Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42].O>CN(C)C=O>[CH:44]1([NH:43][C:41](=[O:42])[CH2:40][O:22][C:18]2[CH:17]=[C:16]([S:13]([N:12]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[CH:9][C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:11]3)(=[O:14])=[O:15])[CH:21]=[CH:20][CH:19]=2)[CH2:46][CH2:45]1
Reactant: O=C(CBr)NC1CC1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (100 mg, 0.22 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of cesium carbonate (215 mg, 0.66 mmol) and 2-bromo-N-cyclopropyl-acetamide (61 mg, 0.34 mmol, prepared by a known method disclosed in “Journal of Medicinal Chemistry, 1987, 30(1), 20-24”) and then the reaction solution was stirred for 16 h. 50 mL of water were added, and the reaction solution was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product tert-butyl ((1-((3-(2-(cyclopropylamino)-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 3a (100 mg, a yellow oil), which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O>>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(Cl)cc4Cl)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2,4-dichlorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(2′,4′-dichloro-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (4 mg, 3%): m/z (ES+) 434 [MH+].
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]([C:14]1[N:18]2[CH:19]=[CH:20][C:21]3[C:26]([C:17]2=[C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15]=1/[CH:33]=[CH:34]/[C:35](OCC)=[O:36])=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.O1CCCC1>[CH:11]([C:14]1[N:18]2[CH:19]=[CH:20][C:21]3[C:26]([C:17]2=[C:16]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:15]=1[CH2:33]/[CH:34]=[CH:35]/[OH:36])=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH3:13])[CH3:12]
Reactant: CCOC(=O)/C=C/c1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1c(C/C=C/O)c(-c2ccccc2)c2c3ccccc3ccn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisobutyl aluminium hydride in toluene (1.5M; 16.8 ml) was added dropwise to a stirred solution of ethyl (E)-3-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)propenoate (2.4 g) in dry tetrahydrofuran (50 ml) at 0° C. under an atmosphere of argon. The mixture was stirred at 0° C. for 30 minutes and then the reaction mixture was quenched by the dropwise addition of saturated aqueous sodium sulphate solution (50 ml) at 0° C. The resulting gel was then allowed to warm to 20° C. and it was then treated with sufficient aqueous hydrochloric acid (2N) to dissolve the gel. The organic phase was separated and the aqueous phase was extracted with diethyl ether (50 ml). The organic solutions were combined, washed with brine, dried over magnesium sulphate and evaporated, to give (E)-3-(3-isopropyl1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)propen-1-ol in the form of an orange oil (2.14 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C([N:21](CC)CC)C.NC[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:21][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CCN(CC)CC
Reactant: NCCN1CCOCC1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2cc(NCN3CCOCC3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 4-(2-aminoethyl)morpholine (15 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture can be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].IC.[C:14]([O-])(=O)C.[Na+]>C1COCC1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][CH3:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: CC(=O)[O-]
Reactant: COc1cc(N)cc(OC)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CNc1cc(OC)cc(OC)c1
Yield: 29.9 %

Procedure:
A solution of 3,5-dimethoxyaniline (13.8 g, 90 mmol), Iodomethane (12.7 g, 90 mmol), and sodium acetate (7.4 g, 90 mmol) in 100 ml of anhydrous THF was stirred under nitrogen atmosphere for 10 hr. Then, THF was removed by rotary evaporation. The crude product was partitioned between water and ethyl ether. The ethereal extraction was separated and washed with water, brine, and dried over Na2SO4. Filtration and removal of solvent provided 13.6 g of crude product. The crude product was chromatographed on silica gel (33% acetone-petroleum ether) to afford the expected product 4.5 g (27% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH3:7].[CH2:8]([O:10][C:11](=[O:32])[N:12]([C:21]1[CH:26]=[C:25](Br)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:9]>>[CH2:8]([O:10][C:11](=[O:32])[N:12]([C:21]1[CH:26]=[C:25]([C:4]2[O:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=2)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:9]
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: Cc1ncoc1C
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nc(C)c(C)o2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4,5-dimethyl-oxazole (47 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (75 mg) as a yellow gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])C(OC)=O.[CH3:13][Mg]Br.C([O:19][CH2:20][CH3:21])(=O)C>C1COCC1.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([C:20]([OH:19])([CH3:21])[CH3:13])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: CCOC(C)=O
Reactant: C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)O)cc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask, Methyl 3-bromo-4-methylbenzoate (25 g, 109 mmol) was added under nitrogen, dissolved in THF (110 mL), and cooled to −78° C. 3M methylmagnesium bromide (85 ml, 251 mmol) was added slowly to the cooled solution and allowed to stir for 30 minutes. The reaction was warmed to room temperature for 30 minutes until complete conversion over starting material. The solution was diluted with ethyl acetate and sodium bicarbonate. Extracted (3×) with ethyl acetate, and washed the combined organic layers with brine, dried over sodium sulfate, filtered, and concentrated to afford the desired 2-(3-bromo-4-methylphenyl)propan-2-ol (3-1). MS (M+H)+: observed=211.0/213.0, calculated=211.1/213.1.
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)CN([C@H]1CCCN([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)C2C=C(C(F)(F)F)C(C)=CC1=2)C1N=NN(C)N=1.[Cl:43][C:44]1[CH:45]=[C:46]([CH:72]=[C:73]([C:75]([F:78])([F:77])[F:76])[CH:74]=1)[CH2:47][N:48]([C@H:55]1[CH2:61][CH2:60][CH2:59][NH:58][C:57]2[C:62]([CH3:71])=[C:63]([C:67]([F:70])([F:69])[F:68])[C:64]([CH3:66])=[CH:65][C:56]1=2)[C:49]1[N:50]=[N:51][N:52]([CH3:54])[N:53]=1.N1C=CC(C=O)=CC=1>ClC(Cl)C>[Cl:43][C:44]1[CH:45]=[C:46]([CH:72]=[C:73]([C:75]([F:78])([F:76])[F:77])[CH:74]=1)[CH2:47][N:48]([C@H:55]1[CH2:61][CH2:60][CH2:59][N:58]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:57]2[C:62]([CH3:71])=[C:63]([C:67]([F:68])([F:69])[F:70])[C:64]([CH3:66])=[CH:65][C:56]1=2)[C:49]1[N:50]=[N:51][N:52]([CH3:54])[N:53]=1
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccncc1)CCC[C@@H]2N(Cc1cc(F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: O=Cc1ccncc1
Solvent: CC(Cl)Cl
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(Cc1ccncc1)CCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1

Procedure:
Prepare the title compound by essentially following the procedure described in the synthesis of (S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 186, Step 2) by using (S)-(3-chloro-5-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.08 g, 0.15 mmol) and pyridine-4-carboxaldehyde (0.045 mL, 0.45 mmol) in dichloroethane (2 mL) at room temperature for 15 h to afford the title compound. Purification by silica gel column (gradient eluent, 0-5% MeOH in ethyl acetate) provides the title compound (0.09 g, 91%). MS (ES+): 624 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[C:13]1([CH:12]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClC(Cl)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Brc1ccc(OC(Oc2ccc(Br)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Inside a nitrogen purged glove box, to a solution of 4-bromophenol (12.0 grams, 69.4 millimoles, 2.5 equivalents) dissolved in anhydrous 1-methyl-2-pyrrolidinone (100 milliliters), was added 95% sodium hydride (1.82 grams, 72.1 millimoles, 2.6 equivalents) in small portions over a 30 minute period. The reaction was stirred for an additional 90 minutes at room temperature. α,α-Dichlorotoluene (4.13 milliliters, 27.7 millimoles, 1.0 equivalent) was added and the reaction was heated to 70° C. overnight. The reaction was quenched by addition to water (200 milliliters). The aqueous phase was extracted with a 1:1 mixture of diethyl ether and ethyl acetate (3×120 milliliters). The combined organic phases were then washed with de-ionized water (5×100 milliliters), brine (1×100 milliliters) and dried over magnesium sulfate. After filtration and concentration on the rotary evaporator, the residue was taken up in diethyl ether (60 milliliters) and filtered through a plug of basic alumina. The product was fully eluted with additional diethyl ether (700 milliliters) and concentrated on the rotary evaporator. Further drying under high vacuum for several days yielded the product quantitatively in form of a yellow oil that crystallizes over time to give an off-white solid (12.0 grams, 27.7 millimoles, 100%). m.p.: 50.8° C.; 1H-NMR (400 MHz, CDCl3) δ 7.59-7.51 (m, 2H), 7.44-7.37 (m, 3H), 7.37-7.29 (m, 4H), 6.93-6.82 (m, 4H), 6.59 (s, 1H); 13C-NMR (101 MHz, CDCl3) δ 155.07, 136.58, 132.59, 129.65, 128.86, 126.78, 119.60, 115.42, 100.77; FTIR: 605, 658, 674, 694, 741, 792, 816, 848, 886, 928, 984, 1031, 1060, 1100, 1115, 1167, 1178, 1210, 1242, 1280, 1304, 1363, 1449, 1483, 1584, 1689, 3033, 3065 cm−1; UV/Vis 223 (shoulder), 237, 278 nm; GC/MS/EI+: 432, 434, 436 [M+] (2×Br isotope pattern); 261, 263 [Br—C6H4—O—CHPh]+ (1×Br isotope pattern); 182 [C6H4—O—CHPh]•+ HRMS (EST): calc. for C19H13Br2O2 [M+Na]+ 430.9288. found 430.9287.
Reaction SMILES: [CH2:1]([SH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=1>O1CCCC1>[C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:11]=1)#[N:17]
Reactant: CCCCCS
Reactant: N#Cc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCSc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Pentyl mercaptan (0.83 g, 7.9 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.35 g, 8.7 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (1.00 g, 7.2 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (1.48 g, ca. 100%) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[CH:12]=1.[I:13]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[I:13][C:12]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[CH2:3][O:2][CH3:1]
Reactant: COCc1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
[step 3] To 2-(methoxymethyl)imidazo[1,2-a]pyridine (1.8 g, 11 mmol) obtained in step 2 were added DMF (22 mL) and N-iodosuccinimide (2.75 g, 12 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction was discontinued with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate and the extract was dried over sodium sulfate. Filtration, concentration under reduced pressure and purification by silica gel column chromatography (chloroform/methanol=10/1 v/v) gave 3-iodo-2-(methoxymethyl)imidazo[1,2-a]pyridine (3.1 g, 99%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:18])[CH:8]=1>ClCCl>[ClH:3].[Cl:3][CH2:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:18])[CH:8]=1
Reactant: Cn1cc(CO)c(=O)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: Cn1cc(CCl)c(=O)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of thionyl chloride (9.48 g.) in dichloromethane (800 ml.) was added during 4 hours to a refluxing suspension of finely ground 3-hydroxymethyl-1-methyl-4-quinolone (15.01 g.) in dichloromethane (200 ml.). The mixture was boiled under reflux for a further 1.5 hours, cooled to room temperature and filtered to give the novel compound 3-chloromethyl-1-methyl-4-quinolone hydrochloride m.p. 178°-181°. This compound (12.71 g.) was added to a stirred solution of sodium methanethiolate in methanol at 0° (116 ml. containing 0.109 mole NaSCH3) during 5 minutes. The resulting mixture was allowed to warm to room temperature and kept overnight. The mixture was cooled to 0° and water added to form a solution. The solution was neutralised to pH 7.0 with dilute hydrochloric acid and filtered. Methanol was distilled from the filtrate and the residue extracted with dichloromethane (3×50 ml.). The combined extracts were dried over anhydrous magnesium sulphate and evaporated to give a solid product. The product was purified by high pressure liquid chromatography over silica gel, eluting with isopropanol:dichloromethane 15:85 at a flow rate of 300 ml. per minute. The same solvent was used for applying the product to the silica gel. This procedure gave the novel 1-methyl-3-methylthiomethyl-4-quinolone m.p. 118°-120°.
Reaction SMILES: N=C=N.[C:4]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14]C(O)=O)=[O:10])([CH3:7])([CH3:6])[CH3:5].C1C=CC2N([OH:27])N=NC=2C=1.C([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH2:37][CH2:36]1)C1C=CC=CC=1.C(O)C(N)(CO)CO>ClCCl>[C:4]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH2:37][CH2:36]1)=[O:27])=[O:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: COC(=O)CCCN1CCN(Cc2ccccc2)CC1
Reactant: On1nnc2ccccc21
Agent: N=C=N
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: COC(=O)CCCN1CCN(C(=O)CCNC(=O)OC(C)(C)C)CC1
Reaction time: 24 h
Yield: 81.1 %

Procedure:
To a suspension of PS-carbodiimide (1.7 g, 1.5 mmoles) in dichloromethane (2 mL) was added 4-(tert-butoxycarbonylamino)butyric acid (305 mg, 1.5 mmoles) and HOBT (230 mg, 1.7 mmoles). After 20 min 186 mg of methyl 4-(4-benzylpiperazin-1-yl)butanoate (186 mg, 1.0 mmol) was added to the reaction mixture and stirred 24 h. PS-trisamine (1.08 g, 5 eq.) was added and stirred 16 h. The reaction mixture was filtered and evaporated to afford methyl 4-{4-[N-(tert-butoxycarbonyl)-beta-alanyl]piperazin-1-yl}butanoate (290 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[N:10](CCCCCCN=C=O)=[C:11]=[O:12]>C(Cl)(Cl)Cl>[CH2:7]=[CH:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1.[C:5]1([CH3:6])[CH:8]=[CH:9][C:2]([NH:1][C:11]([NH2:10])=[O:12])=[CH:3][CH:4]=1
Reactant: C=Cc1ccc(N)cc1
Reactant: O=C=NCCCCCCN=C=O
Solvent: ClC(Cl)Cl
Product: C=Cc1ccccc1
Product: Cc1ccc(NC(N)=O)cc1

Procedure:
1,6-Hexyl Urea Styrene Dimer: 1.00 g (8.40 mmol) of p-aminostyrene (99% Tokyo Kasei) was added to a 250 ml round bottom flask containing 100 ml of chloroform. After ten minutes of mixing, 0.706 g (4.20 mmol) of 1,6-diisocyanato hexane (98% Aldrich) was added dropwise. After twenty minutes, a white, pinkish precipitate formed. The precipitate was filtered to remove the reaction liquid, then washed with 20 ml of chloroform resulting in a pale white powder (0.87 g, 51% crude yield, mp=228° C.).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:19]([CH2:21][C:22]([NH2:24])=[O:23])#[N:20]>O.CCO>[NH2:24][C:22](=[O:23])/[C:21](/[C:19]#[N:20])=[N:10]/[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Br:1]
Reactant: N#CCC(N)=O
Reactant: Nc1ccccc1Br
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#C/C(=N\Nc1ccccc1Br)C(N)=O
Yield: 50 %

Procedure:
To a stirred vessel containing 2-bromoaniline (10.3 g, 59.9 mmol) was added concentrated hydrochloric acid (15 mL) dropwise while maintaining the mixture temperature <5° C. To the cold suspension was added dropwise a solution of sodium nitrite (4.13 g, 59.9 mmol) in water (12.5 mL). The mixture was stirred and cooled for 15 minutes. A solution of sodium acetate (14.74 g, 180.0 mmol) in water (60 mL) was added dropwise to the reaction mixture. The resulting diazonium salt solution (cloudy yellow suspension) was set aside. While the diazonium salt solution was stirred and cooled, a solution of sodium acetate (4.91 g, 59.9 mmol) in water (17.5 mL) was added to a solution of 2-cyanoacetamide (5.03 g, 59.9 mmol) in water (85 mL) and EtOH (60 mL). The mixture was cooled to a temperature <10° C. at which point the diazonium salt solution was added portion-wise and with vigorous stirring over a span of 25 minutes while maintaining the reaction temperature <10° C. Upon completion of the addition, a thick reddish yellow precipitate formed, which was stirred overnight at room temperature. The solid product was collected by vacuum filtration, washed with water (500 mL), EtOH (500 mL), and Et2O (500 mL), and then dried in a vacuum to afford the title compound as a yellow solid (8.0 g, 53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.06-7.13 (m, 1H), 7.43 (t, J=7.71 Hz, 1H), 7.57-7.72 (m, 2H), 7.92-8.02 (m, 2H), 10.03 (s, 1H).
Reaction SMILES: [CH:1]([O:3][CH:4]1[CH2:9][C:8]([CH3:12])([CH2:10]C)[NH:7][C:6]([CH3:15])([CH2:13]C)[CH:5]1C)=[CH2:2].C(O[CH:20]1[CH2:25][C:24](C)(C)N(CC=C)[C:22]([CH3:32])([CH3:31])[CH2:21]1)=C.C(OC1CC(C)(C)N(CCCC)C(C)(C)C1)=C.C(OC1CC(C)(C)NC(C)(C)C1)=C>>[CH:1]([O:3][CH:4]1[CH2:5][C:6]([CH3:13])([CH3:15])[N:7]([CH2:32][C:22]2[CH:21]=[CH:20][CH:25]=[CH:24][CH:31]=2)[C:8]([CH3:10])([CH3:12])[CH2:9]1)=[CH2:2]
Reactant: C=CCN1C(C)(C)CC(OC=C)CC1(C)C
Reactant: C=COC1CC(C)(CC)NC(C)(CC)C1C
Agent: C=COC1CC(C)(C)N(CCCC)C(C)(C)C1
Agent: C=COC1CC(C)(C)NC(C)(C)C1
Product: C=COC1CC(C)(C)N(Cc2ccccc2)C(C)(C)C1

Procedure:
The following compounds were obtained in a similar manner: 2,3,6-trimethyl-2,6-diethyl-4-piperidyl vinyl ether, boiling point 121°/18 mm Hg; 1-allyl-2,2,6,6-tetramethyl-4-piperidyl vinyl ether, boiling point 63°/0.1 mm Hg; 1-butyl-2,2,6,6-tetramethyl-4-piperidyl vinyl ether, boiling point 66°-67°/0.1 mm Hg and 2,2,6,6-tetramethyl-4-piperidyl vinyl ether, boiling point 78°/19 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:14])[CH:3]=1.[OH:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][C:39]=1[N+:48]([O-])=O>>[NH2:48][C:39]1[CH:40]=[C:41]([S:44]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH2:30][CH3:31])([CH3:28])[CH3:29])=[CH:23][C:22]=3[C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:14])[CH:3]=2)(=[O:46])=[O:45])[CH:42]=[CH:43][C:38]=1[OH:37]
Reactant: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1O
Product: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(NS(=O)(=O)c3ccc(O)c(N)c3)c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
This compound was prepared in two steps by conventional procedures of the type well known in the art. 4-Amino-1-hydroxy-N-[4-(2,4-di-tert-pentylphenoxy)butyl]-2-naphthamide (U.S. Pat. No. 3,954,476, column 25) was converted to the sulfonamide by reaction with 4-hydroxy-3-nitrobenzenesulfonyl chloride. Secondly, the nitro group was reduced to the amino compound by catalytic hydrogenation.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:30][N:31]([CH3:39])[CH:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1>CN(C)C=O>[Cl-:1].[CH3:30][N+:31]([CH3:39])([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)[CH:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: CN(C)C1CCC(=O)CC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+](C)(C)C4CCC(=O)CC4)cc2)CCO3)cc1
Product: [Cl-]
Reaction time: 14 h
Yield: 105.6 %

Procedure:
To a solution of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (214 mg, 0.530 mmol) in N,N-dimethylformamide (1 ml) was dropwise added a solution of 4-dimethylaminocyclohexanone (112 mg, 0.795 mmol) in N,N-dimethylformamide (1 ml). Under nitrogen atmosphere, the mixture was stirred for 14 hours. The solvent was evaporated to give crude product, which was washed with ether to give N,N-dimethyl-N-(4-(((7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl)carbonyl)-amino)benzyl)-N-(4-oxocyclohexyl)ammonium chloride (Compound 249) (305 mg) as colorless powder.