Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=3)[N:9]=[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>N1C=CC=CC=1>[NH2:19][C:13]1[C:14]([NH:18][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[C:15]([NH2:17])[N:16]=[C:11]([N:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:9]2)[N:12]=1
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1N
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under argon, 300 mg (0.814 mmol) of the compound from example 6A were initially charged in pyridine (10 ml), the mixture was cooled to 0° C. and 78 μl (0.814 mmol) of ethyl chloroformate were then added dropwise. The reaction mixture was stirred at 0° C. for 1 h and then concentrated. The residue was separated by means of preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)−gradient) and the product fractions were concentrated. This gave 77 mg (21% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[C:10]([NH2:21])[C:11]([NH2:20])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=O)=[CH:25][CH:24]=1.O>N1C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[NH:20][C:11]3=[N:12][C:13]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])[N:9]=[C:10]3[N:21]=2)=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1nc(-c2cccnc2)c(-c2ccncc2F)nc1N
Solvent: O
Solvent: c1ccncc1
Product: Fc1ccc(-c2nc3nc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 120 °C
Yield: 33.3 %

Procedure:
A mixture of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazine-2,3-diamine (Example 153, 0.100 g, 0.35 mmol) and 4-fluorobenzoyl chloride (0.074 g, 0.46 mmol) in pyridine (1 mL) was stirred and heated to 120° C. in a sealed tube for 24 hours. Water was added and the filtered solid was purified by silica gel chromatography eluting with CH2Cl2/MeOH (98:1 to 95:5) to give the title compound (0.045 g, 33%) as an off-white solid.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[C:16](Cl)(=[O:18])[CH3:17].O>C1(C)C=CC=CC=1>[C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:15][CH:14]=2)(=[O:18])[CH3:17]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A 1.0 M solution of SnCl4 (10 mL, 10.0 mmol) was added to a stirred solution of 5-bromoindole (ab) (980 mg, 5.0 mmol) and acetyl chloride (0.714 mL, 785 mg, 10.0 mmol) in 20 mL of dry toluene at 0° C. The resulting mixture was stirred at room temperature during 4 hours, and then 50 ml, of water was added. The mixture was extracted with EtOAc (3×20 mL) and the collected organic layers were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum. Column chromatography using EtOAc-pentane (from 5/95 to 80/20) yielded pure acetylindole (jb) (1.0 g, 4.2 mmol) as a white solid. Yield: 84%.
Reaction SMILES: CN(C)C=O.S(Cl)(Cl)=O.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O.[CH:18]([N:21](CC)C(C)C)(C)[CH3:19].C(N)C>C1(C)C=CC=CC=1>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:21][CH2:18][CH3:19])=[O:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CCCCBr
Agent: CCN
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCNC(=O)CCCCBr
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Dimethylformamide (116 μL, 1.5 mmol, 0.1 eq.) and thionyl chloride (1.63 ml, 22.5 mmol, 1.5 eq.) were added to a solution of 5-bromovaleric acid (2.71 g, 15 mmol, 1 eq.) in toluene (20 ml) and the reaction mixture was stirred at 50° C. for 4 h. The volatiles were removed under high vacuum, THF (130 ml) was added and the mixture was cooled to 0° C. N,N-Diisopropylethylamine (4.2 ml, 24 mmol, 1.6 eq.) and ethylamine (2 M solution in THF, 9.0 ml, 18 mmol, 1.2 eq.) were added dropwise. The reaction mixture was stirred for 1 h at 0° C. before being quenched by the addition of saturated aq. NH4Cl (100 ml). The reaction mixture was extracted with Et2O (4×75 ml) and the combined organic phases were washed with brine (100 ml) before being dried (MgSO4), filtered, and concentrated to give the crude material. This was purified by flash chromatography, eluting with petrol/EtOAc (4:6), giving the title product 95 as a clear, colourless oil (2.75 g, 88%). Analytical data consistent with the literature (Halazy, S. et al., WO 9612713, Pierre Fabre Medicament (1996)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
(2E)-3-(3,4-Dichlorophenyl)acrylic acid (800 mg, 3.69 mmol) was dissolved in tetrahydrofuran (80 mL), and the resulting solution was cooled to 0° C. Then, lithium aluminum hydride (280 mg, 7.38 mmol) was added thereto, and the temperature of the resulting mixture was raised to room temperature, and the mixture was stirred for 8 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 70:30 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (229 mg, yield: 30%).
Reaction SMILES: COC[O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[CH:18][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:33]COC)[N:27]=3)=[N:16]4)[N:13]=2)[CH:9]=[CH:8][CH:7]=1.Cl>CO>[OH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[CH:18][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][OH:33])[N:27]=3)=[N:16]4)[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COCOCc1cccc(-c2ccc3ccc4ccc(-c5cccc(COCOC)n5)nc4c3n2)n1
Agent: Cl
Solvent: CO
Product: OCc1cccc(-c2ccc3ccc4ccc(-c5cccc(CO)n5)nc4c3n2)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To compound (20) (1.09 g; 2.26 mmol), 6N-hydrochloric acid (5 mL) and methanol (25 mL) were added, and the resulting reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was evaporated under reduced pressure, and while there was some solvent left the mixture was made alkaline with a 5% aqueous sodium carbonate. Solids which precipitated out were separated by filtration. The resulting solids were dissolved in chloroform/methanol=3/1, insoluble matters were filtered out and the filtrate was evaporated under reduced pressure to give 0.72 g (yield: 81%) of the title compound (21).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)[O:29][C@@H:28]([CH2:37][C:38]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: NCC[C@@H]1C[C@H](CC(=O)N2CCOCC2)OC2(CCCCC2)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N2CCOCC2)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)-1-morpholinoethanone.
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]=[CH:6][C:5]=2[S:4][C:3]=1[CH3:17].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.[Pd].ClP(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:3]1[S:4][C:5]2[CH:6]=[CH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10]=2[C:11](=[O:12])[C:2]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1sc2ccc3ccccc3c2c(=O)c1I
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc2ccc3ccccc3c2c(=O)c1-c1ccccc1
Yield: 93 %

Procedure:
The compound (1.0 mmol, 352 mg) obtained in (1) above, dichloro triphenylphosphine palladium (0.03 mmol, 21 mg), phenylboronic acid (1.3 mmol, 159 mg) and potassium carbonate (4.0 mmol, 552 mg) were dissolved in degassed dimethylformamide (3.2 mL) and water (0.8 mL), and the resulting solution was stirred under a nitrogen atmosphere at 80° C. for 4 hours. After the disappearance of the starting materials was confirmed by thin-layer chromatography, water was poured into the reaction solution to terminate the reaction. The organic substances were extracted with ethyl acetate, the obtained organic layer was dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the title compound (0.98 mmol, 296 mg) was obtained in a 93% yield.
Reaction SMILES: CI.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[N:13]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2=[O:24])=[CH:7][CH:6]=1.[C:25](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:16](=[O:17])[N:15]([CH3:25])[C:14](=[O:18])[N:13]([CH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:12]2=[O:24])=[CH:9][CH:10]=1
Reactant: COc1ccc(-n2c(=O)[nH]c(=O)n(CC(C)(C)C)c2=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(-n2c(=O)n(C)c(=O)n(CC(C)(C)C)c2=O)cc1
Yield: 94.9 %

Procedure:
5.2 g (0.037 mol) of methyliodide are added dropwise to a solution of 10.0 g (0.033 mol) of 1-(4-methoxyphenyl)-3-(2,2-dimethylpropyl)-1,3,5-triazine-2,4,6-trione in 100 ml of absolute acetonitrile and 9 g (0.066 mol) of potassium carbonate at room temperature. The reaction mixture is boiled under reflux for 5 hours. After cooling the solid constituents are separated off and the mother liquor is concentrated under reduced pressure. The residue obtained after stripping off the solvent is ground with cold water for purification. The resulting crystals are filtered off with suction and dried. 10.0 g (95% of theory) of 1-(4-methoxyphenyl)-3-(2,2-dimethylpropyl)-5-methyl-1,3,5-triazine-2,4,6-trione are obtained in this manner in the form of crystals of melting point 134° C., IR:1685 cm-1. The substances listed by way of their formulae in the following Table 1 are also prepared by the method just described:
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>C(OCC)(=O)C>[F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: COc1c(F)ccc(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1c(F)ccc(C(=O)Cl)c1F

Procedure:
A mixture of 2,4-difluoro-3-methoxybenzoic acid (2.1 g, 11.1 mmol), thionyl chloride (5 mL), and ethyl acetate (30 mL) is refluxed for 4 h. All volatiles are removed in vacuo, and the remaining residue is used directly in the next synthetic step.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[OH:19])[CH2:6][CH2:5]1)(=O)C.[ClH:21]>>[ClH:21].[OH:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:10]([CH:7]1[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)=[O:20]
Reactant: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)c(O)c1
Agent: Cl
Product: COc1ccc(C(=O)C2CCNCC2)c(O)c1
Temperature: 25 °C

Procedure:
To a round-bottom flask, equipped with a condenser and mechanical stirrer, was added 25.0 g of 1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)piperidine and 148 ml of 6N hydrochloric acid. The reaction mixture was stirred under reflux for 6 hrs and overnight at ambient temperature. The precipitate was collected, washed with acetone and recrystallized twice from ethanol to yield 16.70 g of product, mp, 264°-266°.
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][C:20]=2[F:36])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][F:11])(C)(C)C.[ClH:38].O1CCOCC1>C(Cl)Cl>[ClH:38].[F:36][C:20]1[CH:21]=[C:22]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:7][CH2:8][CH2:9][CH2:10][F:11])=[CH:14][CH:15]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CN(CCCF)C(=O)OC(C)(C)C)cc3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CNCCCF)cc3)c(F)c2)C(=O)O1
Reaction time: 12 h
Yield: 95.3 %

Procedure:
A solution of BOC-amine 121 (15.65 g, 30.3 mmol) in CH2Cl2 (30 mL) was treated with a solution of 4 N hydrogen chloride in 1,4-dioxane (37.5 mL, 150.0 mmol, 5.0 equiv) at room temperature and stirred for 12 h. When TLC and HPLC/MS showed that the reaction was complete, the solvents were removed in vacuo. The residue was suspended in a mixture of acetonitrile (CH3CN, 200 mL) and methanol (MeOH, 50 mL), and the resulting slurry was stirred at room temperature for 1 h. The solids were collected by filtration, washed with 20% MeOH/CH3CN (2×50 mL), and dried in vacuo to afford the desired (5S)—N-(3-{2-fluoro-4′-[(3-fluoro-propylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide mono hydrochloride salt 11 (13.0 g, 95.3% yield) as white crystals. 1H NMR (300 MHz, DMSO-d6) δ 1.90 (s, 3H, COCH3), 2.11-2.20 (m, 2H), 3.10 (m, 2H), 3.50 (t, 2H, J=5.4 Hz), 3.87 (dd, 1H, J=6.4, 9.2 Hz), 4.24 (t, 1H, J=9.1 Hz), 4.27 (s, 2H, ArCH2), 4.54 (t, 1H, J=5.8 Hz), 4.70 (t, 1H, J=5.8 Hz), 4.83 (m, 1H), 7.50 (dd, 1H, J=2.2, 8.6 Hz), 7.65-7.74 (m, 6H, aromatic-H), 8.37 (t, 1H, J=5.8 Hz, NHCOCH3), 9.43 (br. s, 2H, RArN+H2). C22H25F2N3O3HCl, LCMS (EI) m/e 418 (M++H).
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)CN([C@H]1CCCN([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)C2C=C(C(F)(F)F)C(C)=CC1=2)C1N=NN(C)N=1.[Cl:43][C:44]1[CH:45]=[C:46]([CH:72]=[C:73]([C:75]([F:78])([F:77])[F:76])[CH:74]=1)[CH2:47][N:48]([C@H:55]1[CH2:61][CH2:60][CH2:59][NH:58][C:57]2[C:62]([CH3:71])=[C:63]([C:67]([F:70])([F:69])[F:68])[C:64]([CH3:66])=[CH:65][C:56]1=2)[C:49]1[N:50]=[N:51][N:52]([CH3:54])[N:53]=1.N1C=CC(C=O)=CC=1>ClC(Cl)C>[Cl:43][C:44]1[CH:45]=[C:46]([CH:72]=[C:73]([C:75]([F:78])([F:76])[F:77])[CH:74]=1)[CH2:47][N:48]([C@H:55]1[CH2:61][CH2:60][CH2:59][N:58]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:57]2[C:62]([CH3:71])=[C:63]([C:67]([F:68])([F:69])[F:70])[C:64]([CH3:66])=[CH:65][C:56]1=2)[C:49]1[N:50]=[N:51][N:52]([CH3:54])[N:53]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccncc1)CCC[C@@H]2N(Cc1cc(F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: O=Cc1ccncc1
Solvent: CC(Cl)Cl
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(Cc1ccncc1)CCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1

Procedure:
Prepare the title compound by essentially following the procedure described in the synthesis of (S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 186, Step 2) by using (S)-(3-chloro-5-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.08 g, 0.15 mmol) and pyridine-4-carboxaldehyde (0.045 mL, 0.45 mmol) in dichloroethane (2 mL) at room temperature for 15 h to afford the title compound. Purification by silica gel column (gradient eluent, 0-5% MeOH in ethyl acetate) provides the title compound (0.09 g, 91%). MS (ES+): 624 (M+H).
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[Na+:2].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:12]=1[C:13]([O-:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc(C(F)(F)F)ccc1OCc1ccccc1

Procedure:
To a solution of 400 mg. (0.01 mole) of sodium hydroxide in 30 ml. of water is added, in portions and with stirring, 2.96 g. (0.01 mole) of 2-benzyloxy-5-trifluoromethylbenzoic acid. The slightly hazy solution is filtered and the filtrate concentrated at room temperature and under reduced pressure to dryness. The residual sodium salt is triturated with acetone and filtered.
Reaction SMILES: CN(C)CCNC.BrC1SC(C=O)=CC=1.[CH3:16][N:17]([CH3:29])[CH2:18][CH2:19][N:20]([CH3:28])[C:21]1[S:25][C:24]([CH:26]=O)=[CH:23][CH:22]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][C:36]#[N:37]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[C:35](=[CH:26]/[C:24]2[S:25][C:21]([N:20]([CH2:19][CH2:18][N:17]([CH3:29])[CH3:16])[CH3:28])=[CH:22][CH:23]=2)/[C:36]#[N:37])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CN(C)CCN(C)c1ccc(C=O)s1
Agent: CNCCN(C)C
Agent: O=Cc1ccc(Br)s1
Product: COc1ccc(/C(C#N)=C/c2ccc(N(C)CCN(C)C)s2)cc1OC
Yield: 32.3 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from N,N,N′-trimethylethylenediamine (6.13 g) was introduced into 5-bromothiophene-2-carboxaldehyde (3.82 g), to thereby yield 5-[(2-dimethylamino-ethyl)-methyl-amino]-thiophene-2-carbaldehyde (yield: 3.26 g, 77%). The produced 5-[(2-dimethylamino-ethyl)-methyl-amino]-thiophene-2-carbaldehyde (2.12 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.77 g) through Method A (production step 2), to thereby yield the target product (yield: 1.20 g, 32%).
Reaction SMILES: O.[OH-].[Li+].[C:4]([CH2:6][C:7]1([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:10][N:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([O:19]C)=[O:18])=[N:15][CH:16]=2)[CH2:8]1)#[N:5].Cl>CO.O>[C:4]([CH2:6][C:7]1([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:10][N:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=2)[CH2:8]1)#[N:5]
Reactant: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)nc5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of lithium hydroxide monohydrate (0.87 g, 21 mmol) and methyl 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyridine-2-carboxylate (3.70 g, 6.79 mmol) in methanol (10.0 mL) and water (5.0 mL) was stirred at room temperature overnight. The mixture was adjusted to pH 3 with aqueous HCl (1.0 N), and concentrated under reduced pressure to remove methanol. The solid formed was filtered and washed with water, and dried under reduced pressure to afford the crude product. LCMS (M+H)+: m/z=531.1.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[NH2:10][C@H:11]([C:15]([NH2:17])=[O:16])[CH2:12][CH2:13][CH3:14].[OH-].[Na+]>CO>[OH:16][C:15]1[C:11]([CH2:12][CH2:13][CH3:14])=[N:10][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[N:17]=1
Reactant: O=C1CCCCC1=O
Reactant: CCC[C@H](N)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc2c(nc1O)CCCC2
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
1,2-cyclohexanedione (5.4 g, 48 mM) was added all at once to a methanol solution (80 ml) of norvalineamide hydrochloride (6.1 g, 40 mM) at -30° C., and aqueous 12.5N NaOH (8 ml) was added dropwise thereto. The reaction mixture was stirred at -30° C. for 30 mins., cooling was removed, and the mixture stirred at room temperature for 3 hours. Conc. hydrochloric acid (10 ml) was added to the reaction mixture under ice-cooling, sodium bicarbonate (8 g) was added after 10 mins., the methanol then being distilled off in vacuo. The residue was extracted with chloroform, and the extract washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals (3.8 g., yield: 50%, m.p.: 131°-133° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][C:10]3=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:37]1[C:42]([F:43])=[C:41]([F:44])[C:40]([F:45])=[C:39]([F:46])[C:38]=1[F:47])=O>CN(C=O)C>[F:43][C:42]1[C:37]([O:15][C:14](=[O:16])[CH:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[CH2:25][CH2:24][CH2:23][C:11]=23)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:38]([F:47])[C:39]([F:46])=[C:40]([F:45])[C:41]=1[F:44]
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid (300 mg, 836 umol) in DMF (3 ml) was added pyridine (70 ul, 920 umol) and pentafluorophenyl trifluoroacetate (290 ul, 1.7 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 12 h, poured onto ice water/0.1 N HCl 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/sat. aqueous NaHCO3 solution 1/1, ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester as an orange oil (762 mg; quant.) which was directly used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH:17]=[O:18])[CH:9]=1)=[O:4].COC(C1N(C)N=C(OCC2C(C3C=CC(F)=CC=3)=NOC=2C=O)C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2C=O)nn1C
Agent: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C=O)nn1C
Product: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Yield: 96.3 %

Procedure:
As described for example 91g, 5-[3-(4-chloro-phenyl)-5-formyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (2.4 g, 6.6 mmol), instead of 5-[3-(4-fluoro-phenyl)-5-formyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester, was converted to the title compound (2.4 g, 100%) which was obtained as a white solid. MS: m/e=378.2 [M+H]+.