Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:25])C(=O)C1>CC#N>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:25])[NH:10][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CC)c(=O)c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCCCn1c(=O)n(CC)c(=O)c2[nH]c(Cl)nc21
Temperature: 120 °C

Procedure:
3-Butyl-1-ethyl-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.42 mmol) and NCS (56 mg, 0.42 mmol) were suspended in MeCN (5 mL) and heated at 120° C. under microwave irradiation. The reaction mixture was concentrated under reduced pressure and the title compound isolated using HPLC. [HPLC conditions used for the purification: 23 minute run time. Solvents: 0.1% TFA in MeCN and 0.1% TFA in water. MeCN increased from 5% to 95% linearly over 15 minutes. Held at 95% for 2 min. Then decreased to 5% linearly over 1 min., equilibrated at 5% for 5 minutes before next injection.]; 1H NMR (400 MHz; CDCl3) δ: 0.97 (3H, t), 1.31 (3H, t), 1.38-1.45 (2H, m), 1.72-1.80 (2H, m), 4.09-4.20 (4H, m), 13.40 (1H, br.s); m/z 271[MH+].
Reaction SMILES: [OH-].[Na+].CC(O)CC.[F:8][C:9]([F:46])([F:45])[C:10]1[CH:44]=[CH:43][C:13]2=[N+:14]([O-])[N:15]([C:17]3[CH:22]=[C:21]([C:23]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:31]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)([CH3:33])[CH3:32])[C:18]=3[OH:41])[N:16]=[C:12]2[CH:11]=1.ClC1C(=O)C2C(C(=O)C=1Cl)=CC=CC=2>C(C(C)=O)C>[F:46][C:9]([F:8])([F:45])[C:10]1[CH:44]=[CH:43][C:13]2=[N:14][N:15]([C:17]3[CH:22]=[C:21]([C:23]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[CH3:25])[CH:20]=[C:19]([C:31]([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)([CH3:33])[CH3:32])[C:18]=3[OH:41])[N:16]=[C:12]2[CH:11]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3cc(C(F)(F)F)ccc3[n+]2[O-])c(O)c(C(C)(C)c2ccc(F)cc2)c1
Agent: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: CCC(C)O
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)c2ccc(F)cc2)c1
Temperature: 83 °C

Procedure:
To a 500 mL three-necked flask equipped with a mechanical stirrer, 3.7 g of sodium hydroxide pellets and 50 mL of 2-butanol are charged and heated to 83° C. To this solution is added over a 90-minute period a solution of 230 mL of methyl ethyl ketone, 20 g of the benzo-triazole-N-oxide prepared in Example 15 and 0.85 g of 2,3-dichloro-1,4-naphthoquinone. The mixture is refluxed at 88° C. for one hour while distilling off methyl ethyl ketone. After cooling down to ambient temperature, 25 g of water and 30 mL of ethyl acetate are added at which time the pH is reduced to 3 with 30% aqueous sulfuric acid. After splitting off the aqueous layer, the solvent is removed by distillation. The crude solid is purified by silica gel chromatography using heptane/ethyl acetate (49/1) as eluent. After collecting the desired fractions and crystallizing from methanol/toluene, the title compound is obtained in a yield of 14 g as a light yellow solid melting at 120-122° C. The structure is consistent with analyses by 1Hnmr, 19Fnmr and mass spectroscopy.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33]Cl>CS(C)=O.O>[CH2:7]([NH:19][CH2:33][CH2:32][CH2:31][O:30][C:21]1[CH:22]=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: CCCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCNCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-dodecylamine (0.51 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-dodecyl)-(3-(naphthalen-2-yloxy)-propyl)amine, solid. m.p. 126° C., (yield 0.78 gm, 92.8%).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:32])[C:12]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:13]3[C:18](=[O:19])N(CCC)C=C[N:14]3[CH:23]=2)=[O:9])=[CH:4][CH:3]=1.[C:35]([OH:38])(=[O:37])[CH3:36].Cl[CH2:40]Cl>>[CH3:40][O:37][C:35]([C:36]1[N:14]([CH2:13][CH:18]=[O:19])[CH:23]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]2[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=2)[C:11](=[O:32])[C:12]=1[O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:38]
Reactant: CC(=O)O
Reactant: ClCCl
Reactant: CCCn1ccn2cc(C(=O)NCc3ccc(F)cc3)c(=O)c(OCc3ccccc3)c2c1=O
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Yield: 82 %

Procedure:
According to the method of synthesizing a compound 17-1, the crude purified product (503 mg) of a compound 48 was obtained at a yield of 82% from a compound 16 (600 mg), 2) To a solution of a compound 48 (100 mg, 0.22 mmol), isobutylaldehyde (39 μl, 0.432 mmol) and acetic acid (25 μl, 0.432 mmol) in dichloromethane (4 ml) was added sodium triacetoxyborohydride (92 mg, 0.432 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Further, isobutylaldehyde (200 and sodium triacetoxyborohydride (46 mg) were added, and the mixture was stirred for 30 minutes. To the reaction solution was added water, this was extracted with chloroform, and the organic layer was washed with an aqueous saturated sodium bicarbonate solution. After drying, the solvent was distilled off under reduced pressure, and this was purified by silica gel column chromatography. A compound 49 (87 mg) was obtained as a colorless crystal at a yield of 78%.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[CH:24]([NH2:27])([CH3:26])[CH3:25].N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[CH:24]([NH:27][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Reactant: CC(C)N
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC(C)C)on1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a solution of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol) and isopropyl amine (22 mg, 0.37 mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (26 mg, 0.19 mmol) and the reaction stirred under argon for 3 h at 50° C. Then the mixture was evaporated and the residue purified by chromatography (silica, heptane:ethyl acetate=4:1 to 1:1) to afford the title compound (95 mg, 83%) which was obtained as an off-white solid. MS: m/e=343.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[Br:22])[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:9][CH2:10]1)(=[O:3])[CH3:2].[C:1]([O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[C:12]([Br:22])=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CCN(c2cc3c(cc2Br)NC(=O)CC3)CC1
Product: CC(=O)OC1CCN(c2ccc3c(c2Br)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 300 mg of 6-(4-acetoxypiperidino)-3,4-dihydrocarbostyril in 7 ml of chloroform was added 370 mg of N-bromosuccinimide, and the mixture was stirred at room temperature for 1 hr. Then, an aqueous sodium thiosulfate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with brine, dried and evaporated under a reduced pressure. The crude mixture was purified by a silica gel column chromatography to give 87 mg of 6-(4-acetoxypiperidino)-7-bromo-3,4-dihydrocarbostyril and 41 mg of 6-(4-acetoxypiperidino)-5-bromo-3,4-dihydrocarbostyril.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]([CH3:35])=[C:13]([CH2:15][N:16]([CH2:33][CH3:34])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:14]=2)[CH:5]=1.[Li+].[OH-].Cl.CCOCC>C1COCC1.O>[CH2:33]([N:16]([CH2:15][C:13]1[N:14]=[C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:36])=[O:2])[O:11][C:12]=1[CH3:35])[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:19][CH:18]=1)[CH3:34]
Reactant: CCN(Cc1nc(-c2cccc(C(=O)OC)c2)oc1C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(Cc1nc(-c2cccc(C(=O)O)c2)oc1C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of 92 mg (0.18 mmol) of 3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic acid methyl ester (example 30.2) in 1 mL of THF was treated with 1 mL of 1M aqueous LiOH and stirred at RT for 1 h. The mixture was acidified to pH 4-5 with aqueous HCl and distributed between Et2O and H2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 79 mg (88%) of 3-[4-({ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic acid, light yellow solid, MS: 503 (MH+).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH2:5]=O.[C:7]([C:11]1[CH:12]=[CH:13][C:14]2[S:18](=[O:19])[CH:17]=[N:16][C:15]=2[CH:20]=1)(=[O:10])[CH2:8][CH3:9]>C(OC(=O)C)(=O)C>[CH3:2][N:3]([CH3:5])[CH2:4][CH:8]([CH3:9])[C:7]([C:11]1[CH:12]=[CH:13][C:14]2[S:18](=[O:19])[CH:17]=[N:16][C:15]=2[CH:20]=1)=[O:10]
Reactant: C=O
Reactant: CNC
Reactant: CCC(=O)c1ccc2c(c1)N=CS2=O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CC(CN(C)C)C(=O)c1ccc2c(c1)N=CS2=O

Procedure:
Acetic anhydride (70 ml) was added to a solution of dimethylamine hydrochloride (12.7 g) in 37% aqueous solution (10.5 ml) of formaldehyde at 80° C. To the solution was added 5-propionylbenzothiazolone (21.5 g) and the resultant mixture was stirred at the same temperature for 2 hours. After the solvent was evaporated in vacuo, the residue was treated with a mixture of saturated aqueous solution of sodium bicarbonate and ethyl acetate. Insoluble powder was collected by filtration to give 5-(3-dimethylamino-2-methylpropionyl)benzothiazolone (12.5 g) as light red-violet powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1.BrC1C=CC([C@H]2C[C@@H]2C[OH:24])=CC=1>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][CH2:12][OH:24])=[CH:4][CH:3]=1
Reactant: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: OC[C@H]1C[C@@H]1c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCC[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
The alkene intermediate from Example 29F (1.64 g, 7.35 mmol) was converted to the alcohol by the method of Example 26F, followed by chromatography (7:3 hexane/ethyl acetate) provided the title compound. 1H NMR (300 MHz, CDCl3): δ 0.96-0.79 (m, 2H), 1.00-1.14 (m, 1H), 1.54-1.76 (m, 3H), 4.91-4.97 (m, 1H), 3.76 (t, J=6 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 7.35 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 258 (M+NH4)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1cccc(-c2cc(Cl)ccn2)c1
Agent: Cl
Product: OCCc1ccc(Nc2ccnc(-c3cccc(Cl)c3)c2)cc1
Yield: 64.8 %

Procedure:
Following general procedure A2, 4-chloro-2-(3-chlorophenyl)pyridine hydrochloride (0.114 g, 0.44 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.072 g, 0.53 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.103 g, 65%) as a light yellow solid. MW=361.27. 1H NMR (DMSO-d6, 500 MHz) δ 14.08 (s, 1H), 10.70 (s, 1H), 8.28 (d, J=7.0 Hz, 1H), 7.96 (t, J=2.0 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.37-7.28 (m, 5H), 7.13-7.08 (m, 1H), 3.64 (t, J=7.0 Hz, 2H), 2.76 (t, J=7.0 Hz, 2H); APCI MS m/z 325 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl(O)(=O)(=O)=O.[OH-:17].[NH4+:18]>Cl>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:18]2[CH2:10][CH2:11][C:6](=[O:17])[CH2:7][CH2:8]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: [OH-]
Reactant: CCCCNc1ccccc1
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCNc1ccc(N2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
A solution of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (13.01 g, 49 mmol) was hydrogenated under 45 psi for one hour using 10% palladium on carbon (2.5 g) as catalyst. The reaction mixture was filtered through celite pad and the filtrate was concentrated down to give a white solid (11.46 g, 100%). This material was taken onto next step immediately. To a stirred mixture, under N2 atmosphere, of the aniline (11.46 g, 49 mmol), butryaldehyde (4.43 mL, 49 mmol) in tetrahydrofuran (250 mL) was added sodium triacetoxyborohydride (14.62 g, 68.6 mmol), and glacial acetic acid (2.82 mL, 49 mmol). The reaction was stirred for two hours. The reaction was quenched with 1N NaOH (50 mL), diluted with water, extracted with ether 3 times and dried over sodium sulfate. The product was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give an oil (5.80 g, 41%). This material was immediately taken onto next step. A solution of the N-butyl aniline (5.80 g, 19.9 mmol) in a 1:1 mixture of perchloric acid and hydrochloric acid (100 mL) was stirred at room temperature for three days. The reaction mixture was poured onto ice and made basic with concentracted ammonium hydroxide, extracted with ether four times, dried over sodium sulfate and concentrated to give a yellow oil. The yellowish oil was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give 1-[4-(butylamino)phenyl]-4-piperidineone as an oil (3.84 g, 82%). To a stirred mixture of 1-[4-(butylamino)phenyl]-4-piperidineone (2.46 g, 10 mmol), triethylamine (1.81 mL, 13 mmol), and 4-(dimethylamino)pyridine (DMAP) (catalytic amount) was added ethyl 3-chloro-3-oxopropionate (2.18 g, 13 mmol) dropwise. The reaction was stirred for 18 hours. The reaction mixture was filtered, concentrated in vacuo, taken up in methylene chloride, and washed with saturated sodium bicarbonate two times and dried over sodium sulfate. The product was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give a yellow oil (3.84 g, 68%); MS (ES) m/z: 361.3 (MH+, 100%).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]2[C:27]([CH2:28][NH:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([Cl:42])[C:36]=4[Cl:43])[N:33]=[N:32][N:31]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[C:3]([OH:5])(=[O:4])[CH3:2].[C:3]([OH:5])(=[O:4])[CH3:2].[N:18]1([C:22]2[C:27]([CH2:28][NH:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([Cl:42])[C:36]=4[Cl:43])[N:33]=[N:32][N:31]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:19][CH2:20][CH2:21][NH:15][CH2:16][CH2:17]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ncccc2CNc2nnnn2-c2ccc(F)c(Cl)c2Cl)CC1
Solvent: ClCCl
Product: CC(=O)O
Product: Fc1ccc(-n2nnnc2NCc2cccnc2N2CCCNCC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of the product of Example 288C (0.40 g, 0.744 mmol) in dichloromethane (15 mL) at 0° C. 5 minutes later, the ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by preparative HPLC on a Thermoquest, hyperprep HS C18 column (250×21.2 mm., 8 μm particle size) using a gradient of 5% to 75% acetonitrile to ammonium acetate (10 mM) over 20 minutes at a flow rate of 21 mL/min to provide the title compound. MS (ESI+) m/z 437.3 (M+H)+; Rt=1.41 min. 1H-NMR (400 MHz, DMSO-d6), 1.78 (m, 2H), 1.98 (s, 6H), 2.84 (m, 2H), 2.90 (m, 2H), 3.38 (m, 4H), 4.46 (d, J=5.1 Hz, 2H), 6.85 (dd, J=4.8 Hz, J=7.5 Hz, 1H), 7.53 (dd, J=1.9 Hz, J=7.5 Hz, 1H), 7.61 (t, J=5.6 Hz, 1H), 7.74 (t, J=8.8 Hz, 1H), 7.86 (dd, J=5.3 Hz, J=9.0 Hz, 1H), 8.08 (dd, J=1.9 Hz, J=4.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:35]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:35])=[CH:16][C:15]=2[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)CC(c2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
To a mixture of 4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (2.93 g, 7.31 mmol) produced in Example (8a), sodium acetate (6 g, 73.14 mmol) and methanol (50 mL) was added bromine (0.37 mL, 7.22 mmol), followed by stirring for 20 minutes at room temperature under a nitrogen atmosphere. Saturated aqueous solution of sodium thiosulfate, ethyl acetate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2.67 g of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].[CH3:35]I>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH3:35])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CI
Reactant: Cc1ccccc1N1C(=O)NCC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(=O)N(C)CC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=500.2 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-2-one and methyl iodide.
Reaction SMILES: [CH2:1]([NH2:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[Cl-].[CH2:13]([O:15][C:16](=[O:20])[C:17](O)=[O:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:20])[C:17]([NH:11][CH2:1]/[CH:2]=[C:3](\[CH3:4])/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:18])[CH3:14]
Reactant: CC(C)=CCC/C(C)=C/CN
Reactant: CCOC(=O)C(=O)O
Agent: [Cl-]
Product: CCOC(=O)C(=O)NC/C=C(\C)CCC=C(C)C

Procedure:
Said substance is manufactured according to AAV 1, by converting geranylamine and oxalic acid monoethylester chloride with each other and the product is purified by column chromatography (pentane/diethyl ether=2/1).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]([C:18](=[O:38])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]2[C:35]([C:36]#[N:37])=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH:20]=1)[CH3:17])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:16]([CH3:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][C:6]([OH:39])=[O:5])=[O:38])=[CH:20][C:21]=1[C:26]1[C:35]([C:36]#[N:37])=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1
Reactant: CN(C(=O)c1ccc(Cl)c(-c2nc3ccccc3cc2C#N)c1)c1ccccc1CCCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)c(-c2nc3ccccc3cc2C#N)c1)c1ccccc1CCCC(=O)O

Procedure:
4-(2-{[4-Chloro-3-(3-cyano-quinolin-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyric acid tert-butyl ester (20 mg, 0.037 mmol) was stirred in a mixture of DCM (0.2 mL) and TFA (0.2 mL) for 1 hr. The mixture was concentrated, dissolved in MeOH and purified by prep LCMS to yield 4-(2-{[4-chloro-3-(3-cyano-quinolin-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyric acid 15-1. MS [M+H]+: 483.9; tR=7.05 min, (method 2)
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.Br[CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:22]=[C:21]2[C:34]1[N:35]=[N:36][N:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:40]=2)[CH:38]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:48][O:47][C:45]([C:42]1[CH:43]=[CH:44][C:39]([N:37]2[CH:38]=[C:34]([C:21]3[C:20]4[C:24](=[CH:25][CH:26]=[C:18]([CH2:17][N:13]5[C:12](=[O:15])[CH:11]=[CH:10][C:9]([C:6]6[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=6)=[N:14]5)[CH:19]=4)[N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:22]=3)[N:35]=[N:36]2)=[CH:40][CH:41]=1)=[O:46]
Reactant: O=c1ccc(-c2ccncc2)n[nH]1
Reactant: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(CBr)cc34)nn2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(Cn5nc(-c6ccncc6)ccc5=O)cc34)nn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydride (106 mg; 2.43 mmol; 7.4 eq.) was added in one portion to a solution of 6-pyridin-4-ylpyridazin-3(2H)-one (176 mg; 1.02 mmol; 3.1 eq.) in DMF (6 mL). After 10 min a solution of tert-butyl 5-(bromomethyl)-3-{1-[4-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole-1-carboxylate (565 mg; 0.33 mmol; 1.0 eq.) in DMF (6 mL) was added dropwise over 2 min and the reaction solution stirred for 4 h at RT. The reaction mixture was then poured into saturated solution of NaHCO3 and extracted with EtOAc. Combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to give the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.75-8.62 (m, 3H), 8.30 (d, J=8.8 Hz, 2H), 8.24-8.18 (m, 3H), 8.15 (d, J=9.2 Hz, 1H), 7.93 (dd, J=1.6, 4.6 Hz, 2H), 7.78-7.72 (m, 1H), 7.19 (d, J=9.8 Hz, 1H), 5.59 (s, 2H), 3.92 (s, 3H), 1.68 (s, 9H). MS (ESI+): 605.3.