Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:41])[NH:11][CH:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]([OH:33])[CH2:14][N:15]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25](F)[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[F:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45][NH2:46]>O1CCCC1>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:41])[NH:11][CH:12]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:13]([OH:33])[CH2:14][N:15]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH:46][CH2:45][C:44]3[CH:47]=[CH:48][C:49]([F:51])=[CH:50][C:43]=3[F:42])[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NCc1ccc(F)cc1F
Solvent: C1CCOC1
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc([N+](=O)[O-])c(NCc2ccc(F)cc2F)c1
Yield: 100 %

Procedure:
{1-Benzyl-3-[(3-fluoro-4-nitro-benzenesulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester (7) (0.40 g, 0.67 mmol, 1 equiv) and 2,4-difluoro-benzylamine (0.14 g, 1 mmol, 1.49 equiv) were dissolved in tetrahydrofurane (10 mL). The solution was heated to reflux for 18 h. The solution was concentrated and the crude product was dissolved in dichloromethane (15 mL). The organic layer was washed with saturated NaHCO3 solution (15 mL). The organic layer was separated and evaporated under reduced pressure to yield the title compound (0.48 g, 0.67 mmol, quantitative). LRMS (ES+): m/z 719 [M+H]+.
Reaction SMILES: C(OC([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH:12]([CH2:19][CH3:20])[CH2:13][CH2:14][O:15][C:16]=3[CH:17]=[CH:18][C:9]=2[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>CCO.Cl.O>[CH2:19]([CH:12]1[C:11]2[C:10]3[CH2:21][CH2:22][NH:6][CH2:7][CH2:8][C:9]=3[CH:18]=[CH:17][C:16]=2[O:15][CH2:14][CH2:13]1)[CH3:20]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(CC)CCO3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC1CCOc2ccc3c(c21)CCNCC3
Temperature: 120 °C
Yield: 55.2 %

Procedure:
Into a sealed tube, the product from step (i) (95 mg, 0.313 mmol) dissolved in EtOH (2 ml) and water (500 μl) was added. To this stirred solution, KOH (275 mg, 4.9 mmol) was added. The reaction mixture was heated to 120° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and was diluted with 2M HCl (15 ml) and water (15 ml). The aqueous mixture was washed with EtOAc (2×). The aqueous layer was then basified with 2M NaOH to pH 10 and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title compound as a yellow oil (40 mg). 1H NMR (300 MHz, CDCl3) δ 6.86 (d, J=8.1 Hz, 1H); 6.57 (d, J=8.1 Hz, 1H); 4.22-4.17 (m, 1H); 4.12-4.03 (m, 1H); 3.00-2.84 (m, 8H); 2.83-2.72 (m, 1H); 2.06 (bs, 1H); 1.97-1.92 (m, 2H); 1.56-1.45 (m, 2H); 1.01 (t, J=6.0 Hz, 3H); MS: ESI (positive): 232 (M+H).
Reaction SMILES: C([C:3]1[C:4]([C:29]([F:32])([F:31])[F:30])=[N:5][N:6]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[N:23][CH:24]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=[CH:10][CH:9]=1)C.BrC1C=CC(C2(CC)N(C3C=CC(S(N)(=O)=O)=NC=3)NC(C(F)(F)[F:56])=C2)=CC=1>>[F:56][C:3]1[C:4]([C:29]([F:31])([F:30])[F:32])=[N:5][N:6]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:26])=[O:27])=[N:23][CH:24]=2)[C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCC1(c2ccc(Br)cc2)C=C(C(F)(F)F)NN1c1ccc(S(N)(=O)=O)nc1
Reactant: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(-c2cncs2)cc1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(F)c2-c2ccc(-c3cncs3)cc2)cn1

Procedure:
The title compound was prepared according to the procedure of step 1 in the Example 10 using 5-[4-fluoro-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (Example 8, step 1), instead of 5-[5-(4-bromophenyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: N1C=CC=CC=1C[N:8]1[C:12]([C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:11][C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:9]1.O1CCOCC1.[Se](=O)=O>O>[C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:13]([C:12]3[NH:8][CH:9]=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:11]=3)=[O:26])=[CH:19][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cc(C(=O)c2ccc(-c3ccccc3)cc2)n(Cc2ccccn2)c1
Agent: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c[nH]c(C(=O)c2ccc(-c3ccccc3)cc2)c1
Yield: 75.2 %

Procedure:
Ethyl 1-(2-pyridylmethyl)-5-(4-phenylbenzoyl)pyrrole-3-carboxylate (5.3 g.) was combined with 150 ml. of dioxane, 5 ml. of water and 10 g. of selenium dioxide and refluxed for approximately 16 hours. Insoluble material was separated by filtration, the filtrate was diluted with 150 ml. of ether and 150 ml. of water, the mixture equilibrated, the ether phase separated, back-washed twice with 100 ml. portions of water, filtered and concentrated to yield ethyl 5-(4-phenylbenzoyl)pyrrole-3-carboxylate (3.1 g, solid; Rf 0.4 on silica gel thin layer chromatography with ethyl acetate-1/hexane-5/5% acetic acid as eluant).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:15]
Reactant: Cc1occc1C(=O)Cc1ccccn1
Reactant: COC(OC)N(C)C
Product: Cc1occc1C(=O)C(=CN(C)C)c1ccccn1
Temperature: 100 °C

Procedure:
A mixture of 1-(2-methyl-3-furanyl)-2-(2-pyridinyl)ethanone (1.207 g, 6 mmol) in N,N-dimethylformamide dimethyl acetal (0.797 ml, 6.00 mmol) was heated at 100° C. for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried and evaporated to give the title product as a dark orange oil which was used in the next step (1.1 g, 72%). LC/MS [M+H]+=257.
Reaction SMILES: [CH2:1]([C:4]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[O:18][CH:17]([C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15]2)[CH2:2][CH3:3].I[CH3:39]>>[CH2:1]([C:4]1[CH:30]=[C:29]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[O:18][C:17]([CH3:39])([C:22]([OH:24])=[O:23])[CH2:16][CH2:15]2)[CH2:2][CH3:3]
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCCOc1ccc2c(c1)CCC(C(=O)OCC)O2
Reactant: CI
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCCOc1ccc2c(c1)CCC(C)(C(=O)O)O2

Procedure:
The title compound was prepared from ethyl 6-(4-(2-propyl-4-phenoxyphenoxy)butoxy)-chromane carboxylate following the procedures described in Example 2, Step A employing iodomethane instead of iodopropane, and subsequently the procedure in Example 1 Step C.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[CH2:12][C:13]([CH2:15][C:16](=[O:18])[CH3:17])=[O:14].CCCCCC.C(OCC)(=O)C>CS(C)=O.O>[C:13]([CH:15]([O:8][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16](=[O:18])[CH3:17])(=[O:14])[CH3:12]
Reactant: CC(=O)CC(=O)CCl
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Reaction time: 3 h

Procedure:
Sodium benzoate (106.5 g, 0.74 mol) is suspended in 500 ml of dry DMSO in a three necked flask equipped with a mechanical stirrer and under a gentle stream of argon. Chloroacetylacetone (50 g, 0.37 mol) is then added and the resulting orange mixture is stirred vigorously. After 3 hours the reaction is complete (TLC hexane/ethyl acetate 8/2); the melange is cooled by means of iced water and diluted with 500 ml of water. The solution is then extracted into ether (3×400 ml), washed with water (2×1 L), dried over Na2SO4 and concentrated to dryness in vacuo. The resulting viscous orange oil is pure enough for the next step. The yield is 81.4 g (100%).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:40])[CH:14]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[N:15]2[C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[N:17]=[C:16]2[C@H:25]([O:32][CH3:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-].Cl>C(#N)C>[CH:34]1([CH:14]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[N:17]=[C:16]2[C@H:25]([O:32][CH3:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]([NH:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:5][C:4]([OH:41])=[O:3])[CH2:11][CH2:10]2)=[O:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)C[C@H]1CC[C@H](NC(=O)C(C2CCCCC2)n2c([C@H](OC)c3ccccc3)nc3cc(F)ccc32)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)N[C@H]1CC[C@H](CC(=O)O)CC1)C1CCCCC1
Temperature: 110 °C

Procedure:
To a solution of (trans-4-{2-cyclohexyl-2-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetylamino}-cyclohexyl)-acetic acid ethyl ester (190 mg, 0.34 mmol, 1.0 equiv) in acetonitrile (3 mL) was added a solution of 1 M LiOH (2 mL) and the reaction mixture heated by microwave irradiation to 110° C. for 30 min. A solution of 1 M HCl (25 mL) was added, the organic solvents removed by evaporation under reduced pressure and the residue extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 138 mg (76%) of the title compound. MS (ISP): 536.4 [M+H]+.
Reaction SMILES: C([NH:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][CH2:7][S:8][CH3:9])(=O)C>[Co](Cl)Cl.O>[NH2:4][C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH2:7][S:8][CH3:9]
Reactant: CSCCC(NC(C)=O)C(=O)O
Agent: Cl[Co]Cl
Solvent: O
Product: CSCC[C@H](N)C(=O)O
Temperature: 37 °C

Procedure:
The enzymatic activity of the acylase in solution, before and after fixing, is determined by adding 0.1 ml. of the enzyme solution to 5 ml. of an 0.4 weight percent solution of N-acetyl-DL-methionine in 0.1 M TRIS buffer, of pH 8, containing 5·10-4 mols of cobalt chloride. The mixture is maintained for 30 minutes at 37° C., whereupon the reaction is stopped by immersing the receptacle in boiling water for 3 minutes. After cooling, the L-methionine formed is determined.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH:4]1[CH2:10][CH3:11])[CH3:2].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([O:9][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:5][CH:4]1[CH2:10][CH3:11])[CH3:2]
Reactant: CCC1CC(O)CCN1CC
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CCC1CC(Oc2ccc([N+](=O)[O-])cc2)CCN1CC

Procedure:
In a manner similar to Preparation 2, react 1,2-diethyl-4-piperidinol with 4-fluoronitrobenzene to obtain the title compound.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:25][CH:24]=4)=[N:20]3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(C)(C)C.C(Cl)Cl.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[N:29]1([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:19]3[N:18]=[CH:17][C:16]4=[CH:15][CH:14]=[C:13]([C:10]5[CH:11]=[CH:12][C:7]([C:6]([OH:35])=[O:5])=[CH:8][CH:9]=5)[N:21]4[N:20]=3)=[CH:24][CH:25]=2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-neck round-bottom flask, [A] 4-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzoic acid tert-butyl ester (0.34 g, 0.72 mmol), Methylene chloride (10 mL, 200 mmol) and Trifluoroacetic Acid (5.0 mL, 65 mmol) were added and stirred at room temperature overnight. The solvent was removed under vacuum. The resulting solid was washed with DCM to give 4-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzoic acid; compound with trifluoro-acetic acid as a yellow solid. LCMS (E/I+) 416.16 (M+H). NMR 1H (DSMO-d6)-9.45 (s, 1H), 9.01 (s, 1H), 8.35 (d, 2H, J=8.40 Hz), 8.07 (d, 2H, J=8.41 Hz), 7.88 (s, 1H), 7.71 (d, 1, J=8.80 Hz), 7.30 (d 1H, J=4.76 Hz), 7.17 (d, 2H, J=8.44 Hz), 6.98 (d, 1H, J=4.80 Hz), 3.83 (t, 4H, J=4.78 Hz), 3.24 (bs, 4H).
Reaction SMILES: [OH-].[Na+:2].[CH:3]1([P:9]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.O>CO>[CH:26]1([P:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:10]2[CH2:11][CH2:12][CH:13]([C:16]3[CH:17]=[CH:18][C:19]([S:22]([O-:25])(=[O:24])=[O:23])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1.[Na+:2]
Reactant: O=S(=O)(O)c1ccc(C2CCC(P(C3CCCCC3)C3CCCCC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])c1ccc(C2CCC(P(C3CCCCC3)C3CCCCC3)CC2)cc1

Procedure:
Sodium hydroxide (1.82 g; 45.5 mol.) is dissolved in 50 mL of methanol and added dropwise under nitrogen to 4-[4-(dicyclohexylphosphino)-cyclohexyl]benzenesulfonic acid (19.86 g; 45.5 mmol.) in 200 mL of methanol. The pH of the resulting system upon mixing with water is about 9.4. The mixture in methanol is filtered, the solvent is evaporated and the residue is dried in vacuum to constant weight. Yield of sodium 4-[4-(dicyclohexyl-phosphino)cyclohexyl]benzenesulfonate, Cy2PC6H10C6H4SO3Na, is 20.4 g (98%). 31P{1H} NMR CD3OD, ppm): −1.28. 1H NMR (δ CD3OD, ppm): 1.2-2.2 (m, 31H, cyclohexyl), 2.74 (m, 1H, PhCH), 7.34 and 7.74 (dd, J=8.2 Hz, 4H, aromatic).
Reaction SMILES: CC(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=[C:10]([N+:33]([O-:35])=[O:34])[CH:9]=1)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N+:33]([C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1)([O-:35])=[O:34]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OC(C)(C)C)cc([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc([N+](=O)[O-])c1
Reaction time: 3.5 h
Yield: 97.5 %

Procedure:
To a solution of 4.6 g of 3-nitro-5-(octadecyloxy)phenylcarbamic acid dimethylethyl ester in 100 ml of methylene chloride stirred at room temperature was added 20 ml of trifluoroacetic acid. The reaction mixture was kept at room temperature for 3.5 hours and the solvent was then removed at reduced pressure. The residue was treated with water and the product was filtered and recrystallized from ethyl acetate-hexane to give 3.6 g (97% yield, mp 106°-108°) of 3-nitro-5-(octadecyloxy)benzenamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[C:14]#[N:15].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl.C(O)(C)C>[C:16]([C:11]1[NH:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:13]([C:14]#[N:15])[CH:12]=1)(=[O:18])[CH3:17]
Reactant: N#Cc1cc[nH]c1-c1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(=O)c1cc(C#N)c(-c2ccc(Cl)cc2Cl)[nH]1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a mixture of 2-(2,4-dichloro-phenyl)-1H-pyrrole-3-carbonitrile (6.00 g, 25.30 mmol, see EP 0312,723) in 120 mL of dichloromethane was added acetyl chloride (3.18 g; 40.49 mmol) at room temperature, under nitrogen. The resulting mixture was cooled to +2° C. and anhydrous aluminum trichloride (8.10 g, 60.73 mmol) was added in small portions during a period of 20 minutes, keeping the internal temperature below 5° C. Upon complete addition, the mixture was brought to room temperature and allowed to stir for 3 hours. Then, the mixture was slowly poured in a solution of ice-cooled 2M HCl (120 mL) and isopropanol (28 mL). The aqueous layer was separated and extracted twice with a mixture of dichloromethane (120 mL) and isopropanol (28 mL). The combined organic extracts were concentrated under reduced pressure to slurry, which was treated under stirring with isopropanol (30 mL) and diluted with water (60 mL) at room temperature. The solid was collected by suction and dried under vacuum at +50° C. to afford the 6.51 g of product as white, fluffy crystals. Yield=92%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:24])[CH3:23])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:23])[CH3:24])=[N:7][C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=3)=[CH:19][CH:20]=2)=[N:9][C:10]=1[N:11]([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(N)cc2)nc1N(C)C
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of methyl[2-(4-aminobenzyl)-4,6-bis(dimethylamino)pyrimidin-5-yl]acetate (4.00 g, 11.65 mmol) in dichloromethane (120 mL) was treated with 4-trifluoromethylbenzoyl chloride (2.92 g, 13.98 mmol) and triethylamine (3.54 g, 34.94 mmol). After stirring for 1 hour at room temperature, the reaction mixture was partitioned between water and chloroform and the aqueous layer was extracted with chloroform. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product as a yellow colored solid which was recrystallized from methanol to give methyl[4,6-bis(dimethylamino)-2-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)pyrimidin-5-yl]acetate (4.34 g, 73%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)[CH3:2].[BrH:13].BrBr>O>[CH2:1]([C:3]1[CH:9]=[C:8]([Br:13])[C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N)c([N+](=O)[O-])c1
Reactant: Br
Agent: BrBr
Solvent: O
Product: CCc1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 7 °C
Reaction time: 1 h

Procedure:
5-Ethyl-7-bromo-4-[benzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester ##STR24## Mix 4-ethyl-2-nitroaniline (16.6g, 0.1mol) in water (400mL) and add 48% hydrobromic acid (1kg). Add bromine (16g, 0.1mol) with stirring and stir for 1 hour. Dilute to 2L and cool to 7° C. Filter, wash with water and dry to give 4-ethyl-2-nitro-6-bromoaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].N1C=CC=CC=1.[Br:29][CH2:30][C:31](Br)=[O:32]>O1CCOCC1>[Br:29][CH2:30][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[O:32]
Reactant: CCOC(=O)Cc1ccc(N)c(C(=O)c2ccccc2Cl)c1
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(NC(=O)CBr)c(C(=O)c2ccccc2Cl)c1
Reaction time: 24 h

Procedure:
20.9 g (0.66 mol) of ethyl 4-amino-3-(2-chlorobenzoyl)-phenylacetate are dissolved in 170 ml of anhydrous dioxane. First 5.2 ml of absolute pyridine are added and then 13.3 g (0.066 mol) of bromoacetylbromide are added dropwise at room temperature and the mixture is stirred for 24 hours. The suspension is filtered through Kieselgur. The Kieselgur is washed with ether, and the combined filtrates are concentrated in vacuo. The resulting residue is induced to crystallise by addition of ethanol.
Reaction SMILES: [Li+].[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O-])=[O:19])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:59]([C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)=[CH:64][C:63]=1[C:75]([F:78])([F:77])[F:76])([O-:61])=[O:60]>CN(C)C=O.ClCCl.O1CCCC1>[N+:59]([C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH:69]2[CH2:70][CH2:71][N:72]([C:18](=[O:19])[CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([O:9][CH2:8][C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:24])([F:2])[F:23])=[CH:22][CH:21]=4)[CH2:11][CH2:12]3)[CH2:73][CH2:74]2)=[CH:64][C:63]=1[C:75]([F:78])([F:76])[F:77])([O-:61])=[O:60]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: O=C([O-])CCN1CCC(OCc2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCN1CCC(OCc2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
3-[4-(4-Trifluoromethyl-benzyloxy)-piperidin-1-yl]-propionic acid lithium salt (130 mg; 0.36 mmol, prepared in accordance with Example 56), diisopropylethyl amine (87 μL; 0.50 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (132 mg; 0.35 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (15 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 105 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (96 mg; 0.16 mmol). The structure was confirmed using Protocol I-B. Calculated mass=603; observed mass=603; HPLC retention time=5.038 min.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[C:10]([C:14]1[CH:15]=[C:16]([NH2:35])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11].ClC(Cl)(Cl)COC(=O)NC1N(C2C=CC=C(SCCO)C=2)N=C(C(C)(C)C)C=1>>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](=[O:6])[NH:35][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:15]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Agent: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(SCCO)c2)n1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1

Procedure:
The title compound was prepared starting from 2,2,2-trichloroethylchloroformate and Intermediate 39a by using an analogous procedure to that described for Intermediate 35c. LCMS (Method 4): Rt 3.85, m/z 536 [MH+].