Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+]([O-])=O)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[N+:39]([O-])([OH:41])=[O:40]>OS(O)(=O)=O>[N+:39]([C:11]1[C:10]2[C:9](=[O:22])[C:8]3[C:17](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=3)[C:16](=[O:18])[C:15]=2[CH:14]=[CH:13][CH:12]=1)([O-:41])=[O:40]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Yield: 30 %

Procedure:
Similarly, there has hitherto been no commercially and economically practicable process for the production of pure 1,8-dinitroanthraquinone. It is known that the commercially very important α,α-dinitration products of anthraquinone can be obtained in particularly high yields by nitration in concentrated nitric acid. Since the quantity of nitric acid required for this process is not appreciably higher than the quantity of sulphuric acid required for dinitration in H2SO4, nitric acid is economically superior to dinitration in sulfuric acid. The much simpler regeneration of the solvent is another factor in favour of nitric acid. According to Moiseva (Org.Polyprod, i. Krasitel, Moscow 1969, No. 4, 70-79), it is possible by the nitric acid process to obtain a 1,5-dinitroanthraquinone in a yield of 30 % of the theoretical amount. However, it is not possible under the conditions quoted by Moiseva (98 % HNO3, 24 hours at 24°-25°C) to obtain pure 1,5-dinitroanthraquinone. Instead the products obtained still contain at least 5 % of 1,8-dinitroanthraquinone (cf. Example 18 below). Even under more stringent conditions (filtration under suction at elevated temperature, increasing the quantity of nitric acid used for washing), we were unable to obtain 1,5-dinitroanthraquinone with a purity of more than 95 % in a yield of more than 20 % of the theoretical amount. In addition, it is subsequently no longer possible to isolate pure 1,8-dinitroanthraquinone from the mother liquors, because they then contain too much 1,5-dinitroanthraquinone.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:31]2[C:32](=[O:38])[C:33](=[O:37])[C:34]=2OC)[CH2:4]1)[CH3:2].Cl.[F:40][C:41]([F:46])([F:45])[CH2:42][CH2:43][NH2:44].CCN(C(C)C)C(C)C>CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:21])=[O:22])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:31]2[C:32](=[O:38])[C:33](=[O:37])[C:34]=2[NH:44][CH2:43][CH2:42][C:41]([F:46])([F:45])[F:40])[CH2:4]1)[CH3:2]
Reactant: NCCC(F)(F)F
Reactant: CC[C@@H]1C[C@H](Nc2c(OC)c(=O)c2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C[C@H](Nc2c(NCCC(F)(F)F)c(=O)c2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 50 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A mixture of 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione (0.090 g, 0.17 mmol, Preparation #29), 3,3,3-trifluoropropan-1-amine hydrochloride (0.050 g, 0.337 mmol, Fluorochem Limited), DIEA (0.18 mL, 1.0 mmol) and MeOH (1.2 mL) was heated at about 50° C. After about 18 h, the reaction was cooled to rt. The solid was collected via vacuum filtration, while washing with MeOH (about 3-5 mL), and then dried in a vacuum oven at about 60° C. to give 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-(3,3,3-trifluoropropylamino)cyclobut-3-ene-1,2-dione (0.083 g, 79%) as an off-white solid: LC/MS (Table 1, Method a) Rt=2.27 min; MS m/z: 616 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12][C:13]1[O:17][N:16]=[CH:15][C:14]=1[C:18](Cl)=[O:19]>C([O-])(O)=O.[Na+].CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH3:12][C:13]1[O:17][N:16]=[CH:15][C:14]=1[C:18]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:9][CH:8]=1)=[O:19]
Reactant: Cc1oncc1C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
4-Trifluoromethylaniline (5.75 g, 35.7 mm) was dissolved in a mixture of NaHCO3 (3.16 g, 37.6 mm), N,N-dimethylacetamide (0.7 ml, 7.5 mm) and toluene (70 ml). The mixture was warmed to 40° C. and 5-methylisoxazole-4-carboxylic acid chloride (5 g, 34.4 mm) was added dropwise over 20 min. The mixture was stirred at this temperature for another 3 h. and then it was heated to reflux temperature. The hot mixture was washed with water (3×10 ml). The organic phase was allowed to cool to ambient temperature, which induced leflunomide to precipitate as a white powder. The powder was isolated by filtration and then dried at 60° C. to give leflunomide (8.0 g, 86%) in 99.5% purity.
Reaction SMILES: CN1C(=O)CCC1.[CH2:8]([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:18][C:17]([NH2:27])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[N:39]=2)=[CH:31][CH:30]=1>CCOC(C)=O>[CH2:8]([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:18][C:17]([NH:27][C:37]([C:38]([NH:39][C:35](=[O:36])[C:32]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=2)([CH3:41])[CH3:40])=[O:42])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)N=C(c2ccc(F)cc2)OC1=O
Reactant: Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a 5 mL Biotage microwave vial were added NMP (1 ml), 1-benzyl-5-(4-fluorophenyl)-1H-1,2,4-triazol-3-amine (150 mg, 0.559 mmol), 2-(4-fluorophenyl)-4,4-dimethyloxazol-5(4H)-one (116 mg, 0.559 mmol,), under N2. Then it was placed in 100° C. oil bath and stirred for 2.5 h. It was cooled to r.t. and diluted with 2 ml of EtOAc. It was stirred for 10 min that resulted precipitation of the desired product. Then 2 mL of water was added and it was stirred for additional 10 min followed by addition of a couple drops of heptane. The precipitates were collected by filtration and dried under vacuum overnight. This afforded the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 1.50 (s, 6H) 5.40 (s, 2H) 7.08-7.14 (m, 2H) 7.24-7.39 (m, 7H) 7.63-7.71 (m, 2H) 7.96-8.04 (m, 2H) 8.33 (s, 1H) 10.17 (s, 1H). MS (m/z) 476.2 M(+1), tR=1.36, Method A.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([OH:31])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([N:40]2[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][CH2:39]2)=[O:31])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: Cl
Product: CC(C)n1c(C(=O)N2CCN(S(C)(=O)=O)CC2)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound was synthesized in analogy to example 47a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid and 1-methanesulfonyl-piperazine hydrochloride. White solid. MS (m/z): 576.4 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][NH:5][CH:4]=1)#[N:2].[O:12]1CCC[CH2:13]1.C=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:12][CH2:13][N:5]1[CH:6]=[C:7]([C:8]([F:11])([F:9])[F:10])[C:3]([C:1]#[N:2])=[CH:4]1
Reactant: N#Cc1c[nH]cc1C(F)(F)F
Reactant: C1CCOC1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: N#Cc1cn(CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
585 mg of 3-cyano-4-trifluoromethyl-1H-pyrole, 10 ml of tetrahydrofuran and 10 ml of formaldehyde 36% in water were mixed. 0.1 ml of tetrabutylammonium hydroxide 10% in water was added to the mixture at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 1-hydroxymethyl-3-cyano-4-trifluoromethyl-1H-pyrole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6](C2C(C(OC)=O)=CC([N+]([O-])=O)=CC=2)[CH:7]=1.Br[C:24]1[C:33]([CH3:34])=[CH:32][C:31]([N+:35]([O-:37])=[O:36])=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].FC1C=CC(OC)=C(B(O)O)C=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[CH:6][C:7]=1[C:24]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][C:31]([N+:35]([O-:37])=[O:36])=[CH:32][C:33]=1[CH3:34]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1Br
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(F)cc1B(O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1cc(OC)ccc1F
Yield: 38 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5′-Fluoro-2′-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from methyl 2-bromo-3-methyl-5-nitrobenzoate (1.73 g, 6.31 mmol), (PPh3)4Pd (0.22 g, 0.19 mmol), and 5-Fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) (1.50 g, 8.8 mmol) to afford 0.77 g (38%) of methyl 2′-Fluoro-5′-methoxy-6-methyl-4-nitro-2-biphenylcarboxylate. Data for 2′-Fluoro-5′-methoxy-6-methyl-4-nitro-2-biphenylcarboxylate: 8.61 (d, J=2.3, 1H), 8.27 (d, J=2.4, 1H), 7.09 (m, 1H), 6.91 (dd, J=9.0, 4.3, 1H), 6.73 (dd, J=8.2, 3.0, 1H), 3.70 (s, 3H), 3.69 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].O=[C:9]([CH3:25])[CH:10]=[CH:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>O>[O:6]=[C:5]1[CH:7]=[SH:1](=[C:9]([CH3:25])[CH:10]=[CH:11][C:12]2[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=2[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2](=[S:3])[NH:4]1
Reactant: O=C1CSC(=S)N1
Reactant: CCOC(=O)COc1ccccc1C=CC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COc1ccccc1C=CC(C)=[SH]1=CC(=O)NC1=S
Yield: 35.8 %

Procedure:
A mixture of 1.33 g (0.01 mol) of rhodanine, 2.48 g (0.01 mol) of ethyl 2-(3-oxo-1-butenyl]phenoxyacetate, 0.77 g (0.01 mol) of ammonium acetate and 20 ml of toluene was heated under reflux for 3 hours. After cooling, 100 ml of water were added to the reaction mixture which was extracted with ethyl acetate (3×100 ml). The ethyl acetate layer was washed twice with water and once with a saturated saline solution, dried and concentrated under reduced pressure to give orange crystals. The crystals were purified by silica gel column chromatography (eluent, chloroform : ethyl acetate) to obtain ethyl 2-[3-(4-oxo-2-thioxo-5-thiazolinylidene)-1-butenyl]phenoxyacetate (35.8% yield) from the first eluate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(OC(C)C)(=O)C.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21]>CCCCCCC>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][C:20](=[O:21])[C:19]([F:26])([F:25])[F:18]
Reactant: NC1Cc2ccccc2C1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Solvent: CCCCCCC
Product: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with 2-aminoindan, (104 g, 0.781 mole) and isopropyl acetate (200 mL) at 20-25° C. The solution was cooled to 0-5° C. Ethyl trifluoroacetate (133 g, 0.936 mol) was added over 40 minutes while maintaining the internal temperature at 0-10° C. (in a 0-5° C. bath). The thick slurry was stirred at 0-10° C. for 2 hours. The reaction mixture is warmed to 20-25° C. over 30 minutes and heptane (60 mL) was added. The slurry was stirred for 30 minutes and the solids were collected by filtration over a polypropylene filter paper in a Büchner funnel with suction. The filter cake was washed with 0.003% (w/v) Stadis-450 (4.5 mg Lot # 200 Dolder)/heptane (3×50 mL) or until the filtrate was colorless. The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain 149.2 g (83.4% yield) of N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide as a beige white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][CH3:20])[C:11]3=[O:21])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:23]1[NH:31][C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[N:24]=1.O>CN1C(=O)CCC1>[CH2:19]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:23]2[NH:31][C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[N:24]=2)[CH2:2][CH2:3]3)[C:11]1=[O:21])[CH3:20]
Reactant: Clc1nc2cccnc2[nH]1
Reactant: CCn1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Solvent: O
Solvent: CN1CCCC1=O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3c2nc3cccnc3[nH]2)c2ncccc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
Under nitrogen atmosphere, a mixture of 3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and 2-chloro-3H-imidazo[4,5-b]pyridine (60.3 mg) in NMP (4 mL) was stirred at 150° C. for 2 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC. Crystallization from EtOH/H2O to give the title compound (18.0 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[NH:3]1.[C:15](Cl)(=[O:19])[C:16](Cl)=[O:17].CCl>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4]3=[C:5]([C:15](=[O:19])[C:16](=[O:17])[N:3]13)[CH:6]=[C:7]([CH3:13])[CH:8]=2
Reactant: CC1=CC(C)(C)Nc2ccc(C)cc21
Reactant: O=C(Cl)C(=O)Cl
Agent: CCl
Solvent: ClCCl
Product: CC1=CC(C)(C)N2C(=O)C(=O)c3cc(C)cc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2-Dihydro-2,2,4,6-tetramethylquinoline (16.7 g., 0.09 mole) in 50 ml. dry methylene chloride was added slowly dropwise with stirring to oxalyl chloride (12.6 g., 0.1 mole) in 150 ml. dry methyl chloride under nitrogen at 30° C. Addition required 20 min., and when complete the very dark solution was stirred 15 min. at ambient temperature and one hour at a gentle reflux. The solvent was removed at reduced pressure and the dark red residue crystallized from methanol to yield a solid melting at 157°-161° C. Two additional recrystallizations from 25% chloroform in ligroine (60°-110° C.) gave a deep red crystalline solid melting at 163.5°-165.5° C. The yield was 44%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]([C:24](O)=[O:25])[CH:15]=[N:16][C:17]=1[O:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:58][C@@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[C:12]1[C:17]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:16][CH:15]=[C:14]([CH:13]=1)[C:24]([NH:58][C@@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65])=[O:25]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
5-(2-Chloro-5-trifluoromethyl-phenyl)-6-cyclopentyloxy-3-pyridinecarboxylic acid (0.14 g, 0.3 mmol) was dissolved in DMF (5 mL). To the solution was added TBTU (0.12 g, 0.4 mmol), N,N-diisopropylethyl amine (0.3 mL, 1.7 mmol) and (1R,2R)-2-amino-cyclohexanol (58 mg, 0.4 mmol). The reaction mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 0.11 g of the title compound as a colorless solid oil, MS (ISP) 483.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[C:2]([F:13])([F:12])[F:1])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (92%). m.p. 95-98° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.74, 7.65-7.52, 7.35, 6.99, 4.08-3.22, 1.55-1.46, 0.80-0.67, 0.48-0.42, 0.10-0.07. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.4, 134.2, 132.3, 129.5, 127.2, 127.1, 126.9, 121.8, 118.2, 112.5, 46.3, 44.5, 44.4, 41.2, 39.6, 34.5, 8.6, 4.2. MS (ES+) m/z 448.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-fluoro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.6 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.91 g, 4.8 mmol). The product was isolated as a white foam. Yield 0.75 g (40%). mp 94°-97° C. FDMS m/e=407 (M+ of free base). α[D]589 =+7.97 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:29])=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 34.9 %

Procedure:
1.41 g (0.00733 mol) of 1-benzyl-4-hydroxypiperidine and 1.8 ml (0.0129 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.79 ml (0.00586 mol) of 4-methoxy-benzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3→1:2). 0.666 g (35%) of 1-benzyl-piperidin-4-yl 4-methoxy-benzoate was obtained as yellowish crystals; m.p. 55°-56°.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:16]([CH3:15])[C:10](=[O:12])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)COc1ccc([N+](=O)[O-])cc1

Procedure:
MP 95°-96°. Prepared from (4-nitrophenoxy) acetic acid and N-methylbenzylamine according to the method used in Intermediate 34(a) in EP-A-494623.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[N:17]=[C:16]([O:21][CH3:22])[N:15]=1>C(N(CC)CC)C>[Cl:13][C:14]1[N:15]=[C:16]([O:21][CH3:22])[N:17]=[C:18]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)[N:19]=1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: COc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Product: COc1nc(Cl)nc(Nc2ccc(-n3ccnc3)cc2)n1
Yield: 84 %

Procedure:
This compound was prepared in analogy to example 8 from 4-(imidazol-1-yl)-aniline, triethylamine and 2,4-dichloro-6-methoxy-1,3,5-triazine. The title compound was isolated as a slightly brownish solid in 84% yield.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])[CH:47]=1>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([NH:56][CH2:55][CH2:54][CH2:53][CH2:52][C:48]2[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C(O)c1ccc(-c2ccccc2)c(-c2ccccc2)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCCc1cccnc1)c1ccc(-c2ccccc2)c(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 0.508 g 1.85 mmol) of 3,4-diphenylbenzoic acid in 10 mL of anhydrous DMF was added 0.44 mL of diphenylphosphoryl azide with stirring. Triethylamine (0.28 mL) was then added and stirring at 3° C. 0 was continued for 1 hour. 3-pyridinebutanamine (0.309 g) was added and stirring was continue for 30 minutes at 3° C. and for 17 hours at room temperature. The solvent was removed under the oil pump vacuum and ethyl acetate was added to the residue. The solution was washed with aqueous 5% sodium bicarbonate. dried (MgSO4) and concentrated in vacuo. The residual oil was chromatographed on 50 g of silica gel, eluting with methylene chloride-methanol-conc.ammonium hydroxide (95:5:0.05). The pure fractions were combined and lyophilized from benzene to yield a 0.708 g of 3,4-Diphenyl-N-[4-(3-pyridinyl)butyl]benzamide 0.25 molar hydrate as a colorless foam.