Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1.[CH3:21][NH:22][C@H:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:21][N:22]([CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)[C@H:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Reactant: CN[C@@H]1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)[C@@H]1CCCc2ccccc21

Procedure:
A mixture of 1-(1,1-dimethylethyl) 4-(4-chloromethyl-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 1, Step C) (0.15 g, 0.47 mmol), (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (0.076 g, 0.47 mmol) and potassium carbonate (0.072 g, 0.52 mmol) in dry acetonitrile (5 mL) was heated at reflux for two days. Then the reaction mixture was filtered, concentrated under reduced pressure, diluted with dichloromethane, and washed with 1 N aqueous hydrochloric acid and water. The organic layers were dried (MgSO4) and concentrated under reduced pressure to give 0.19 g of the title compound as a tan foam.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[CH2:39]([O:45][C:46](Cl)=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].O>ClCCl>[C:46](=[O:47])([O:45][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:31][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:6]4[C:3]5[CH:4]=[CH:5][S:1][C:2]=5[CH:9]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[CH:22][CH:23]=2)[N:28]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCOC(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2n1
Yield: 105.2 %

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added triethylamine (0.65 ml), with stirring under ice-cooling, hexylchloroformate (0.6 g) was added at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl hexyl carbonate (1.09 g).
Reaction SMILES: [N-]=[C:2]=[O:3].C[C:5]1[C:6](N=C=O)=[CH:7][C:8]([N:11]=C=O)=[CH:9][CH:10]=1>>[NH2:11][C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1.[CH2:2]=[O:3]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: [N-]=C=O
Product: C=O
Product: Nc1ccccc1

Procedure:
41.4 parts, by weight, of an isocyanate mixture of which 40%, by weight, consists of a tolylene diisocyanate mixture (2,4- and 2,6-isomer in a ratio of 65:35) and 60%, by weight, of a polyphenyl polymethylene polyisocyanate (viscosity approximately 200 cP at 25° C). The polyphenyl polymethylene polyisocyanate was obtained by condensing aniline with formaldehyde, followed by phosgenation (NCO content 38% b.w.).
Reaction SMILES: [NH:1]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:2]([C:10]([NH:12][C@@H:13]([C:24]([NH:26][C@H:27]([C:43](O)=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:63][C@H:64]([C:68]([NH:70][C@H:71]([C:82]([NH:84][C@H:85]([CH2:89][OH:90])[C@@H:86]([CH3:88])[OH:87])=[O:83])[CH2:72][S:73][CH2:74][C:75]1[CH:81]=[CH:80][C:78]([CH3:79])=[CH:77][CH:76]=1)=[O:69])[C@@H:65]([CH3:67])[OH:66].FC(C(O)=O)(F)F.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CCN(CC)CC>[NH:1]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:2]([C:10]([NH:12][C@@H:13]([C:24]([NH:26][C@H:27]([C:43]([NH:63][C@H:64]([C:68]([NH:70][C@H:71]([C:82]([NH:84][C@H:85]([CH2:89][OH:90])[C@@H:86]([CH3:88])[OH:87])=[O:83])[CH2:72][S:73][CH2:74][C:75]1[CH:76]=[CH:77][C:78]([CH3:79])=[CH:80][CH:81]=1)=[O:69])[C@@H:65]([CH3:67])[OH:66])=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(CSC[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(CSC[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.5 ml NEt3, 11.2 g BOC-Phe-(D)Trp-Lys(Z)-OH and 4 g HOBT are added to 9 g H-Thr-Cys(MBzl)-Thr-ol trifluoroacetate in 100 ml DMF. 3.7 g DCCI in 10 ml DMF are added to the solution at -20° C. and the whole is stirred for ca. 18 hours at 0° C. and 2 hrs. at room temperature. Precipitated dicyclohexyl-urea is filtered off and the filtrate concentrated under vacuum and diluted with methanol. H2O is added until the product precipitates. The precipitate is filtered, washed with MeOH/H2O (4:1) and dried to yield the title compound:
Reaction SMILES: [CH2:1]([C:5]1[C:6]([NH:18][C:19]([O:21]C(C)(C)C)=O)=[C:7]([NH:10][C:11](OC(C)(C)C)=[O:12])[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[CH2:1]([C:5]1[C:6]2[NH:18][C:19](=[O:21])[C:11](=[O:12])[NH:10][C:7]=2[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1csc(NC(=O)OC(C)(C)C)c1NC(=O)OC(C)(C)C
Solvent: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: CC(C)Cc1csc2[nH]c(=O)c(=O)[nH]c12
Yield: 62.4 %

Procedure:
A mixture of di-t-butyl 4-isobutylthiophene-2,3-dicarbamate (3.70 g, 10 mmol), diethyl oxalate (30 ml, 220 mmol) and glacial acetic acid (30 ml) was refluxed for 20h. The mixture was concentrated and the residue was recrystallized from aqueous acetic acid to afford 1.4 g (62.5%) of the title compound. M.p.>270° C. 1H-NMR (DMSO-d6, δ): 0-9 (d, 6H), 1.75 (m, 1H), 2.45 (d, 2H), 6.75 (s, 1H), 11.9 (s, 1H), 12.2 (br.s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)C1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Yield: 56.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.69 g, 1.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.25 g, 1.5 mmol) according to the procedure as described in Example 1, Step C to afford the title compound as a yellow solid (0.43 g, 56%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[Cl:12].C([BH3-])#N.[Na+]>>[Cl:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccc(F)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)cc1Cl

Procedure:
Reduction of 2-chloro-4-fluoro-benzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution dichloromethane-ethyl acetate 95:5) (54% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.55 (3H, s, OCH3), 4.16 (2H, s, NCH2), 6.99 (1H, m, aromatic), 7.15 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.41 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic). The hydrochloride salt was obtained as a white solid: mp 159° C. Anal. calcd for C8H9ClFNO—HCl: C, 42.50; H, 4.46; N, 6.20. Found: C, 42.50; H, 4.36; N, 5.98.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(=O)CC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: Cc1ccc(OCC#N)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 97.2 %

Procedure:
4-Methyl-3-nitrophenol (5.0 g) (TCl America, Portland, Oreg.) and 4.70 g of bromoacetonitrile were dissolved in 30 ml of 2-butanone; then 13.5 g of potassium carbonate was added and the mixture was stirred and heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into ethyl acetate, washed with water, dried, and evaporated to give 6.1 g of (4-methyl-3-nitrophenoxy)-acetonitrile as a brown oil. ##STR74##
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:12](=O)([O:18]N1C(=O)CCC1=O)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].CO>O.[OH-].[K+]>[C:14]([O:13][C:12]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To the solution of 575 mg of lysine monohydrochloride in 2 ml of water, 6.2 ml of 1N methanolic potassium hydroxide was added and then 645 mg of t-butyl succinimidyl carbonate in 3 portions was mixed in over 20 minutes while stirring at room temperature. Stirring was continued for another 2 hours, then the reaction mixture was acidified to pH 5, methanol evaporated and the white precipitate collected by filtration giving 779 mg (quantitative yield) of the crude title compound. This was twice recrystallized from warm water to give 529.7 mg (68%) of pure compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:35]
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 102.9 %

Procedure:
A mixture of 7.16 g (20 mmol) of rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (preceding example), 4.37 g (22.4 mmol) of ethyl 4-bromobutyrate, 8.32 g (60.29 mmol) of anhydrous, granular potassium carbonate, and 50 mL of dry dimethyl sulfoxide was stirred at room temperature for 23 hr. The resulting mixture was diluted with ether and worked-up in the usual manner. There was obtained 9.73 g of rac-(E)-4-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenoxy]butanoic acid ethyl ester as a yellow oil containing ca. 10% of ethyl 4-bromobutyrate (NMR analysis). This material was used without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:8][OH:9])[NH2:7].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].C>O1CCOCC1.B(F)(F)F.C(OCC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=2)[O:9][N:8]=1
Reactant: NC(=NO)c1ccco1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: C
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2nc(-c3ccco3)no2)cc1
Yield: 74.6 %

Procedure:
To a solution of 2-furanamidoxime (12.6 g, 0.1 mole) and p-nitrobenzoyl chloride (18.1 g, 0.1 mole) in 500 ml of dry dioxane, 1 ml of BF3 -ethyl ether is added and the mixture is heated to reflux for 16 hours. Evaporation of the solvent in vacuo gives a light brown solid. It is decolorized with Darco (CHCl3) and crystallized from ethanol-acetonitrile to give 19.2 g (75%) of product, m.p. 168°-170° .
Reaction SMILES: [CH3:1][O:2][C:3]1C=CC(C=NO)=[CH:5][CH:4]=1.[Cl:12][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=O.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:16]([C:17]([NH:13][Cl:12])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(C=NO)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCl)cc1

Procedure:
Dissolved in 65 ml of dimethylformamide were 6.5 g (43 mmol) of 4-methoxybenzaldoxime, followed by the gradual addition of 6.3 g (47 mmol) of N-chlorosuccinimide at room temperature. After the resultant mixture was stirred for 3 hours, 300 ml of water were added to the reaction mixture. The mixture thus formed was extracted with ethyl ether. The ether layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, whereby 4-methoxybenzhydroxamic acid chloride was obtained. Analytical results of the compound obtained: Yield: 7.98 g (100%).
Reaction SMILES: [CH3:1]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52]C)=[O:51])=[CH:34][C:35]=3[N:36]3[CH:42]=[C:41]([C:43](O)=[O:44])[CH2:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:49]1[C:38]2[C:37]3=[C:29]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:30]4[CH:31]=[CH:32][C:33]([C:50]([OH:52])=[O:51])=[CH:34][C:35]=4[N:36]3[CH:42]=[C:41]([C:43]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:44])[CH2:40][C:39]=2[CH:46]=[CH:47][CH:48]=1
Reactant: C1COCCN1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C=C(C(=O)O)Cc1ccccc1-3
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc2c1-c1c(C3CCCCC3)c3ccc(C(=O)O)cc3n1C=C(C(=O)N1CCOCC1)C2
Temperature: 22 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
TBTU (145 mg, 0.45 mmol) was added to a stirred solution of 14a (R=H, 125 mg, 0.30 mmol), morpholine (26 μL, 0.30 mmol), and N,N-diisopropylethylamine 200 μL, 1.15 mmol) in DMF (2 mL). The mixture was stirred at 22° C. for 20 min. The resulting solution was injected on a Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave methyl 13-Cyclohexyl-6-(morpholinylcarbonyl)-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid as a yellow solid (64 mg, 44%). ESI-MS m/z 487 (MH+), 1H NMR (500 MHz, CDCl3) δ 1.21 (m, 1H), 1.34-1.55 (m, 3H), 1.77 (m, 2 H), 1.91 (m, 1 H), 2.06 (m, 3 H), 2.83 (m, 1 H), 2.97-3.85 (m, 8 H), 3.97 (s, 3 H), 4.45 (m, 1 H), 5.07 (m, 1 H), 6.89 (s, 1 H), 7.41 (d, 1 H), 7.49 (m, 2 H), 7.57 (m, 1 H), 7.75 (m, 1 H), 7.89 (d, J=8.55 Hz, 1 H), 8.15 (s, 1 H).
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1.[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[C:16]#N.C([O:25]CC)C>C1(C)C=CC=CC=1.ClCCl>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:16]([C:15]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:14]=2[Cl:13])=[O:25])=[CH:7][CH:6]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: CCOCC
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: 135 °C
Yield: 67 %

Procedure:
Part A: Magnesium (3.04 gram, 0.125 mol) is suspended in anhydrous diethyl ether (500 mL) under a nitrogen atmosphere and an iodine crystal is added. A solution of 4-chlorobenzyl chloride (20.12 gram, 0.125 mol) in anhydrous diethyl ether (100 mL) is slowly added to maintain a gentle reflux. After cooling the resulting mixture to room temperature a solution of 2,4-dichlorobenzonitrile (17.2 gram, 0.10 mol) in toluene (100 mL) is slowly added. Temperature is raised to 135° C. and the diethyl ether is removed by distillation, toluene is added and the resulting mixture is refluxed for two additional hours. After cooling to room temperature a solution of HCl (1N, 400 mL) is slowly added under cooling and stirring. The resulting mixture is extracted twice with diethyl ether, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (dichloromethane) gives 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone as a yellow oil (19.96 gram, 67% yield). Crystallisation from cyclohexane gives pure 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)ethanone. Melting point: 65-66° C. 1H-NMR (200 MHz, CDCl3): δ 7.02-7.45 (m, 7H), 4.22 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21](CC3C=CC(OC)=CC=3)[C:20](=[O:32])[N:19]2[CH3:33])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>O>[CH2:1]([O:3][C:4](=[O:34])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:32])[N:19]2[CH3:33])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CNC(=O)N2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 118.5 %

Procedure:
A mixture of 2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (2.72 g, 5.78 mmol) and triethylsilane (1.34 g, 11.5 mmol) was treated with trifluoroacetic acid (70 mL) and stirred at room temperature under N2 for 5 h. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 98:2 CH2Cl2:MeOH to afford 2.40 g (100%) 2-methyl-2-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid ethyl ester. Rf=0.09 (1:1 hexanes:acetone); MS (ES+) Calc'd for C18H27N2O5 (M+1) 351. Found m/z 351 (100%). 1H NMR.
Reaction SMILES: [CH2:1]([N:3]([N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH3:2].[Cl:15]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[ClH:15].[Cl:15][C:11]1[N:10]([N:3]([CH2:1][CH3:2])[C:4]2[CH:5]=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCN(c1ccncc1)n1cccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(c1ccncc1)n1cccc1Cl
Product: Cl
Temperature: 25 °C
Yield: 52.4 %

Procedure:
To a solution of N-ethyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (10.2 g) in 200 ml of anhydrous tetrahydrofuran was added N-chlorosuccinimide (7.3 g). After stirring twenty hours at ambient temperature, the reaction mixture was stirred with an aqueous solution of sodium sulfite and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 12 g of an oil. This oil was purified by HPLC (silica, 25% dichloromethane in ethyl acetate) to give 3.7 g of the desired product as an oil. This oil was converted to the hydrochloride salt and twice recrystallized from isopropanol-ether to give 3.1 g of crystals, mp 206°-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Al+3].[Cl-:14].[Cl-].[Cl-].O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:2]2[CH:12]=[CH:11][C:5]([Cl:14])=[CH:4][CH:3]=2)[CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: [Cl-]
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: [Al+3]
Solvent: Clc1ccccc1
Solvent: O
Product: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
To a suspension of 4-chlorocinnamic acid (10.0 g, 54.8 mmol) in chlorobenzene (75 mL) at 0° C. was added AlCl3 (12.0 g, 90 mmol) in 4 portions. The mixture was stirred for 10 min at 0° C. then was warmed to 40° C. and stirred for 1 h. Crushed ice (75 g) was added carefully, followed by water (75 mL). The aqueous layer was extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated to provide the crude acid as a tan solid. Recrystallization from EtOH provided 7.81 g (48%) of the desired acid as a pale yellow solid. 1H NMR (400 MHz, CDCl3): 7.31-7.22 (m, 4H), 7.14-7.07 (m, 4H), 4.47 (t, J=8.0, 1H), 3.03 (d, J=7.9, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22](S(C)(=O)=O)[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.C[O-].[Na+].O.[C:40](OCC)(=[O:42])C>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22]([O:42][CH3:40])[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)c1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of the compound obtained in Example 33 (100 mg) in tetrahydrofuran/methanol (3 mL/3 mL) was added sodium methoxide (102 mg) and the mixture was stirred at 50° C. overnight. After cooling to room temperature, to the reaction mixture was added water and ethyl acetate and the mixture was stirred. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80/20 to 60/40) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylcarbamoyl)-2-methoxypyrazol o[1,5-a]pyrimidine (57.2 mg; yield: 63%) as a pale yellow powder.