Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:2]=1.BrC1C=NC=CC=1.CC1(C)C(C)(C)OB(C2CCC3(OCCO3)CC=2)O1.[NH:40]1[CH2:43][CH:42]([NH:44][C:45](=[O:62])[CH2:46][NH:47][C:48]2[C:57]3[C:52](=[CH:53][CH:54]=[C:55]([C:58]([F:61])([F:60])[F:59])[CH:56]=3)[N:51]=[CH:50][N:49]=2)[CH2:41]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][CH:10]([N:40]3[CH2:41][CH:42]([NH:44][C:45](=[O:62])[CH2:46][NH:47][C:48]4[C:57]5[C:52](=[CH:53][CH:54]=[C:55]([C:58]([F:59])([F:61])[F:60])[CH:56]=5)[N:51]=[CH:50][N:49]=4)[CH2:43]3)[CH2:9][CH2:8]2)[CH:2]=1
Reactant: O=C1CCC(c2cccnc2)CC1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: [Na+]
Solvent: Brc1cccnc1
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3cccnc3)CC2)C1

Procedure:
Reaction of 4-(pyridin-3-yl)cyclohexanone (prepared by the reaction of 3-bromopyridine with 8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene using the sequence described in Example 1 Step A-C) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product. 1H NMR (MeOD) δ: 8.62 (s, 1 H), 8.56 (s, 1 H), 8.43 (d, J=2.0 Hz, 1 H), 8.33 (dd, J=5.1, 1.5 Hz, 1 H), 8.04 (dd, J=8.8, 1.8 Hz, 1 H), 7.88 (d, J=8.8 Hz, 1 H), 7.77 (dt, J=7.8, 1.8 Hz, 1 H), 7.35 (dd, J=7.7, 5.2 Hz, 1 H), 4.51 (quin, J=7.1 Hz, 1 H), 4.28 (s, 2 H), 3.65-3.73 (m, 2 H), 2.95 (t, J=7.6 Hz, 2 H), 2.56-2.69 (m, 1 H), 2.43 (d, J=2.8 Hz, 1 H), 1.68-1.92 (m, 4 H), 1.49-1.62 (m, 4 H); ESI-MS (m/z): Calcd. For C25H27F3N6O: 484.22. found: 485 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.O.[C-:11]#[N:12].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: BrCc1ccccc1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccccc1Br
Temperature: 0 °C
Yield: 96.4 %

Procedure:
25 g (100 mmol) of 2-bromobenzyl bromide is mixed in 100 ml of N,N-dimethylformamide and 64 ml of water with 9.75 g (150 mmol) of potassium cyanide and stirred overnight at room temperature. The reaction mixture is poured into ice water. After 3× extraction with methyl-tert butyl ether, the combined organic extracts are washed with brine, dried, and the solvent is spun off. The residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 18.9 g (96.4%) of the desired compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][OH:16].[Li]CCCC.[CH3:22][S:23]SC.Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([S:23][CH3:22])[C:4]=1[CH2:15][OH:16]
Reactant: CSSC
Reactant: COc1cc(CO)c(OC)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(CO)c(SC)c(OC)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
Following the procedure of Flader et al.,22 alcohol 26 (0.521 g, 2.39 mmol) was dissolved in THF (9.0 ml) in a flame-dried 25 mL round bottom flask under Argon, and then cooled to 0° C. At 0° C. nBuLi (2.5 M in hexanes, 2.4 ml, 6.0 mmol) was added slowly, then the ice bath was removed and the reaction was stirred at room temperature for 1 hour. Dimethyldisulfide (0.50 mL, 5.6 mmol) was added slowly at room temperature and the reaction was stirred for another 30 minutes at room temperature before being poured into water, acidified with 2 M HCl, and extracted with ethyl acetate. The organic fractions were combined and washed with brine, dried over MgSO4, and filtered. The resulting solid was purified via flash column chromatography (1:4 EtOAc:hexanes) to afford 56 (0.446 g, 1.69 mmol, 71%) as a green solid.
Reaction SMILES: [CH3:1][C:2]([NH:11][N:12]=C(C)C)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=[C:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][C:19]([O:21]CC)=O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:10][C:2]([N:11]1[C:19](=[O:21])[CH2:18][C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:12]1)([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CC(C)=NNC(C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(Cc1ccccc1)N1N=C(c2ccccc2)CC1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
500 mg (2.45 mmol) of 1-(2-methyl-1-phenylpropan-2-yl)-2-(propan-2-ylidene)hydrazine was dissolved in 3.0 mL of glacial acetic acid, mixed with 429 mg (2.23 mmol) of ethyl 3-oxo-3-phenylpropanoate and stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate (100 ml) and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (100:1 to 9:1) as the eluent to give 330 mg of the desired product as a pale orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccc2F)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 27.7 %

Procedure:
To a solution of ethyl 2-[(2-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.050 g, 0.34 mmol) in ethanol (2.0 mL), piperidine (0.0034 mL, 0.034 mmol) was added at ambient temperature. The mixture was refluxed for 36 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.037 g, y. 27%).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4](=[O:6])[NH2:5].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])=[O:9])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
58 g BocAsnOH (0.25 moles) and 29 g HOSu are dissolved in 250 ml DMF and cooled to -20°. 52 g DCC dissolved in 250 ml DMF is added. After 4 hours stirring at room temperature 85 g GlyOBzl, pTos and 35 ml TEA is added. After stirring overnight the DCU i filtered off, DMF removed in vacuo on a Rotavap, and the resulting oil dissolved in EtAc. After extraction with sat. NaCl, sat. NaHCO3, and 10% citric acid, the solvent is dried with Na2SO4 and evaporated. The resulting crystalline ma is dried in a desiccator. Yield: 64 g (67%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][N:28]([CH:26]=[O:27])[CH2:29][CH2:30]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: O=CN1CCNCC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCN(C=O)CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2yl)ethyl]aminocarbonyl}benzoic acid, 4-formylpiperazine, pentafluorophenyl-N,N′,N′-tetramethyluroniumhexafluorophosphate (PFTU), and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.01 minutes; C22H21Cl2N5O3 (474.35); mass spectrum: (M−H)−=473/475/477 (chlorine isotope).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:13]([B:15]([CH2:18][CH3:19])OC)[CH3:14]>>[CH2:13]([B:15]([CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: CCB(CC)OC
Reactant: Brc1ccncc1
Agent: [Li]CCCC
Product: CCB(CC)c1ccncc1

Procedure:
4-Bromopyridine was reacted with n-butyllithium and then with diethylmethoxyborane using a procedure similar to that in Preparation 49. This gave the title compound, which was used without characterisation.
Reaction SMILES: [ClH:1].Cl.[CH3:3][NH:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1N.C(C(CC)(CC)C([O-])([O-])[O-])C.[C:31](#[N:33])[CH3:32]>>[ClH:1].[CH3:32][C:31]1[N:4]([CH3:3])[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[N:33]=1
Reactant: CC#N
Reactant: CNC(Cc1ccccc1N)c1ccccc1
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: Cl
Product: CC1=Nc2ccccc2C=C(c2ccccc2)N1C
Temperature: 70 °C
Yield: 83 %

Procedure:
A heterogeneous mixture of N-methyl-2-amino-α-phenylphenethylamine dihydrochloride (150 g. 0.5 mol) in acetonitrile (500 ml) was treated with triethylorthoacetate (202 ml, 1.1 mol) and heated to 70° C. for 2 hours with stirring under a dry nitrogen atmosphere. The reaction mixture was filtered, concentrated in vacuo, and the residual solid recrystallized from 2-propanol at -10° C. to give 2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepin hydrochloride (118 g, 0.413 mol) in 83% yield. The product had a melting point of 239.5°-241° C.
Reaction SMILES: CS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:40][CH3:41])=[C:21]([O:24][CH2:25][CH2:26][N:27]([CH2:32][C:33]([O:35][C:36](C)(C)[CH3:37])=[O:34])[CH2:28][C@@H](O)C)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1>C(#N)C.C(OCC)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:40][CH3:41])=[C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][C@H:36]([CH3:37])[O:35][C:33](=[O:34])[CH2:32]4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OCCN(CC(=O)OC(C)(C)C)C[C@H](C)O
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OCCN1CC(=O)O[C@@H](C)C1

Procedure:
90 μl of methanesulphonic acid are added to 380 mg of 4-[(3-bromo-phenyl)amino]-6-(2-{N-[(tert.butyloxycarbonyl)methyl]-N-((S)-2-hydroxy-propyl)-amino}-ethoxy)-7-methoxy-quinazoline in 8 ml of acetonitrile. The reaction mixture is refluxed for about three hours, then another equivalent of methanesulphonic acid is added and refluxing is continued until the reaction is complete. For working up the reaction mixture is diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. The flask residue is stirred with diethylether and suction filtered. The title compound is obtained as a white solid.
Reaction SMILES: I[CH2:2][O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C:16]([NH:29][C:30]([O:32][CH2:33][C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[CH:38]=2)=[O:31])([C:18](=[O:28])[NH:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[CH3:17])=[CH:7]1)=[O:5].[C:43]([C:46]1[CH:53]=[CH:52][C:49]([CH:50]=[O:51])=[CH:48][CH:47]=1)([OH:45])=[O:44]>C1(C)C=CC=CC=1.[Ag]>[CH:50]([C:49]1[CH:52]=[CH:53][C:46]([C:43]([O:45][CH2:2][O:3][C:4]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([CH2:15][C:16]([NH:29][C:30]([O:32][CH2:33][C:34]3[O:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[CH:38]=3)=[O:31])([C:18](=[O:28])[NH:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH3:17])=[CH:7]2)=[O:5])=[O:44])=[CH:47][CH:48]=1)=[O:51]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(NC(=O)C(C)(Cc1cn(C(=O)OCI)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Agent: [Ag]
Solvent: Cc1ccccc1
Product: CC(NC(=O)C(C)(Cc1cn(C(=O)OCOC(=O)c2ccc(C=O)cc2)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Yield: 80.4 %

Procedure:
Compound 7 (1.7 g, 2.5 mmol) and the silver salt of 4-carboxybenzaldehyde (1.29 g, 5.0 mmol) in dry toluene (50 mL) was refluxed for 30 minutes to give a yellow suspension. The solid was removed by filtration through celite, and the solid cake was washed with toluene. The filtrate was concentrated to give a syrup, which was purified by silica gel column eluting with CHCl3 to give compound 19 as a white foam (1.41 g, 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11]C1C=CC(Br)=CN=1.C([Li])CCC>O1CCCC1>[CH3:10][O:11][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1
Reactant: COc1ccc(Br)cn1
Reactant: CSc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(SC)cn1

Procedure:
For example, 2-bromo-5-methylthiopyridine may be prepared by the treatment of 2-methoxy-5-bromopyridine (Shiao. M. J. et. al. Syn. Comm. 20(19), 2971, 1990) with n-butyllithium in anhydrous tetrahydrofuran at -78 ° C. followed by quenching the reaction with dimethyldisulfide to afford 2-methoxy-5-methylthiopyridine. Demethylation provides 2-hydroxy-5-methylthiopyridine which upon reaction with phosphorousoxybromide yields the desired 2-bromo-5-methylthiopyridine starting material. (Scheme 7) ##STR19##
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[Cl:48][C:49]1[C:50]([O:61][CH3:62])=[C:51]([C:55]([O:59][CH3:60])=[C:56]([Cl:58])[CH:57]=1)[C:52](O)=[O:53].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:52](=[O:53])[C:51]3[C:55]([O:59][CH3:60])=[C:56]([Cl:58])[CH:57]=[C:49]([Cl:48])[C:50]=3[O:61][CH3:62])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: COc1c(Cl)cc(Cl)c(OC)c1C(=O)O
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)cc(Cl)c(OC)c1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3,5-dichloro-2,6-dimethoxybenzoic acid (9.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=4)[CH:25]=3)[CH2:21][C:20](=[O:38])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(Cl)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M113) (0.32 g, 0.57 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (170 mg, 67%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][N:39]([CH2:43][CH3:44])[CH2:38]1.O>CS(C)=O>[OH2:22].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:36][CH:37]4[CH2:42][CH2:41][CH2:40][N:39]([CH2:43][CH3:44])[CH2:38]4)=[O:23])=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: CCN1CCCC(N)C1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CS(C)=O
Solvent: O
Product: CCN1CCCC(NC(=O)Cc2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
7.0 Grams (0.02 mole) of 2-[4-(7-chloro-4-quinolylamino)phenyl]acetic acid hydrochloride were dissolved in 150 milliliters of dimethyl sulphoxide by heating the stirred mixture to 100° C. under nitrogen. The solution was cooled to room temperature, 6.48 grams (0.04 mole) of carbonyl di-imidazole were added and the mixture was stirred for 21/2 hours under nitrogen. 7.68 Grams (0.06 mole) of 3-amino-1-ethylpiperidine were added, the solution was stirred for another 21/2 hours and poured into 500 milliliters of water. The mixture was refrigerated overnight and the resulting solid was broken up, stirred with water, collected and dried. The solid was dissolved in chloroform and chromatographed on an alumina column made up in chloroform. Elution with chloroform/methanol (4:1) gave 8.15 grams (92.5% yield) of 2-[4-(7-chloro-4-quinolylamino)phenyl]-N-(1-ethyl-3-piperidyl)acetamide monohydrate, melting point 160°-162° C.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:43][C@H:44]([C:55]([OH:57])=[O:56])[CH2:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[NH:48][CH:47]=1>>[C:1]([O:18][CH:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:20][C:21]([NH:23][CH2:24][C:25]([NH:43][C@H:44]([C:55]([OH:57])=[O:56])[CH2:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[NH:48][CH:47]=1)=[O:27])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 48.1 %

Procedure:
N-(3-hexadecanoyloxyoctadecanoyl)glycine (1.3 g) prepared by the method described in Example 27 and L-tryptophan (1.45 g), N-[N-(3-hexadecanoyloxyoctadecanoyl)glycyl]-L-tryptophan (820 mg) was obtained as powders according to a similar manner to that of Example 29.
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].[C:17](#[N:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:12]([C:17]([NH2:24])([CH2:12][CH2:13][CH2:14][CH3:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH3:15]
Reactant: [Li]CCCC
Reactant: N#Cc1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(N)(CCCC)c1ccccc1
Reaction time: 2 h
Yield: 90 %

Procedure:
Cerium chloride heptahydrate (15.0 g 40.2 mmol) was dried with magnetic stirring at 140°-150° under 0.1 mm vacuum for two hours. Nitrogen was admitted and the flask containing the solid was cooled with an ice bath. Anhydrous tetrahydrofuran (80 mL) was added and the suspension was stirred at room temperature for 2 hours. n-Butyllithium (24 mL of a 1.6M solution in hexanes, 40 mmol) was added below -55° by syringe, and the mixture was stirred in a dry ice acetone bath for 30 minutes. Benzonitrile (1.34 g, 13 mmol) in 2 mL of anhydrous tetrahydrofuran was added, and the cooling bath was removed. Aqueous ammonium hydroxide (25 mL) was added after 2 hours, keeping the temperature below 0°, and the mixture was filtered with the aid of celite™. The solids were washed three times with methylene chloride, and the aqueous layer of the filtrate was extracted twice with methylene chloride. The combined organic phases were dried and concentrated and the residue was short-path distilled to give 2.53 g (90%) of the title compound distilling at a bath temperature of 80°-130° (0.003 mm). 1H-NMR (in CDCl3) ∂0.8 (t, J=6 Hz, 6H), 1.0 (m, 2H), 1.2 (m, 6H), 1.4 (br, 2H), 1.6 (m, 2H), 1.8 (m, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: S(=O)(=O)(O)O.O.[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23](CC#N)=[CH:22][C:21]=3[C:33]([F:36])([F:35])[F:34])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8].C(OCC)(=O)C.[C:43]([OH:46])(=[O:45])[CH3:44]>>[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20]3[C:25]([C:26]([F:27])([F:29])[F:28])=[CH:24][C:23]([CH2:44][C:43]([OH:46])=[O:45])=[CH:22][C:21]=3[C:33]([F:36])([F:34])[F:35])[CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: CC(=O)O
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC#N)cc3C(F)(F)F)cc12
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC(=O)O)cc3C(F)(F)F)cc12
Temperature: 105 °C
Reaction time: 4 h

Procedure:
A mixture of 5 ml of concentrated sulphuric acid and 5 ml of water is added dropwise to a solution of 0.35 g (0.82 mmol) of nitrile derivative from Example VIII in 5 ml of acetic acid (100% strength). The reaction solution is stirred at 105° C. for 4 hours, then cooled to room temperature and treated with ice-cold water and ethyl acetate. The organic phase is separated off, the aqueous solution is extracted again with ethyl acetate, and the combined organic phases are dried over sodium sulphate, filtered and concentrated to give an oil. The crude product (120.3 mg) is chromatographed on silica gel 60 by means of methylene chloride/methanol (95:5 and95:11).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])[CH2:5]1.[H][H].O>CN(C)C=O>[CH2:7]([C:10]([CH:6]1[CH2:7][CH2:8][CH2:9][CH:4]([CH3:3])[CH2:5]1)([C:11]([O:13][CH3:14])=[O:12])[C:15]([O:17][CH3:18])=[O:16])[CH2:8][CH2:9][CH2:4][CH:5]=[CH2:6]
Reactant: COC(=O)C(C(=O)OC)C1CCCC(C)C1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCCC(C(=O)OC)(C(=O)OC)C1CCCC(C)C1

Procedure:
To a slurry of sodium hydride (2.53 g, 0.06 mol) in anhydrous N,N-dimethylformamide (50 mL) was added dropwise dimethyl 2-(3-methylcyclohexyl)-malonate (14.46 g, 0.06 mol). After complete addition, the reaction was stirred until no more hydrogen gas was evolved. To the reaction was then added dropwise 1-bromo-6-hexene (10.33 g, 0.06 mol) followed by stirring. The progress of the reaction was followed by analytical chromatography using silica plates and ethyl acetate:hexanes (40:60). After complete reaction, water (20 mL) was added and most of the solvents removed under high vacuum. The remaining material was partitioned between water and ether and the ether layer washed twice with water. The ether solution was dried with MgSO4 and evaporated to give a thick yellow oil. The product was then distilled at 127-134° C. and 0.4 mm pressure to give clear oil.