4.67 (s, 2H, --OCH2C=O), 4.74(d, J=2 Hz, 2H,--NCH2), 6.87-7.12 (m, 3H, aromatic H's), 15.10 (broad s, 1H, enol H); (Compound 11).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[CH2:17]([C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:4][CH:5]=2)[C:12](=[O:25])[CH:13]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1cc(CCc2ccccc2)ccn1CCc1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: O=c1cc(CCc2ccccc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 85 mg (0.21 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-phenethyl-1H-pyridin-2-one (example 18.1b) in 1.0 mL DMF is added 36 μL (0.43 mmol) pyrrolidine at RT. The reaction mixture is stirred overnight at RT, filtered and directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[CH2:29](C([SnH3])=C(CCCC)CCCC)[CH2:30]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[N:7]1[C:8]2[C:3](=[C:2]([CH:29]=[CH2:30])[C:11]([F:12])=[C:10]([F:13])[C:9]=2[F:14])[C:4](=[O:28])[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:6]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)c(Br)c2c1=O
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2-c1ccc(F)cc1F
Yield: 66.3 %

Procedure:
4.6 g of ethyl 5-bromo-1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 4.5 g of tributylvinylstannane and 0.46 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 10 hours in 40 ml of absolute toluene under a nitrogen atmosphere. The product is filtered off with suction at room temperature, washed with water and dried. 2.7 g of the title compound are obtained (66% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)=[O:22]
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Product: COc1ccc(Cl)cc1C(=O)Nc1ccc(CCC(=O)O)cc1

Procedure:
By the reaction of ethyl β-(4-aminophenyl)-propionate hydrocholoride with 5-chloro-2-methoxybenzoyl chloride, there is obtained β-[4-(5-chloro-2-methoxybenzamido)-phenyl]-propionic acid; m.p. 188°-190° C., after recrystallization from ethanol.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].O=P(Cl)(Cl)Cl.CN([CH:22]=[O:23])C>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:22]=[O:23])=[CH:4]1)[CH3:2]
Reactant: CCn1ccc2ccc(OC)cc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1cc(C=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
1-Ethyl-6-methoxy-1H-indole (900 mg, 5.14 mmol) was dissolved in DMF (1.5 mL). This was added dropwise to an ice-cold solution of POCl3 (500 μL, 5.2 mmol) in DMF (1.75 ml). After stirring at room temperature for 90 minutes, the reaction mixture was re-cooled in an ice bath and was slowly quenched with 6N NaOH (4 mL). The reaction mixture was partitioned between EtOAc and H2O. Purification by silica gel chromatography (EtOAc/CH2Cl2, 5/95) yielded 1-ethyl-6-methoxy-1H-indole-3-carbaldehyde (849 mg, 81%) as a yellow solid.
Reaction SMILES: [CH:1]12[NH:16][CH:5]([CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]1)[CH2:4][O:3][CH2:2]2.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH:5]12[N:16]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH:1]([CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.500 g, 2.2 mmol) in dichloromethane (5 ml) was added triethylamine (0.443 g, 4.4 mmol) at room temperature. The mixture was stirred at room temperature for a few mins, and then benzyl chloroformate (0.751 g, 4.4 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between dichloromethane and water. The organic phase was dried, and concentrated. The residue was purified by silica gel chromatography to give 9-benzyl 7-tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7,9-dicarboxylate 133b (0.637 g, 80.0%). MS: calc'd (MH+) 363, measured (MH+) 363.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:24]Br.O>C(O)(=O)C>[Br:24][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)CBr)cc2)cc1
Temperature: 50 °C

Procedure:
To a solution of 30.9 g of 4-acetyl-4'-octylbiphenyl in 50 ml of acetic acid there are added 5.1 ml of bromine for one hour under stirring at the temperature of 50° C. The reaction mass is stirred for 1 hour at room temperature, poured into water, the organic layer is extracted with chloroform, the extract is washed with a 5% aqueous solution of soda, then with water and dried with sodium sulphate. Chloroform is distilled-off in vacuum and the residue is recrystallized from a minimum amount of ethanol to give 38 g of 4-bromoacetyl-4'-octylbiphenyl; from 19.6 g of the product and 16.5 g of benzaldehydeguanylhydrazone there is obtained, following the procedure of Example 1, 0.65 g of 1,1'-bisbenzylideneamino-4,4'-di-[4-(4-octylphenylene)-phenylene]-2,2'-azoimidazole (II /3/). The analysis data are shown in Table 1 hereinbelow.