Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[C:22]#[N:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>N.CCO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[CH2:22][NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(CN)c1
Reaction time: 2.5 h
Yield: 94.5 %

Procedure:
To a solution of 4-(2-cyano-4-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (680 mg, 2.14 mmol) in NH3/EtOH (2M, 15 mL) was added Raney Nickel (5 mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 2.5 h. After this time the mixture was filtered through celite and concentrated to yield the title compound (650 mg). m/z (M+1) 321.57.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([O:20][C:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22])[CH3:19].C(OCC)(=O)C.[F-].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:21]([O:20][C:18]([C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1)=[CH2:19])[CH3:22]
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(OCC)c1cc(OC)c(Oc2ccccc2C)nn1
Reaction time: 8 h
Yield: 14.1 %

Procedure:
In toluene (6.5 mL) was dissolved 321 mg (1.28 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 534 mg (1.48 mmol) of (1-ethoxyvinyl)(tributyl)tin, then 155.3 mg (0.134 mmol) of tetrakis(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours and 20 minutes. The reaction mixture was allowed to stand at room temperature overnight, then, ethyl acetate, water and sodium fluoride were added to the mixture and the resulting mixture was stirred for 2 hours. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, and the organic layer was separated, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 51.8 mg (0.181 mmol, Yield: 14.1%) of 6-(1-ethoxyvinyl)-4-methoxy-3-(2-methylphenoxy)pyridazine.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[NH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[NH2:8][CH2:9][C:10]([NH:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC1CC1
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NCC1CC1

Procedure:
The title was compound prepared from tert-Butoxycarbonylamino-acetic acid, using aminomethylcyclopropane and TFA, following procedures analogous to that described in Example 1A.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:26]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=O)C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:3])[C:7]=2[OH:26])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(F)cc2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(Cc3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 403 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5]I)[CH2:3][CH2:2]1.C([Li])(C)(C)C.[Cl:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]=[C:18]3[C:23](=[O:27])[NH:24][CH:25]=[N:26][C:17]3=[C:16]([C:28]([F:31])([F:30])[F:29])[C:15]=2[CH:14]=1>CCOCC.C1COCC1>[Cl:12][C:13]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:27])[NH:24][CH:25]=[N:26][C:17]=3[C:16]([CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)([C:28]([F:30])([F:29])[F:31])[C:15]=2[CH:14]=1
Reactant: ICCC1CC1
Reactant: O=c1[nH]cnc2c(C(F)(F)F)c3cc(Cl)ccc3nc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=c1[nH]cnc2c1Nc1ccc(Cl)cc1C2(CCC1CC1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 61.7 %

Procedure:
To a stirred solution of 1-cyclopropyl-2-iodoethane (12.5 g, 63.9 mmol, 5 equiv) in anhydrous Et2O (128 mL) at −78° C. was added tert-butyl lithium (1.7M in pentane, 75 mL, 128 mmol, 10 equiv). The resulting white suspension was stirred at −78° C. for 50 min and added via cannula to a suspension of 7 (3.83 g, 12.8 mmol) in THF (64 mL) at −78° C. The resulting dark yellow mixture was stirred at −78° C. for 30 min and then allowed to warm to 0° C. over 5 h. The reaction was quenched with satd. NH4Cl (100 mL) and H2O (100 mL). The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organic layers washed with brine and dried (MgSO4). Chromatography (SiO2, 40 to 50% EtOAc-hexane) provided the desired product as a yellow solid (2.92 g, 62%). ESI HRMS m/z 370.1735 (M++H, C17H16ClF3N3O requires 370.0934).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]([CH3:22])[C:5]2[O:9][C:8](=[O:10])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)([CH3:11])[C:6]=2[CH:21]=1>C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:21]=[C:6]([C:7]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=2)([CH3:11])[CH2:8][OH:10])[C:5]([OH:9])=[C:4]([CH3:22])[C:3]=1[CH3:23]
Reactant: Cc1c(Br)cc2c(c1C)OC(=O)C2(C)c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(Br)cc(C(C)(CO)c2ccc(C(C)C)cc2)c(O)c1C
Yield: 83 %

Procedure:
Using 5-bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-1-benzofuran-2(3H)-one synthesized in Reference Example 21, the title compound was synthesized in the same manner as in Reference Example 8. Yield 83%. Melting point: 110-111° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)=[CH:27][S:26][C:25]=1[C:39]([O:41]C)=O.[CH:43](OCC)(OCC)[O:44]CC.ClC1C=CC(N)=CC=1>C(O)(=O)C>[CH3:38][O:37][C:31]1[CH:30]=[C:29]([C:28]2[C:24]3[N:23]=[CH:12][N:7]([C:1]4[CH:2]=[CH:3][C:4]([O:44][CH3:43])=[CH:5][CH:6]=4)[C:39](=[O:41])[C:25]=3[S:26][CH:27]=2)[CH:34]=[CH:33][C:32]=1[O:35][CH3:36]
Reactant: COC(=O)c1scc(-c2ccc(OC)c(OC)c2)c1N
Reactant: CCOC(OCC)OCC
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: Nc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: COc1ccc(-n2cnc3c(-c4ccc(OC)c(OC)c4)csc3c2=O)cc1
Yield: 28 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(3,4-dimethoxyphenyl)thiophene-2-carboxylate (80 mg, 0.27 mmol), triethyl orthoformate (0.6 ml), 4-chloroaniline (62.5 mg, 0.51 mmol), and acetic acid (0.09 ml) were used to give 14.5 mg (0.04 mmol, 28% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][N:19]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:33]O>C(OCC)(=O)C.CCCCCC>[CH3:33][O:24][C:23]([C:21]1[NH:22][C:18]([C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:8]=2)=[O:17])=[N:19][CH:20]=1)=[O:25]
Reactant: O=C(O)c1cnc(C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)[nH]1
Yield: 89 %

Procedure:
A solution of 2-[1-(4-chloro-benzyl)-1H-indole-3-carbonyl]-3H-imidazole-4-carboxylic acid (60 mg) and concentrated sulfuric acid (1 mL) in methanol (100 mL) was heated to reflux overnight. After removal of solvent, the mixture was dissolved in ethyl acetate and washed with 5% sodium hydroxide solution. The organic layers were dried over magnesium sulfate and evaporated to dryness. The product 2-[1-(4-chloro-benzyl)-1H-indole-3-carbonyl]-3H-imidazole-4-carboxylic acid methyl ester (55 mg, yield 89%) was purified by flash column chromatography (ethyl acetate:hexane=1:1). 1H NMR (acetone-d6) δ 3.84 (s, 3H), 5.65 (s, 2H), 7.2–7.4 (m, 6 H), 7.48 (m, 1H), 7.95 (s, 1H), 8.45 (m, 1H), 9.48(s, 1H) ppm; ESMS calcd (C21H16ClN3O3): 393.09; found: 394.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[CH:13][CH:12]=1.[H-].[Na+].Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>C(COC)OC>[Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35])[C:9](=[O:28])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1nccc(N(C(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C(=O)OCC(C)C)c1Cl
Temperature: 25 °C
Yield: 32.4 %

Procedure:
1.0 g (2.3 mmol) of N-(3-chloro-2-ethylpyridin-4-yl)-4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetamide was dissolved in 5 ml of dimethoxy ethane, and the solution was stirred at room temperature. Then, 0.067 g (2.8 mmol) of sodium hydride was gradually added thereto, and the mixture was further stirred for one hour at room temperature. Then, 2 ml of a 1,2-dimethoxyethane solution containing 0.38 g (2.8 mmol) of isobutyl chloroformate was dropwise added thereto at a temperature of from -5° to 0° C., and the mixture was stirred for 30 minutes at a temperature of from -5° to 0° C. and for one hour at room temperature. Then, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 0.4 g of the desired product as a yellow viscous substance (refractive index nD20 =1.3582).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]([CH2:10][C:11]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13][CH2:12]1)[C:7](O)=[O:8].[O:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[O:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:7](=[O:8])[C:6](=[O:5])[CH2:10][C:11]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:22])([F:23])[F:24])[CH2:14][CH2:13][CH2:12]2)=[CH:32][CH:31]=1
Reactant: O=C(O)C(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Reactant: Nc1ccc(-c2ncco2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: O=C(CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)Nc1ccc(-c2ncco2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
0.052 ml of thionyl chloride was added to a solution of 0.1 g of 2-oxo-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propionic acid in 2 ml of dimethyl acetamide at −5° C., and stirred for 30 min at −5° C. Then 56 mg of 4-oxazol-2-yl-phenylamine was added in solid form and stirred for 1 hour at room temperature. Potassium carbonate was added and stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined ethyl acetate extracts were washed twice with water, dried and concentrated by evaporation. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 10%-20%) to yield 63 mg of product.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][C:16]=2[CH2:27][N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH:7]=1)C.CO.[OH-].[Li+]>O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:34])=[O:3])=[CH:7][C:8]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:17][C:16]=1[CH2:27][N:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N3CCOCC3)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(N2CCOCC2)cc1CN1CCOC1=O
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
{4-Methoxy-3-[4-morpholin-4-yl-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester (0.43 mmol) ini MeOH and H2O was treated with lithium hydroxide, and the reaction was stirred at 60° C. for 20 minutes. The mixture was acidified and concentrated, and the reside was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>C1COCC1>[CH2:1]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:15]1[CH2:17][CH2:16]1)[CH2:2][CH2:3][CH3:4]
Reactant: Br[Mg]C1CC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tri-n-butyltin chloride (4 g, 11.8 mmol) in THF (20 mL) at 0° C. is added 0.5 M cyclopropylmagnesium bromide in THF (28.3 mL, 14.2 mmol). The reaction mixture is stirred under N2 at ambient temperature for 4 h and poured into pH 7 aqueous buffer. The resulting mixture is extracted with diethyl ether, washed with brine, dried over magnesium sulfate and filtered through sintered funnel. The filtrate is concentrated and the residue is distilled under vacuum to give tributylcyclopropyltin as a colorless oil which is used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:25]4[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:20])[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2cccc(C#N)c2)cn1
Yield: 13 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 3-cyanophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (13 mg, 13%) which was obtained as an off-white solid. MS: m/e=345.6 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26]C(C(O)=O)=CC=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[CH3:30][O:31][C:32](=[O:36])[CH2:33][NH:34][CH3:35].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[O:64]1[CH2:68][CH2:67][CH2:66][CH2:65]1>>[CH3:30][O:31][C:32](=[O:36])[CH2:33][N:34]([CH3:35])[C:68](=[O:64])[C:67]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:65][CH:66]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: C1CCOC1
Reactant: CNCC(=O)OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)CN(C)C(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with sarcosine methyl ester hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a colorless solid, MS (ESI+): m/z=461.3 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:55][C:56]2[S:57][CH:58]=[CH:59][N:60]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: Brc1ccc(OCc2ccccc2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccc(Nc3nccs3)nc2)cc1
Yield: 34 %

Procedure:
5-Benzyloxy-2-bromo-pyridine (0.25 mmol), sodium-tert.-butylate (1.4 eq.), tris-(dibenzylideneaceton)-dipalladium (0.1 eq.), bis(2-diphenylphosphinophenyl)-ether (0.4 eq.) and 2-amino-thiazole (1.5 eq.) are filled under nitrogen in a microwave reaction vessel. Degassed toluene (45 eq.) is added. The reaction suspension is heated for 60 min to 150° C. and 60 minutes to 180° C. Ethyl acetate is added to the reaction suspension and filtrated over celite. The solvent of the filtrate is removed in vacuo. (5-Benzyloxy-pyridine-2-yl)-thiazole-2-yl-amine (“A30”) is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as orange oil in a yield of 34%. HPLC (method C): 1.69 min; LC-MS (method A): 1.44 min, 285.15 (MH+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.108 (s, 1H), 8.072 (d, 1H, J=2.9 Hz), 7.500-7.447 (m, 3H), 7.412-7.383 (m, 2H), 7.349-7.320 (m, 2H), 7.064 (d, 1H, J=9 Hz), 6.926 (d, 1H, J=3.5 Hz), 5.139 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:1][CH2:2][C:3]2[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Reactant: Clc1ccc(CBr)cc1
Product: CC(C)(C)C(=O)Nc1cccc(COCc2ccc(Cl)cc2)n1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(6-hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.73 g) and 4-chlorobenzyl bromide as a yellow oil (0.868 g). MS (ESI): 332.2 (MH+).
Reaction SMILES: [N+]([O-])(O)=O.[C:5]12([OH:15])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.C12([C:26]([OH:28])=[O:27])CC3CC(CC(C3)C1)C2>>[OH:15][C:5]12[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][C:7]([C:26]([OH:28])=[O:27])([CH2:13]3)[CH2:6]1)[CH2:14]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: OC12CC3CC(CC(C3)C1)C2
Solvent: O=[N+]([O-])O
Product: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 25.2 %

Procedure:
The same operations as conducted in Example 1 were repeated, except that the reaction mixture temperature after dropwise addition of nitric acid was set to 80° C. In the first carboxylation reaction step, the conversion of 1-adamantanol was found to be 99.0% and 1-adamantane carboxylic acid was generated in a reaction yield of 97%. In the second oxidation reaction step, the conversion of 1-adamantane carboxylic acid was found to be 98.0% and white crystals of 3-hydroxy adamantane-1-carboxylic acid (9.8 g, yield: 25.2%) were obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[CH3:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[C:25]([CH3:38])[C:24]=1[OH:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.ClCCl>>[OH:39][C:24]1[C:25]([CH3:38])=[CH:26][C:27]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)=[CH:28][C:23]=1[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1O
Yield: 82.1 %

Procedure:
Nitrogen was bubbled through a mixture of tert-butyl 4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate (5.80 g, 0.0175 mol), 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.82 g, 0.0194 mol) and potassium carbonate (7.26 g, 0.0525 mol) in N,N-dimethylformamide (50.0 mL, 0.646 mol) for 10 min. To the reaction mixture was then added [1, F-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (0.8 g, 0.001 mol). The resultant mixture was heated at at 80 Celsius overnight. After quenched with water, the mixture was neutralized with 1N HCl, extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and evaporated to dry. The residue was applied on column, eluting with 0 to 50% EtOAc in hexane, to yield the desired product (4.36 g, 82.09%). MS (ESI): (M-Boc+2) 204.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[NH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl>[CH3:16][CH2:8][CH2:6][CH:5]([CH3:12])[CH3:4].[O:20]1[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:13])[CH2:18][CH2:19]1
Reactant: NCC1CCOCC1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(C)C
Product: O=C(NCC1CCOCC1)c1cnc(Cl)nc1C(F)(F)F
Reaction time: 1 h
Yield: 122 %

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidin-5-carbonyl chloride (1.5 g) in dichloromethane (20 ml) at −20 was added a dropwise a solution of 4-aminomethyltetrahydropyran (0.70 g, ex Combi Blocks) and triethylamine (1.05 ml) in dichloromethane (10 ml) and the solution stirred at 0° for 1 hour. Dichloromethane was removed under reduced pressure and ethyl acetate (30 ml) added. The solution was washed with 2N hydrochloric acid (3×20 ml), dried (MgSO4), evaporated and the residue purified using silica gel chromatography with 1:1 ethyl acetate:isohexane to afford 2-chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid (tetrahydropyran-4-yl-methyl)-amide (1.20 g).