Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2](Br)([CH3:4])[CH3:3].[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:8]=1[NH2:9]>C1C=CC=CC=1>[CH3:1][Si:2]([CH3:4])([CH3:3])[NH:9][C:8]1[C:7]([F:6])=[CH:13][CH:12]=[CH:11][C:10]=1[F:14]
Reactant: Nc1c(F)cccc1F
Reactant: C[Si](C)(C)Br
Solvent: c1ccccc1
Product: C[Si](C)(C)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
Trimethylsilyl bromide, 10.24 ml (77.5 mmole), was added to 6 ml (55.7 mmole) of 2,6-difluoroaniline in 70 ml of benzene. There was a slight exotherm and immediate precipitation. Triethylamine, 10.8 ml (77.5 mmole), was added and the mixture stirred at room temperature for 16 hours. The mixture was filtered and the solvent removed from the filtrate in vacuo. The product was purified as described in Example 1 to provide 8.85 g (51.1 mmole, 91.7 percent yield) of 99.3 percent pure N-trimethylsilyl-2,6-difluoroaniline as a colorless liquid, b.p. 89°-91° C. at 18 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH:19]([F:29])[C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH:19]([F:29])[F:18])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(C(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(C(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-difluoromethyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=397.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[CH:15]OCC)[CH:13]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[C:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1)(=[NH:22])[NH2:21].C[O-].[Na+]>CO>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[N:21][C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=3)=[N:22][CH:15]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Reactant: CCCCCc1ccc(C(C=O)=COCC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCc1ccc(-c2cnc(-c3ccc(C(N)=O)cc3)nc2)cc1

Procedure:
4.46 g. of 2-(4-n-pentylphenyl)-3-ethoxy-acrolein, 3.63 g. of the 4-amidinobenzoic acid amide hydrochloride described above and 0.0254 mol of sodium methylate (obtained by dissolving 0.584 g. of sodium metal in methanol) are suspended in 250 ml. of methanol and stirred overnight at room temperature under an atmosphere of nitrogen. The yellow suspension is then filtered and the residue is washed with a little ethanol and suspended in 1.4 liters of ether for further purification. The suspension is washed with water and then filtered again. Sparingly soluble 4-[5-(4-n-pentylphenyl)-2-pyrimidinyl]benzoic acid amide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[C:48]([CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([C:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)=[O:49])[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccc(F)c(F)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-difluoro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: [C@H:1]1([NH:10][C:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([Cl:24])=[CH:18][C:19]=3[CH3:23])[NH:14]2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.IC.[CH2:27](N(CC)CC)C>CN(C=O)C>[C@H:1]1([NH:10][C:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([Cl:24])=[CH:18][C:19]=3[CH3:23])[N:14]2[CH3:27])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@@H]3CCc4ccccc43)c(=O)c12
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)N[C@@H]1CCc3ccccc31)n2C

Procedure:
In analogy to example 2, 103 mg (0.3 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydro-pyrazolo[3,4-b]pyridine-2-carboxylic acid (R)-indan-1-ylamide were reacted with 64 mg (0.45 mmol) of iodomethane in DMF with triethylamine. Yield: 56 mg (52%), M+H+: 357.09.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](C(=O)C)[CH:9]=[CH:10][C:3]=12.CO>C(O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: CC(=O)n1ccc2c(I)ccnc21
Solvent: CCO
Solvent: CO
Product: Ic1ccnc2[nH]ccc12
Yield: 234.2 %

Procedure:
A solution of meta-chlorobenzoic acid (14 g, 54 mmol) in ethyl acetate (30 mL) was dropwise added to a solution of 1H-pyrrolo[2,3-b]pyridine (5.3 g, 45 mmol) in ethyl acetate (45 mL) over 1 hr with stirring at 0° C. After completion of the dropping, the mixture was stirred at room temperature for 3 hr, followed by leaving to stand at 0° C. The resulting crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure. The crystals were dissolved in water (30 mL), and then 30% K2CO3 was added until the pH of the solution reached 10. The solution was left to stand at room temperature for 1 hr and then at 0° C. for 1 hr. The resulting precipitate was collected by filtration and was washed with ether to yield 3.5 g (58%) of N-oxide. The N-oxide (3.0 g, 22 mmol) was dissolved in DMF (16 mL). The resulting solution was heated at 50° C., and a solution of methanesulfonyl chloride (4.7 mL, 60 mmol) in DMF (6.4 mL) was dropwise added to the solution at 70° C. This reaction solution was stirred at 75° C. for 2 hr. The reaction solution was added to ice and was neutralized with 10 N NaOH at 0° C., followed by stirring at room temperature for 1 hr. The resulting precipitate was collected by filtration, washed with water, and dried at 60° C. under reduced pressure to yield 2.7 g (80%) of the target 4-chloro-1H-pyrrolo[2,3-b]pyridine. 4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.7 g, 18 mmol) and NaI (13 g, 88 mmol) were dissolved in acetonitrile (28 mL), and CH3COCl (3.5 mL, 50 mmol) was added thereto with stirring at room temperature. The reaction solution was heated at 85° C. for 12 hr and then cooled to room temperature, and 10% Na2CO3 (28 mL) and 10% NaHSO3 (28 mL) were added thereto, followed by stirring at room temperature for 15 min. Ethyl acetate was added thereto for separation, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with a silica gel column to yield 4-iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g) and 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g). 4-Iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g, 7.0 mmol) was dissolved in ethanol (70 mL) and refluxed in methanol containing 28% sodium methoxide (1.4 mL, 7.0 mmol) for 1 hr. The reaction solution was concentrated and separated between ethyl acetate and an aqueous saturated ammonium chloride solution. The organic layer was washed with an aqueous saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated, and then combined with 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g) obtained above. The mixture was recrystallized from ethanol to yield 4-iodo-1H-pyrrolo[2,3-b]pyridine (4.0 g, 92%). 4-Iodo-1H-pyrrolo[2,3-b]pyridine: 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.89 (d, 1H, J=5.0 Hz), 7.59 (t, 1H, J=3.1 Hz), 7.51 (d, 1H, J=5.0 Hz), 6.27 (d, 1H, J=3.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:11][C:10]1[N:9]=[C:7]([C:6]2[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:17]2[C:12]=1[CH:13]=[N:14][C:15]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[N:16]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccc(OC)cc3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccc(OC)cc4)n3n2)cc1
Yield: 73.8 %

Procedure:
Applying the Cyclization Procedure 1, using 4-(methyloxy)-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 65) (35 mg, 0.09 mmol), 1,2-dichloroethane (1.8 mL) and phosphorus oxychloride (0.068 mL, 0.73 mmol), to afford 5-methyl-N,7-bis[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (24 mg) as a yellow solid. MS m/z 362 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH2:10][C@@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:6]=[N:7][CH:8]=1)#[CH:2].Cl.Br[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.CN(C=O)C.C(N(CC)CC)C>[Cu]I.C(OCC)(=O)C>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([CH2:12][C@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:10][O:9][C:5]2[CH:6]=[N:7][CH:8]=[C:3]([C:1]#[C:2][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[CH:4]=2)=[CH:14]1
Reactant: C#Cc1cncc(OC[C@H](Cc2c[nH]c3ccccc23)NC(=O)OC(C)(C)C)c1
Reactant: Brc1ccncc1
Agent: [Cu]I
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(C#Cc2ccncc2)c1)Cc1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 20 h
Yield: 76.6 %

Procedure:
A mixture of Example 14B (150 mg, 0.384 mmol), 4-bromopyridine hydrochloride (75 mg, 0.34 mmol), Pd2Cl2(PPh3)2 (27 mg, 0.0384 mmol), and CuI (18 mg, 0.093 mmol), was purged with nitrogen, treated with DMF (4 mL) and triethylamine (214 μL, 1.54 mmol), stirred at 50° C. for 20 hours, cooled to room temperature, treated with ethyl acetate (50 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The residual oil was purified by flash column chromatography on silica gel with 2:1 ethyl acetate/hexanes to provide the desired product (122 mg, 68%). MS (APCI) m/e 469 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH:5]=[CH2:6].[Cl:8][C:9]([Cl:14])(Cl)[C:10](Cl)=[O:11]>C(OCC)C.[Cu].[Zn]>[CH3:1][O:2][C:3](=[O:7])[CH2:4][CH:5]1[CH2:6][C:10](=[O:11])[C:9]1([Cl:14])[Cl:8]
Reactant: C=CCC(=O)OC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Product: COC(=O)CC1CC(=O)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 138.8 %

Procedure:
To a mixture of but-3-enoic acid methyl ester (1.00 g, 10 mmol) and zinc-copper couple (1.97 g) in 1,2-dimethoxyothane (4.89 ml) and diethyl ether (37 ml), trichloroacetyl chloride (2.98 ml, 26.7 mmol) is added at room temperature under nitrogen. The mixture is stirred at room temperature for 3 days. The mixture is filtrated and washed with diethyl ether. The filtrate is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography to give (2,2-dichloro-3-oxo-cyclobutyl)-acetic acid methyl ester (2.93 g, quant.); TLC (hexane/AcOEt, 3:1) Rf 0.35, 1H NMR (400 MHz, chloroform-d) δ ppm 2.68-2.74 (m, 1H), 2.94-3.00 (m, 1H), 3.06-3.13 (m, 1H), 3.33-3.41 (m, 1H), 3.51-3.57 (m, 1H), 3.75 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].Cl[CH2:7][P:8](=[O:11])([OH:10])[OH:9].[OH-].[Na+]>O>[P:8]([CH2:7][NH:1][CH2:2][C:3]([OH:5])=[O:4])([OH:11])([OH:10])=[O:9]
Reactant: NCC(=O)O
Reactant: O=P(O)(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 25 °C

Procedure:
A mixture of about 50 parts of glycine, 92 parts of chloromethylphosphonic acid, 150 part of 50% aqueous sodium hydroxide and 100 parts water was introduced into a suitable reaction vessel and maintained at reflux temperature while an additional 50 parts of 50% aqueous sodium hydroxide was added. The pH of the reaction mixture was maintained between 10 and 12 by the rate of addition of the sodium hydroxide. After all of the caustic solution had been added, the reaction mixture was refluxed for an additional 20 hours, cooled to room temperature and filtered. About 160 ml. of concentrated hydrochloric acid were then added and the mixture filtered to provide a clear solution which slowly deposited N-phosphonomethylglycine. This material had a melting point of 230° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A solution of 3.79 g of 4-(3-fluoro-benzyloxy)-benzaldehyde in 10 ml of tetrahydrofurane was added dropwise at room temperature to a suspension of 1.25 g of lithium-aluminiumhydride in 40 ml of tetrahydrofurane. After 2 h at room temperature, successively 1.25 ml of water were added dropwise under cooling, then 3.75 ml of a sodium hydroxide solution (1 N), finally, 1.25 ml of water. The mixture was filtered over a layer of Dicalit and the tetrahydrofurane distilled off the solution under reduced pressure. The residual phase was extracted with ethyl acetate, the combined organic layers were dried over magnesium sulphate und evaporated under reduced pressure. The residue was crystallised from a mixture of ether and n-hexane to yield 2.26 g (59% of theory) of [4-(3-fluoro-benzyloxy)-phenyl]-methanol as a white solid; MS: m/e=232 (M)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][CH:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:32][N:31]=1
Reactant: CNC(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: CNC(=O)C1CCN(Cc2cc3nc(-c4cnc(OC)nc4OC)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid methylamide was reacted with 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine in General Procedure A. Purification on silica yielded 108. NMR (CDCl3): 1.84-1.89 (m, 4H, 2×CH2), 2.10-2.18 (m, 3H, CH2+CH), 2.84 (d, 3H, CH3, J=4.8 Hz), 3.03-3.06 (m, 2H, CH2), 3.83 (s, 2H, CH2), 3.88-3.90 (m, 4H, 2×CH2), 4.02-4.05 (m, 4H, 2×CH2), 4.08 (s, 3H, CH3), 4.11 (s, 3H, CH3), 5.47 (sbr, H, NH), 7.30 (s, H, ArH), 8.93 (s, H, ArH). MS: (ESI+): MH+=514.27
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:30][C:29]4[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3ccc(C(F)(F)F)cc3)(CC1)CC2
Yield: 74.5 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.0 mg) and 4-trifluoromethylbenzyl bromide (16.2 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(4-trifluoromethylbenzyl)oxycarbonyl bicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (22.2 mg).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:8]([F:14])([F:13])[CH:7]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:20]=3)[CH2:6][CH2:5][C:4]=2[C:3]=1[OH:28].[F:29][C@@H:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:31]O>>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[C:3]=3[O:28][CH2:31][CH:30]([F:29])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:8]2([F:14])[F:13])=[CH:16][N:17]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCOc1ccc(C2CCc3c(cc(F)c(F)c3O)C2(F)F)cn1
Reactant: CCCCCCCC[C@H](F)CO
Product: CCCCCCCCC(F)COc1c(F)c(F)cc2c1CCC(c1ccc(OCCCCCC)nc1)C2(F)F

Procedure:
From 2,3,5,5-tetrafluoro-6-(6-hexyloxypyridin-3-yl)-5,6,7,8-tetrahydronaphthalen-1-ol and 2-(S)-fluorodecan-1-ol by means of the Mitsunobu reaction.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1>CN(C)C=O.COC1C=CC(CN)=CC=1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:7][CH2:6][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(CNC[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-methoxybenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=423.
Reaction SMILES: CC(=CC)C.P([O-])(O)(O)=O.[Na+].Cl([O-])=[O:13].[Na+].[C:16]([NH:19][C:20]1[C:25](=[O:26])[N:24]([CH2:27][CH:28]=[O:29])[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:22][CH:21]=1)(=[O:18])[CH3:17]>>[C:16]([NH:19][C:20]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:13])=[O:29])[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:22][CH:21]=1)(=[O:18])[CH3:17]
Reactant: [O-][Cl+][O-]
Reactant: CC(=O)Nc1cnc(-c2ccccc2)n(CC=O)c1=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CC(=O)Nc1cnc(-c2ccccc2)n(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-2-butene (1.38 ml, 12.98 mmol), an aqueous solution (4.2 ml) of sodium dihydrogen phosphate.1H2O (419 mg, 2.95 mmol) and an aqueous solution (9.3 ml) of sodium chlorite (934 mg, 10.32 mmol) were added to a solution of (5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)acetaldehyde(800mg,2.95 mmol) in2-methyl-2-propanol (14.8 ml), and the mixture was stirred overnight at room temperature. The reaction solution was washed with diethyl ether, and then the aqueous layer was adjusted to pH, 4 with citric acid and extracted 6 times with methylene chloride. After dried over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure whereby 5-acetylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidyl acetic acid (537 mg, 63%) was obtained as white solid.
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[F:32][CH:3]([F:2])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:30][CH2:31]1)=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and methanesulfonyl chloride. Light-yellow foam. MS (m/z): 513.4 (M+H)+.
Reaction SMILES: C1(S([N:10]2[CH2:17][C:16]3[S:15][CH:14]=[N:13][C:12]=3[CH2:11]2)(=O)=O)C=CC=CC=1.C1(O)C=CC=CC=1.[BrH:25].C(OCC)(=O)C>O>[BrH:25].[S:15]1[C:16]2[CH2:17][NH:10][CH2:11][C:12]=2[N:13]=[CH:14]1
Reactant: O=S(=O)(c1ccccc1)N1Cc2ncsc2C1
Agent: Br
Solvent: Oc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: c1nc2c(s1)CNC2
Temperature: 25 °C

Procedure:
A mixture of 5-(benzenesulfonyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (800 mg), phenol (800 μl) and 47% hydrobromic acid (5.00 ml) was heated under reflux for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to conduct liquid separation. The-resultant water layer was concentrated under reduced pressure. Ethyl acetate was added to the residue, colorless powder deposited was collected by filtration to obtain the title compound (521 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([C:22]1C(=O)[CH:26]=[C:25]([CH2:29][CH3:30])[NH:24][C:23]=1[CH3:31])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[C:14]([C:22]1[C:23]([CH3:31])=[N:24][C:25]([CH2:29][CH3:30])=[CH:26][C:12]=1[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1cc(=O)c(C(=O)c2ccccc2)c(C)[nH]1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CC#N
Product: CCc1cc(NS(=O)(=O)c2ccc(C)cc2)c(C(=O)c2ccccc2)c(C)n1
Temperature: 25 °C

Procedure:
4-Methylphenylsulphonyl isocyanate (0.66 ml) was added to a stirred suspension of compound C (0.48 g) in acetonitrile and the mixture was heated at reflux for 2.5 hours. The mixture was cooled to ambient temperature and the product was collected by filtration to give 3-benzoyl-6-ethyl-2-methyl-4-[(4-methylphenylsulphonyl)amino]pyridine (D) (0.65 g) as a solid, m.p. 244°-246° C.; NMR (d6 -DMSO): 1.19(t, 3H), 2.13(s, 3H), 2.31(s, 3H), 2.65(q, 2H), 7.08(s, 1H), 7.15(d, 2H), 7.32(d, 2H), 7.50-7.68(m, 5H), 12.63(s, 1H); mass spectrum (+ve FAB, glycerol/methanol): 395(M+H)+.