Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]2[CH3:31])[C:18]([CH3:32])=[C:17]([CH3:33])[N:16]=1>CN(C)C=O>[ClH:14].[CH3:32][C:18]1[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]2[CH3:31])=[N:20][C:15]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:16][C:17]=1[CH3:33]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NC2CCCC2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 84.8 %

Procedure:
After cyclopentylamine(0.26 ml, 2.61 mmol) and triethylamine(0.36 ml, 2.59 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.5 g, 1.74 mmol) in dimethylformamide, 550 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9](C(O)=O)=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[S:11][C:5]=2[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]1=[O:30].C([N:33](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.ClCCl.CCCC(C)C>C(O)(C)(C)C>[NH2:33][C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:30])[N:4]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:5]=2[S:11][C:10]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:20])([F:21])[F:22]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCCC(C)C
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(N)c(Cc3ccccc3C(F)(F)F)sc21
Reaction time: 36 h

Procedure:
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid made by the method of Example 8a) (3.316 g), triethylamine (1.38 ml) and diphenylphosphoryl azide (2.26 ml) were heated at 90° C. under an atmosphere of nitrogen in tert-butanol for 18 hrs. The reaction was concentrated in vacuo and the residue redissolved in dichloromethane (50 ml) and trifluoroacetic acid (30 ml). The mixture was allowed to stir for 36 hrs before being concentrated in vacuo, and residual acid was removed by azeotroping with toluene. The residue was partitioned between half saturated sodium hydrogen carbonate and dichloromethane. The organics were collected, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography, eluting with 2:1 isohexane:diethyl ether to yield a highly crystalline solid which was recystallised from dichloromethane/isohexane to yield the subtitle compound (1.553 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:17]([Mg]Br)[CH:18]=[CH2:19]>C1COCC1>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH:13]([OH:14])[CH2:19][CH:18]=[CH2:17])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CC[Mg]Br
Reactant: CCCCCCCCc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(CCCCCCCC)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
4-octylbenzaldehyde (10.0 g, 45.8 mmol) (Aldrich) was dissolved in THF (229 ml) under nitrogen. The reaction was cooled to about 0-5° C. in an ice bath. A solution of allylmagnesium bromide (48.1 ml, 48.1 mmol) (Aldrich) was added slowly and the reaction stirred for about 2 h. The reaction was quenched by the addition of saturated ammonium chloride followed by addition of ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to an off-white oil. The residue was dissolved in ether and dried over sodium sulfate and filtered. The solvents were removed under reduced pressure to provide 1-(4-octylphenyl)but-3-en-1-ol (11.54 g, 44.3 mmol, 97% yield) as a light yellow oil: LC/MS (method f) Rt=2.90 min.; MS m/z: 243.21 (M-water)+.
Reaction SMILES: C(C1C=C(/[C:10](/[CH:37]=[CH:38]/[CH:39]=[C:40]2\[C:41]([CH3:59])([CH3:58])[C:42]3[C:43](=[N:57]\2)[N:44]([CH2:49][CH2:50][CH2:51][CH2:52][S:53]([O-:56])(=[O:55])=[O:54])[CH:45]=[C:46]([Cl:48])[CH:47]=3)=[CH:11]\[CH:12]=[CH:13]\[C:14]2[C:22]([CH3:24])([CH3:23])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([S:25]([O-:28])(=[O:27])=[O:26])[CH:20]=3)[N+:15]=2[CH2:29][CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34])C=CC=1)(O)=O.[Na+:60].[Na+].B([C:65]1[CH:66]=[C:67]([CH2:71][CH2:72][CH2:73][C:74]([OH:76])=[O:75])[CH:68]=[CH:69][CH:70]=1)(O)O>>[C:74]([CH2:73][CH2:72][CH2:71][C:67]1[CH:66]=[C:65](/[C:10](/[CH:37]=[CH:38]/[CH:39]=[C:40]2\[C:41]([CH3:59])([CH3:58])[C:42]3[C:43](=[N:57]\2)[N:44]([CH2:49][CH2:50][CH2:51][CH2:52][S:53]([O-:56])(=[O:55])=[O:54])[CH:45]=[C:46]([Cl:48])[CH:47]=3)=[CH:11]\[CH:12]=[CH:13]\[C:14]2[C:22]([CH3:24])([CH3:23])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([S:25]([O-:28])(=[O:26])=[O:27])[CH:20]=3)[N+:15]=2[CH2:29][CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:34])=[O:35])[CH:70]=[CH:69][CH:68]=1)([OH:76])=[O:75].[Na+:60].[Na+:60]
Reactant: O=C(O)CCCc1cccc(B(O)O)c1
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C/C(=C/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C)c1cccc(C(=O)O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C/C(=C/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C)c1cccc(CCCC(=O)O)c1

Procedure:
Compound 44 is prepared analogously to compound 43, except with 4-(3-boronophenyl)butanoic acid as a starting material.
Reaction SMILES: [P:1]([CH2:5][NH:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([OH:4])([OH:3])=[O:2].[OH-].[Na+].[CH3:15][CH:16]1[CH2:21][C:20](=[O:22])[O:19][C:17]1=[O:18]>O>[C:8]([CH2:7][N:6]([CH2:5][P:1]([OH:4])([OH:3])=[O:2])[C:20](=[O:22])[CH2:21][CH:16]([CH3:15])[C:17]([OH:19])=[O:18])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CNCP(=O)(O)O
Reactant: CC1CC(=O)OC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CN(CP(=O)(O)O)C(=O)CC(C)C(=O)O

Procedure:
A suitable reaction vessel is charged with 3.94 grams (0.02 mole) of ethyl N-phosphonomethylglycinate in 15 ml. of water. While cooling below about 15° C. in an icebath, 50% aqueous sodium hydroxide is added to obtain a pH of about 8. There is then added 2.51 grams (0.022 mole) of methylsuccinic anhydride with stirring and continued cooling. Two further 1.0 gram portions of anhydride are added to complete the reaction, the pH being maintained with additional alkali. The reaction mixture is diluted with water and passed through a column of ion exchange resin in the acid form. The first seven 20 ml. cuts are combined in 20 ml. of water, and a further 1.2 gram portion of anhydride is added. The resultant reaction mixture is passed through the column, and the first four 20 ml. cuts are combined and dried. The product is cooled in dry ice to yield N-carbethoxymethyl-N-(phosphonomethyl)-2-methylsuccinamic acid (in the monohydrate form) as a clear glass-gum. Elemental analysis gives 4.01% nitrogen and 9.13% phosphorus as against calculated values of 4.25% and 9.40% for C10H18NO8P.H2O. ##STR18##
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[CH3:15][NH:16][CH3:17]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:16]([CH3:17])[CH3:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Solvent: CCO
Product: CC(=O)c1ccc(N(C)C)c(S(N)(=O)=O)c1

Procedure:
A mixture of 5-acetyl-2-chloro-benzenesulphonamide (0.5 g) in ethanol (10 ml) and dimethylamine in ethanol (33%, 5 ml) was heated in a closed vessel on a steam bath for 16 hours. The solvents were removed under reduced pressure and the residue crystallised from ethanol to give the product 0.31 g, m.p. 184°-185°.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[H-].[Na+].[CH2:11](Br)[CH:12]=[CH2:13]>C1COCC1>[CH2:13]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: CCOC(=O)[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(C)C(=O)OCC
Yield: 100.2 %

Procedure:
23.6 g (0.2 mol) of ethyl (S)-(−)-lactate, dissolved in 100 ml of THF, are added to a suspension of 8.0 g (0.2 mol) of NaH in 150 ml THF. When the addition is complete, 36.3 g (0.3 mol) of allyl bromide, dissolved in 10 ml of THF, are added dropwise. Some KI is then added and the mixture is refluxed for 16 h. The mixture is then cooled and the reaction is quenched with 100 ml of 2N HCl. The aqueous phase is extracted twice more with Et2O before the combined organic phases are dried over Na2SO4. The mixture is then filtered and the filtrate is evaporated to dryness on a rotary evaporator, giving 31.7 g of crude product (GC purity 89.0%), which is used in the next reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[S-:11][C:12]#[N:13].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([F:23])[CH:22]=1)[NH2:19]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:13][C:12](=[S:11])[NH:19][C:18]1[CH:20]=[C:21]([F:23])[CH:22]=[C:16]([Cl:15])[CH:17]=1)=[O:6]
Reactant: Nc1cc(F)cc(Cl)c1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: [K+]
Solvent: CC#N
Product: O=C(NC(=S)Nc1cc(F)cc(Cl)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
3-Chlorobenzoyl chloride (200 g, 1.14 mol) was dissolved in acetonitrile (4.5 L) and the reaction vessel containing this mixture was cooled in an ice/water bath. Potassium thiocyanate (122 g, 1.26 mol, 1.10 equiv) was added to the reaction mixture. The cooling bath was removed from the reaction vessel after 15 minutes and the resulting slurry was stirred at room temperature for approximately 1 hour. Next, 3-chloro-5-fluoroaniline (138 mL, 1.37 mol, 1.2 equiv) was added as a solution in acetonitrile (138 mL) over 5 minutes. The reaction mixture was then stirred at room temperature overnight and subsequently quenched with water (4.30 L), and then stirred at room temperature for 1 hour. The resulting solid was collected by filtration and rinsed with acetonitrile/water (1/1 mixture by volume, 780 mL). The solid was dried at 60° C. in vacuo to provide 390 g (99% yield) of the title compound as a solid. 1H NMR (DMSO-d6) δ 12.5 (s, 1H), 11.9 (s, 1H), 8.01 (t, 1H, J=1.8), 7.89 (d, 1H, J=7.8), 7.69 (m, 3H), 7.56 (t, 1H, J=7.8), 7.34 (dt, 1H, J=8.7, 1.8). HPLC: >99% purity at 23.73 min.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15][CH2:16]CC.ICC>>[CH2:15]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:16]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Solvent: CCI
Product: CCC1c2ccccc2-c2ccccc21
Yield: 97.5 %

Procedure:
Fluorene (5.0 g, 30.1 mmol), n-BuLi (16 ml, 40 mmol, 2.5 M in hexane), RX=iodoethane (7.04 g, 45.1 mmol). 41 was isolated as yellow oil (5.7 g, 97%). Analytical data were identical to those in the literature (K. D. Bartle, P. M. G. Bavin, D. W. Jones, R. L'Amie, Tetrahedron 1970, 26, 911).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC=C(C(C)(C)C)C=3)=CC=2)CC1)=O)(C)(C)C>>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29](=[O:30])[NH:5][C:4]3[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([I:1])[CH:3]=3)=[CH:27][CH:28]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1ccc(N)cc1I
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1I

Procedure:
4-[4-(3-Iodo-4-methyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from 3-iodo-4-methyl aniline and 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of 4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, above. The product was isolated after a silica gel purification with 10-30% Et2O in toluene. HRMS m/z calcd for C23H28N3O3I [M+H]: 522.1248. Found: 522.1246.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:16](O)([CH3:19])([CH3:18])[CH3:17]>FC(F)(F)C(O)=O>[C:16]([C:5]1[NH:6][C:7]2[C:12](=[CH:11][C:10]([C:4]([CH3:12])([CH3:5])[CH3:3])=[CH:9][C:8]=2[C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=1[CH2:3][C@@H:2]([C:13]([OH:15])=[O:14])[NH2:1])([CH3:19])([CH3:18])[CH3:17]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(C(C)(C)C)c2[nH]c(C(C)(C)C)c(C[C@H](N)C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85 %

Procedure:
Tryptophan (4.00 g, 19.59 mmol), trifluoroacetic acid 98% (60 ml) and tert-butanol (15.54 g, 209.66 mmol) were mixed. The reaction mixture was stirred at room temperature for 48 hours. The trifluoroacetic acid was evaporated. The residue was suspended in 40 ml distilled water, and the pH adjusted to neutral with addition of sodium hydrogen carbonate. The crude product was obtained by filtration. Crystallisation from 50% ethanol afforded the product as a white powder (85-90% pure).
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:8][C:7]=1[C:21]([O:23]C)=O)=O.CC1C=CC(C#N)=CC=1.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH:42][C:21]([C:7]2[N:8]=[C:9]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[N:10]([CH3:13])[C:11](=[O:12])[C:6]=2[OH:5])=[O:23])=[CH:39][CH:38]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(-c2ccc(C)cc2)n(C)c(=O)c1OC(=O)C(C)(C)C
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: Cc1ccc(C#N)cc1
Product: Cc1ccc(-c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (prepared from 4-methylbenzonitrile by procedures similar to those set forth in Examples 2 or 3) in DMF 3 equivalents of 4-fluorobenzylamine were added and mixture was stirred at 90° C. for 2 h. The title product precipitated from the cooled reaction mixture after the addition of 2 N HCl, and was collected by filtration and washed with diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.I[CH2:20][CH2:21][CH2:22][CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:6]=[C:5]2[S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1
Reactant: CN1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1
Reactant: CCCCI
Product: CCCCn1cc(SC2CCN(C)CC2)c2cc(Br)ccc21

Procedure:
Prepared as described in Example 56 by reaction of 5-bromo-3[(1-methylpiperidin-4-yl)thio]-1H-indole (prepared in Example 44) with iodobutane.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]I.C([O:14][C:15](=[O:36])[C:16]([S:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][CH2:26][NH:27][C:28]2[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=2)[N:24]=1)([CH3:18])[CH3:17])(C)(C)C.CC(C)CCCCCO.[BrH:46].C(O)(=O)C>C(OCC)C>[BrH:46].[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:27]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:9])[CH3:1])[CH2:26][CH2:25][C:23]2[N:24]=[C:20]([S:19][C:16]([CH3:17])([CH3:18])[C:15]([OH:36])=[O:14])[S:21][CH:22]=2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CC(C)CCCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: Br
Agent: CC(C)CCCCCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1cnc(N(CCCCCC(C)C)CCc2csc(SC(C)(C)C(=O)O)n2)nc1

Procedure:
A compound obtained using 6-methyl-1-iodoheptane, which is synthesized using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 6-methylheptanol as starting materials and in reference to non-patent reference [Tetrahedron, 38, 11461 (1998)], and by an operation similar to that of Example 326, was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.Cl.[CH:34]1[C:39]2[CH2:40][CH2:41][N:42]([CH:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[C:43](=[O:45])[O:44][C:38]=2[CH:37]=[CH:36][CH:35]=1>>[CH:34]1[C:39]2[CH2:40][CH2:41][N:42]([CH:46]3[CH2:51][CH2:50][N:49]([CH2:1][C@@H:3]4[C@@H:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH2:6][N:5]([C@H:14]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=5)=[O:16])[CH2:4]4)[CH2:48][CH2:47]3)[C:43](=[O:45])[O:44][C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: O=C1Oc2ccccc2CCN1C1CCNCC1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(N4CCc5ccccc5OC4=O)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 76 %

Procedure:
The title compound (36 mg) was prepared by reductive amination of 31 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)- cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) with 22 mg of 4-(8,9-dihydro-7H-5-oxa-7-aza-benzocyclo-hepten-6-one-7-yl)-piperidine hydrochloride according to the procedure of Example 1, step D. 1H NMR (500MHz, CDCl3): δ0.9-1.3 (m, 5H), 1.5-2.0 (m, 12H), 2.25-3.3 (m, 13H), 3.63 (m, 2H), 3.82 (s, 3H), 3.96 (m, 1H), 5.13 (ABq, 2H), 6.9-7.4 (m, 13H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[CH:29]=2)=[CH:22][N:21]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[CH:29]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Reactant: CCCCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCn1ccc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)cc1=O

Procedure:
2-[4-(Dimethylaminomethyl)pyrid-2-ylmethylthio]ethylamine (0.90 g) and 2-nitroamino-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (1.12 g) were refluxed in ethanol (15 ml) for 72 hours. As the reaction had not gone to completion, the ethanol was replaced by pyridine (15 ml) and the mixture was refluxed for a further 6 hours.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[C:6]([C:8]1([CH3:32])[CH2:14][C:13]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:12]=2[C:11]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([CH3:31])[CH:23]=2)=[N:10][NH:9]1)#[N:7]>>[C:6]([C:8]1([CH3:32])[CH2:14][C:13]2[CH:15]=[C:16]3[O:21][CH2:20][O:19][C:17]3=[CH:18][C:12]=2[C:11]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([CH3:31])[CH:23]=2)=[N:10][N:9]1[C:1](=[O:4])[CH2:2][CH3:3])#[N:7]
Reactant: Cc1cc(C2=NNC(C)(C#N)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Reactant: CCC(=O)Cl
Product: CCC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2CC1(C)C#N)OCO3
Temperature: 25 °C
Reaction time: 192 h
Yield: 77 %

Procedure:
To 55 ml of propionyl chloride 7.06 g (19.4 millimoles) of (±)-8-cyano-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine are added at 15° C. The reaction mixture is stirred at 25° C. for 8 days and evaporated in vacuo. To the residue 200 ml of water are added. The mixture is stirred under cooling with icecold water for an hour. The precipitated crystals are filtered and washed with icecold water. The crude product obtained is recrystallized from 100 ml of acetonitrile. The crystals are filtered, washed with acetonitrile and ether and dried. Thus 6.30 g of the desired compound are obtained, yield 77%, mp.: 191–193° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:20].N1CCCCC1>C(O)C>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:12]1=[O:20]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1c(Br)cccc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(Br)cccc1C=C1C(=O)Nc2ccccc21
Temperature: 82.5 °C
Reaction time: 15.25 h
Yield: 29.9 %

Procedure:
Step 2 A solution of 3-bromo-2-methylbenzaldehyde (200 mg, 1.01 mmol) and indolin-2-one (134 mg, 1.01 mmol) in ethanol (10 mL) was treated with piperidine (0.099 mL, 1.01 mmol) and heated at 80-85° C. After 15.25 h, the solution was cooled to rt and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 to 30:70 hexane-ethyl acetate) to provide 3-(3-bromo-2-methylbenzylidene)indolin-2-one as a bright yellow solid (94.9 mg, 30%). 1H NMR (400 MHz, chloroform-d) δ 7.89 (1 H, br. s.), 7.85 (1 H, s), 7.64 (1 H, d, J=7.9 Hz), 7.47 (1 H, d, J=7.7 Hz), 7.20 (1 H, td, J=7.7, 1.1 Hz), 7.07-7.16 (2 H, m), 6.87 (1 H, d, J=7.9 Hz), 6.81 (1 H, td, J=7.6, 1.0 Hz), 2.43 (3 H, s). Mass spectrum m/z 314, 316 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:13]1([CH3:23])C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=[O:26].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:26][CH2:13][CH2:23][O:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
A mixture of 4-ethoxycarbonyl cyclohexanone (175 g, 1.03 mol), ethylenegrycol (70 mL), and p-toluenesulfonic acid (2.1 g) in toluene (700 mL) is stirred and refluxed for 6 hours with continuous water removal using Dean-Stark apparatus. After cooling to room temperature, sat. NaHCO3 aq. (1500 mL) and EtOAc (800 mL) are added to the reaction mixture. The organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford crude 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (220 g) as yellow oil, which is used without further purification.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=1[CH2:20][C:21]([OH:23])=O)([O-])=O.[OH-].[Na+]>C(O)C>[NH2:17][C:15]1[CH:16]=[C:11]2[C:12]([CH2:20][C:21](=[O:23])[NH:8]2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)C2
Temperature: 90 °C
Yield: 101.3 %

Procedure:
Tin chloride dihydrate (225 g) was added to a solution of 2,4-dinitrophenylacetic acid (22.6 g) in ethanol (450 ml). The mixture was heated at 90° C. for 10 hours. The reaction mixture was cooled and adjusted to pH 11 with 12M sodium hydroxide. The solids were removed by filtration and the filtrate was concentrated. The residue was treated with ethanol (300 ml). Insoluble materials were removed by filtration and washed with ethanol (5×60 ml). The combined ethanol solutions were evaporated and the solid obtained was dried under vacuum to give 15 g of 6-amino-2-oxindole as a brown powder.