Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:15]C(OCC1C=CC=CC=1)=O)([CH3:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[OH-].[Na+]>CO.O.[OH-].[OH-].[Pd+2]>[CH3:14][C:2]([NH2:15])([CH3:1])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: CC(C)(Cc1ccc2ccccc2c1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(N)Cc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Palladium hydroxide on carbon (19.7 g) was suspended in methanol (500 ml), to the suspension was added a solution of N-[2-methyl-1-(naphthalen-2-yl)propan-2-yl]-benzyloxycarboxamide (237.6 g) obtained in Step 11 in methanol (2 L), and a hydrogenation reaction was performed at room temperature overnight. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and to the solution was added conc. hydrochloric acid (70 ml) to give crystals. The obtained crystals were suspended in water, and after an addition of 4N aqueous sodium hydroxide solution (350 ml), the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crystals of the title compound (138 g).
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1.Cl[CH2:22][CH2:23][CH2:24][N:25]1[C:38]2[CH:37]=[C:36]([S:39][CH3:40])[CH:35]=[CH:34][C:33]=2[S:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2>CN(C)C=O>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][N:25]3[C:38]4[CH:37]=[C:36]([S:39][CH3:40])[CH:35]=[CH:34][C:33]=4[S:32][C:31]4[C:26]3=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:15][CH2:14]2)=[O:12])=[CH:19][CH:20]=1
Reactant: CSc1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)N(CCCN1CCC(C(=O)c3ccc(F)cc3)CC1)c1ccccc1S2
Temperature: 78 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a stirred solution of sodium bicarbonate (10 g) in 40 ml of dimethylformamide was added 2.5 g of 4-(4-fluorobenzoyl)piperidine in 40 ml of dimethylformamide, and 4.5 g of 10-(3-chloropropyl)-2-methylthiophenothiazine in 20 ml of dimethylformamide. The reaction mixture was stirred at 78° C. for four hours, cooled, and filtered. The filtrate was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, filtred and concentrated to an oil. The oil was purified by high pressure liquid chromatography on a silica gel column, utilizing ethyl acetate as the eluent. Concentration of the appropriate fractions yielded 2.97 g (36%) of 4-(4-fluorobenzoyl)-1-[3-(2-methylthio-10H-phenothiazin-10-yl)propyl]piperidine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.I[CH3:13].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:11][CH3:13])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.7 %

Procedure:
A mixture of 6.87 g of ethyl 4-bromobenzoate (10) was allowed to react with 64 mL (1.4 M in toluene) of methyl magnesium bromide in THF at −40° C. for 1 hour, and the reaction mixture was gradually warmed to 0° C. The reaction was quenched with saturated aqueous ammonium chloride solution and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (50:1 to 10:1 hexanes-ethyl acetate) afforded 6.44 g (99% yield) of 2-(4-bromophenyl)propan-2-o1; MS (AP/CI) observed: 199.1 (M+H−H2O)+, 100%; 213.1, 215.1 (M−H)−, 60%, 80%. 2-(4-Bromophenyl)propan-2-o1 (1.77 g) and iodomethane (1.16 g) in THF (100 mL) were treated with sodium hydride, 60% in mineral oil (328 mg). After stirring for 24 h at room temperature, the reaction mixture was quenched with dilute aqueous hydrochloric acid, was extracted with ethyl acetate, and the organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. The resultant oil was purified by silica gel chromatography (200:1 hexanes-ethylacetate) to afford 0.5 g of 1-bromo-4-(1-methoxy-1-methyl-ethyl)-benzene; 13C NMR (400 MHz, CDCl3) δ 145.35, 131.53, 127.91, 121.00, 50.90, 28.60.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[O:11]=[C:7]1[NH:6][C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[N:4][C:3]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]1[C:9]#[N:10]
Reactant: C1CNCCN1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCNCC2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 80 mg (0.30 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 326 mg (3.80 mmol) of piperazine to give 45 mg (49% of theory) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(C2C=CC=CC=2O)C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1I)[O:27][CH2:26][CH:25]([CH2:32][CH2:33][CH3:34])[CH2:24]2.[C:35]([O:43][CH2:44][CH3:45])(=[O:42])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>C1COCC1.[Cu]I.CCOCC>[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:35]([O:43][CH2:44][CH3:45])=[O:42])[O:27][CH2:26][CH:25]([CH2:32][CH2:33][CH3:34])[CH2:24]2
Reactant: CCCC1COc2cc(I)c(F)cc2C1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1-c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC1COc2cc(C(C(=O)OCC)C(=O)OCC)c(F)cc2C1

Procedure:
17.0 g (52.2 mmol) of anhydrous caesium carbonate, 700 mg (3.67 mmol) of copper(I) iodide and 700 mg (4.11 mmol) of o-phenylphenol are initially introduced under dry nitrogen, a solution of 11.4 g (33.5 mmol) of 6-fluoro-7-iodo-3-propylchroman and 16.0 g (100 mmol) of diethyl malonate in 150 ml of THF is added, and the mixture is heated under reflux overnight. MTB ether is subsequently added to the batch, which is washed with dil. hydrochloric acid and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is purified by chromatography on silica gel with heptane/ethyl acetate (4:1). The product fraction (Rf=0.55) is reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([N+:21]([O-])=O)[C:12]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H][H]>C1COCC1.[Ni]>[NH2:21][C:13]1[C:12]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:11]([CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:30]
Reactant: [H][H]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1N1CCCCC1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)cc(C(=O)Nc2ccc(Cl)c(Cl)c2)c1N1CCCCC1

Procedure:
To a solution of N-(3,4-dichlorophenyl)-3-nitro-2-piperid-1-yl-5-trifluoromethylbenzamide, Example 1 (4.15 g) in THF (80 ml), is added Raney nickel (2 g) under nitrogen. The reaction medium is hydrogenated at room temperature under a pressure of 45 bar. At the end of the reaction (stable absorption of hydrogen), the catalyst is removed and the medium is concentrated. 3.15 g of 3-amino-N-(3,4-dichlorophenyl)-2-piperid-1-yl-5-trifluoromethylbenzamide are obtained as a white solid.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[H-].[Na+].[Na].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1C(F)(F)F>CN(C)C=O>[CH:7]1[CH:8]=[CH:9][C:4]([NH:3][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=CNc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 155 °C

Procedure:
the formanilide is treated with a one-molar equivalent of sodium hydride in dimethylformamide and the resulting solution of the sodium salt is treated with 2-chloro-5-nitrobenzotrifluoride (U.S. Pat. No. 3,657,350) at an elevated temperature (e.g., 155° C., reflux), to give the 4-nitrodiphenylamine (J. Organic Chemistry, 42, 1786 (1977) and references therein).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][O:6][CH2:7][CH3:8])=[O:4].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1/[C:14](=[N:18]/[OH:19])/[C:15]([OH:17])=[O:16]>CS(C)=O>[CH2:7]([O:6][NH:5][C:3]([CH2:2][O:19]/[N:18]=[C:14](/[C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)\[C:15]([OH:17])=[O:16])=[O:4])[CH3:8]
Reactant: O=C(O)/C(=N\O)c1ccco1
Reactant: CCONC(=O)CCl
Solvent: CS(C)=O
Product: CCONC(=O)CO/N=C(\C(=O)O)c1ccco1
Yield: 81 %

Procedure:
This compound was prepared from ethyl chloroacetohydroxamate and Z-2-(fur-2-yl)-2-hydroxyimino acetic acid by the method described in Preparation 4, τ(DMSO d6) 2.15, 3.2, 3.39 (furyl), 5.48 (--OCH2CO--), 6.18 (--OCH2 --), 8.88 (--CH3). Yield 81%.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=[CH:12][C:11]=2[C:10]=1[CH:27]=O)C1C=CC=CC=1.[OH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])=O.[NH4+]>ClCCCl>[OH:29][CH:30]1[CH2:34][CH2:33][N:32]([CH2:27][C:10]2[C:9]([OH:8])=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][N:14]3[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH2:31]1
Reactant: O=Cc1c(OCc2ccccc2)ccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: OC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c(CN3CCC(O)C3)c(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 5-(benzyloxy)-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (Intermediate 4, 100 mg, 0.250 mmol) in DCE (3 mL) was added 3-hydroxypyrrolidine, (33 mg, 0.38 mmol) and sodium triacetoxyborohydride (0.16 g, 0.77 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in MeOH (2 mL) and Pd/C 10 wt. % (0.020 g, 0.019 mmol) was added and the mixture was flushed with N2 gas. Ammonium formate (0.050 g, 0.80 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken up in CHCl3/H2O, and the mixture was washed with water and brine, dried (MgSO4) and the solvent was removed under reduced pressure to give 4-[(3-hydroxypyrrolidin-1-yl)methyl]-1-(phenylsulfonyl)-1H-indol-5-ol (85 mg) as an oil. MS m/z 373 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:8]([CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1cc2cc(Cl)cnc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc2cc(Cl)cnc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a stirred solution of methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.986 g, 4.68 mmol) N,N-dimethylformamide (20 ml) at room temperature under a nitrogen atmosphere was added potassium carbonate (0.647 g, 4.68 mmol). After 30 minutes iodomethane (0.321 ml, 5.15 mmol) was added and the resulting mixture was stirred at room temperature overnight. Brine was added and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was coated onto hydromatrix and purified by column chromatography (silica gel; heptane/ethyl acetate 4/1) to give methyl 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.89 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](O)Cc1ccc(Cl)c(Cl)c1
Temperature: -35 °C
Reaction time: 1 h

Procedure:
A solution of 12.2 g (38.0 mmol) (1R)—B-chlorodiisopinocampheylborane in 20 mL THF was added dropwise within 30 min to a solution of 8.0 g (34.3 mmol) 3-(3,4-dichloro-phenyl)-2-oxo-propionic acid and 5.2 mL (38.0 mmol) triethylamine in 40 mL THF cooled to −35° C. and the reaction mixture was kept for 1 h at this temperature. The cooling bath was removed and the reaction solution was stirred for 4 h at RT. Then the reaction solution was carefully combined with 50 mL 1 M NaOH (exothermic) and 30 mL TBME at 5-10° C. and stirred for 15 min. The organic phase was separated off and extracted with 25 mL water and 15 mL 1 M NaOH. The combined aqueous phases were acidified with 2 M HCl and extracted three times with in each case 40 mL TBME. The combined organic phases were dried over Na2SO4 and evaporated down i. vac. The residue was dissolved in 80 mL boiling water and suction filtered through Celite. The filtrate was saturated with NaCl and extracted three times with EtOAc. The combined organic phases were filtered through Na2SO4 and again evaporated down i. vac. The crude product was further reacted without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:27]([O:28][CH2:29][CH:30]3[CH2:34][CH2:33][O:32][CH2:31]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:35])[C:18]([Cl:36])=[CH:17][N:16]=1>>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[C:27]([O:28][CH2:29][CH:30]3[CH2:34][CH2:33][O:32][CH2:31]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:35])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: Fc1cccc(OCC2CCOC2)c1Nc1nc(Cl)ncc1Cl
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCC4CCOC4)n3)cc2N1

Procedure:
Title compound was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-furan-3-ylmethoxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid. (65 mg, 49%) HPLC purity=94%, LCMS=498.20 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.47 (s, 1H), 9.14 (s, 1H), 8.77 (s, 1H), 8.14 (s, 1H), 7.34-7.31 (m, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.94-6.90 (m, 2H), 6.84 (d, J=8.3 Hz, 1H), 3.94-3.85 (m, 2H), 3.55-3.51 (m, 3H), 3.32-3.28 (m, 1H), 2.55-2.51 (m, 2H), 2.07-2.01 (m, 4H), 2.94-2.84 (m, 1H), 1.49-1.43 (m, 1H), 1.05-1.03 (m, 1H).
Reaction SMILES: C([O:8][C:9]([Cl:12])(Cl)Cl)(OC(Cl)(Cl)Cl)=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>ClCCl>[N:13]1([C:9]([Cl:12])=[O:8])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 65.2 %

Procedure:
Into a 500-mL round-bottom flask was placed ditrichloromethyl carbonate (10.2 g, 34.37 mmol, 1.50 equiv) and dichloromethane (100 mL). This was followed by the addition of morpholine (2 g, 22.96 mmol, 1.00 equiv) dropwise with stirring at 0° C. in 2 min. To this was added TEA (4.2 g, 41.51 mmol, 1.81 equiv) dropwise with stirring at 0° C. in 3 min. The resulting solution was stirred for 3 h at room temperature. The reaction was then washed by the addition of 100 mL of water. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). Purification afforded 2.238 g (65%) of morpholine-4-carbonyl chloride as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:29][C:28]3[CH:30]=[CH:31][C:25]([C:24]([F:23])([F:32])[F:33])=[CH:26][CH:27]=3)=[O:14])=[CH:15][CH:16]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(-c2ncccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a suspension of 4-(3-chloro-pyridin-2-yl)-benzoic acid (5.0 g, 21.4 mmol) in methylene chloride (100 mL) at ambient temperature was added oxalyl chloride (5.43 g, 42.79 mmol) followed by two drops of DMF and the mixture was heated to reflux for 30 minutes. The clear solution was then concentrated to dryness, dissolved in methylene chloride (100 mL) and was treated with 4-trifluoromethyl aniline (4.14 g, 25.68 mmol) followed by triethylamine (2.6 g, 25.68 mmol) and the mixture was gently heated to reflux for 30 minutes and agitated overnight at ambient temperature. After treating the mixture with sat. Na2CO3, the organic layer was separated, washed with water, dried and concentrated to give the crude product which was chromatographed on silicagel to obtain 4.0 g (49.6%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[C:6]([CH3:13])[N:5]=1)[CH3:2].[CH3:14][C:15]1([CH3:34])[O:19][CH:18]([CH2:20][O:21][C:22]2[C:31]([CH3:32])=[CH:30][C:25]([C:26]([NH:28]O)=[NH:27])=[CH:24][C:23]=2[CH3:33])[CH2:17][O:16]1>>[CH3:14][C:15]1([CH3:34])[O:19][CH:18]([CH2:20][O:21][C:22]2[C:23]([CH3:33])=[CH:24][C:25]([C:26]3[N:28]=[C:10]([C:8]4[CH:7]=[C:6]([CH3:13])[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=4)[O:12][N:27]=3)=[CH:30][C:31]=2[CH3:32])[CH2:17][O:16]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: CCNc1nc(C)cc(C(=O)O)n1
Product: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC4COC(C)(C)O4)c(C)c3)no2)n1

Procedure:
2-Ethylamino-6-methyl-pyrimidine-4-carboxylic acid and 4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine are coupled followed by cyclisation in analogy to Example 1 to give (4-{3-[4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-phenyl]-[1,2,4]-oxadiazol-5-yl}-6-methyl-pyrimidin-2-yl)-ethyl-amine; LC-MS: tR=1.12 min; [M+H]+=440.21.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[NH:5][NH:4]1.O.NN.FC(F)(F)C1(C2C=C(CN)C=CC=2)N=N1>C(O)C>[F:25][C:2]([F:1])([F:24])[C:3]1([C:6]2[CH:7]=[C:8]([CH2:9][NH2:10])[CH:21]=[CH:22][CH:23]=2)[NH:4][NH:5]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(C2(C(F)(F)F)NN2)c1
Agent: NCc1cccc(C2(C(F)(F)F)N=N2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cccc(C2(C(F)(F)F)NN2)c1
Reaction time: 3.5 h
Yield: 53.5 %

Procedure:
A stirred solution of intermediate 65, 2-[3-(3-trifluoromethyl-diaziridin-3-yl)-benzyl]-isoindole-1,3-dione, (150 mg, 0.43 mmol) in ethanol (2 mL) was treated with hydrazine hydrate (0.4 mL) at room temperature and the solution stirred for 3.5 hrs. After removing ethanol in vacuo, the residue was partitioned between CH2Cl2 and water. The aqueous phase was acidified with dilute HCl, and washed with CH2Cl2. The aqueous phase was basified with dilute NaOH, and extracted with CH2Cl2. The organic extract was dried (MgSO4), filtered, and concentrated to obtain 50 mg (Yield 54%) of (3-(3-(trifluoromethyl)diaziridin-3-yl)phenyl)methanamine and (3-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanamine as a 1:1 mixture; 1H NMR (300 MHz, CDCl3) δ ppm: 3.85 (2H, s) 3.88 (2H, s) 7.08 (2H, s) 7.31–7.40 (4H, m) 7.43–7.50 (1H, m, J=6.2 Hz) 7.54 (1H, s); LC/MS m/z 216 (M+H for diazirine) and 218 (M+H for diaziridine).
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:13]([N-]C(C)C)(C)C.[Li+].CI.CCOC(C)=O.CCCCCC>C1COCC1>[CH3:13][C:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCc2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CCCCCC
Product: CC1(C(=O)O)CCc2ccccc21
Temperature: -20 °C

Procedure:
A solution of indane-1-carboxylic acid (4.1 g, 25.3 mmol) in THF (30 ml) was added in portions to a solution of lithium diisopropylamide in THF (2M, 27.8 ml, 55.6 mmol) with stirring at −20° C. The solution was then stirred at 35° C. for 1 hour, then cooled again to −20° C. and a solution of methyl iodide (2.05 ml, 32.89 mmol) in THF (10 ml) was added. The light yellow solution was warmed at 35° C. for 4 hours before extracting between HCl (2M) and EtOAc to yield the crude product (4.5 g) as a brown oil. This mixture was cromatographed on HPLC with EtOAc/hexane to yield 1-methyl-1-indanecarboxylic acid (1 g) and recovered starting material (700 mg)
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C[O-].[Na+].Br[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][C:25]3=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:14][CH:13]=1>CO>[CH2:1]([S:3][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][C:25]3=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:35][CH:36]=1)[CH3:2]
Reactant: CCS
Reactant: O=C(c1ccc(OCCCBr)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethanethiol (0.125 ml) is dissolved in methanol (10 ml) and thereto is added sodium methoxide (0.11 g). The mixture is stirred at room temperature for 30 minutes. Thereto is added a solution of 1-{1-[4-(3-bromopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.59 g) in methanol (2 ml) and the mixture is stirred at room temperature overnight. The solvent is concentrated and water is added to the residue, extracted with chloroform, dried with sodium carbonate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give 1-{1-[4-(3-ethylthiopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.2 g).