Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C([Sn]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(CCCC)CCCC)CCC.[CH3:34][Si:35]([CH3:44])([CH3:43])[C:36]1[O:40][CH:39]=[C:38]([CH:41]=[O:42])[CH:37]=1>CCCCCC.O1CCCC1>[OH:42][CH:41]([C:38]1[CH:37]=[C:36]([Si:35]([CH3:44])([CH3:43])[CH3:34])[O:40][CH:39]=1)[CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COCCCc1ccc2ccccc2c1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)c1cc(C(O)COCCCc2ccc3ccccc3c2)co1
Reaction time: 0.08 h

Procedure:
n-Butyl lithium (a 1.6M solution in hexane; 0.56 ml, 0.94 mmol) was added dropwise to a solution of (2-naphthyl)propyl tributylstannylmethyl ether (437 mg, 0.89 mmol), prepared as in Example 3, in tetrahydrofuran (5 ml) at -78° under argon. After 5 minutes, a solution of 5-trimethylsilyl-3-furaldehyde (150 mg, 0.89 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued at -78° for 2 hours and at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 30% ethyl ether/hexane. The title alcohol was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20])(=[O:13])=[O:12]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccccc12
Reactant: Nc1cccc(C(=O)O)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccccc12
Yield: 26 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 11) (25 mg, 0.10 mmol) and 3-aminobenzoic acid (28 mg, 0.20 mmol) using a modified reaction time (4 hours) and a modified reaction temperature (60° C.). The title compound was obtained in 26% yield (8.9 mg). MS (ESI+) calcd mass for C16H13NO4S2 347.028599, found 347.028659.
Reaction SMILES: [CH2:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][C:3](=[O:4])[CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16](I)[CH3:17]>CN(C=O)C>[CH2:16]([O:8][C:7]([CH:6]1[CH2:1][CH2:2][C:3](=[O:4])[CH2:5]1)=[O:9])[CH3:17]
Reactant: CCI
Reactant: O=C1CCC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(=O)C1

Procedure:
A solution of cyclopentanone-3-carboxylic acid (5.00 g, 39 mmol), caesium carbonate (12.82 g, 39 mmol) and ethyl iodide (9.12 g, 4.75 ml, 58.5 mmol) in DMF (50 ml) was stirred at RT for 18 h. The mixture was then concentrated i. vac., the residue was taken up in toluene, the mixture was concentrated again and 2 N hydrochloric acid and EtOAc were then added. The aq. phase was extracted with EtOAc (3×30 ml) and the combined organic phases were washed with aq. sodium thiosulfate soln. The organic phase was dried with Na2SO4 and concentrated i. vac.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][C:17](=[O:31])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCO.C(OCC)C>CCO>[F:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:18]1[C:19]2[C:15](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][CH:20]=2)[CH2:16][C:17]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CC(=O)N3Cc2cccc(F)c2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C1Cc2c(N3CCNCC3)cccc2N1Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
4-[1-(3-Fluoro-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (115 mg) was dissolved in 2 mL of EtOH and 500 uL of 2.0 N HCl/EtOH was added. The solution was heated to reflux on a steam bath for 30 minutes and then cooled to room temperature. Diethyl ether was added slowly to precipitate 1-(3-Fluoro-benzyl)-4-piperazin-1-yl-1,3-dihydro-indol-2-one as a hydrochloride salt. MS: 326 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)OC1>O1CCOCC1.O.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>[CH3:28][N:27]1[C:23]([C:2]2[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=2)=[CH:24][CH:25]=[N:26]1
Reactant: O=C(O)c1csc(Br)c1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(C(=O)O)cs1
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-3-thiophenecarboxylic acid (414 mg, 2 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (828 mg, 6 mmol), tetrakistriphenylphosphine Pd(0) (116 mg, 0.1 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (428 mg, 2.2 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (˜100 mg, quant.): LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:15]=[C:16]([NH2:18])[N:17]=2)[C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:15]=[C:16]([NH:18][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)[N:17]=2)[C:7]=1[NH:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Nc1nc2ccc(Br)c(NC3CCCCC3)n2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc2ccc(Br)c(NC3CCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 6-bromo-N5-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A14), 616 mg; 1.99 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (424 mg; 2.38 mmol; 1.2 eq.) as a beige powder (99 mg, 12%). HPLC, Rt: 3.41 min. (purity 94.6%). LC/MS, M+(ESI): 416.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I-].[CH3:25][N:26]1[C:34]2[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:36][N+](C)(C)C)=[CH:27]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:36][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[N:26]([CH3:25])[CH:27]=2)[C:12]1=[O:22])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](c1ccccc1)n1c(=O)[nH]c2ccccc2c1=O
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](c1ccccc1)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a mixture of (S)-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl-acetic acid methyl ester (110 mg, 0.35 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (180 mg, 0.52 mmol) in DMF (2.5 mL) is added K2CO3 (150 mg, 1.09 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, dilutes with EtOAc (50 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated. The resulting residue is purified by flash chromatography with 50% EtOAc in hexanes as the eluent to afford (S)-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-phenyl-acetic acid methyl ester (100 mg, 60%).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][N:49]1[CH:53]=[C:52]([CH2:54][NH2:55])[N:51]=[CH:50]1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:52]4[N:51]=[CH:50][N:49]([CH3:48])[CH:53]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cn1cnc(CN)c1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cn(C)cn1
Yield: 74 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1-methyl-1H-imidazol-4-yl)methanamine, the title compound was obtained as a yellowish solid in 74% yield: 1H NMR (300 MHz, CDCl3) δ 7.39 (s, 1H), 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.87 (s, 1H), 6.28 (t, J=5.0 Hz, 1H), 6.11 (s, 1H), 4.49 (d, J=5.0 Hz, 2H), 4.42 (s, 2H), 3.82-3.74 (m, 2H), 3.66 (s, 3H), 3.46-3.38 (m, 2H), 2.47 (s, 3H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8].[C:39]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:44]=[CH:43][CH:42]=[C:41](B(O)O)[CH:40]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:39]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:44]=[CH:43][CH:42]=[C:41]([N:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[C:20]3[N:19]=[C:18]([CH:36]([CH3:38])[CH3:37])[C:17]([CH:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[C:13]([O:15][CH3:16])=[O:14])=[C:26]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:25]=3[CH2:24]2)[CH:40]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(c1cccc(-c3ccccc3)c1)CC2(C)C
Reaction time: 0.08 h
Yield: 37.4 %

Procedure:
A mixture of Cu(OAc)2 (16 mg, 0.09 mmol) and pyridine (7 μl, 0.09 mmol) in CH2Cl2 (1 mL) was stirred for 5 min. Added to this were methyl 2-(tert-butoxy)-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (20 mg, 0.045 mmol), [1,1′-biphenyl]-3-ylboronic acid (17.9 mg, 0.09 mmol) and 34 mg molecular sieves. The resulting mixture was stirred, uncovered, at room temperature for 21 h. The mixture was adsorbed directly onto silica gel and purified by flash column chromatography (Biotage; 0%-50% EtOAc/hexane) to give methyl 2-(6-([1,1′-biphenyl]-3-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetate (10 mg, 37% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.58-7.52 (m, 2H), 7.41-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.27-7.16 (m, 3H), 7.08-6.99 (m, 2H), 6.79-6.70 (m, 1H), 4.88 (s, 1H), 4.01 (d, J=15.6 Hz, 1H), 3.75 (d, J=15.9 Hz, 1H), 3.73 (s, 3H), 3.56 (dt, J=13.1, 6.6 Hz, 1H), 3.49-3.41 (m, 1H), 3.38-3.30 (m, 1H), 1.59 (s, 1H), 1.51 (d, J=4.0 Hz, 6H), 1.35 (s, 3H), 1.17 (d, J=6.7 Hz, 3H), 1.02 (s, 9H). 19F NMR (500 MHz, CDCl3) δ ppm −113.64. LCMS (M+H) calcd for C38H44FN2O3: 595.33. found: 595.4.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.Cl.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:21]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 100 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (97 mg, 0.45 mmol), ethyl (trans-4-aminocyclohexyl)acetate hydrochloride (from Activate Scientific, 120 mg, 0.54 mmol) and triethylamine (0.19 mL, 1.4 mmol) in isopropyl alcohol (4 mL) was heated at 100° C. for 1 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C17H22N3O4S (M+H)+: m/z=364.1. Found: 364.1.
Reaction SMILES: N1C2C(=CC=CC=2)C(CC(=O)C(O)=O)=C1.C(O)(=O)C(C)=O.[OH:22][C:23]([CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)([C:30]([OH:32])=[O:31])[CH2:24][C:25](=O)[C:26]([OH:28])=[O:27].Cl.[NH2:44][OH:45].Cl>[OH-].[Na+]>[OH:22][C:23]([CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)([C:30]([OH:32])=[O:31])[CH2:24][C:25](=[N:44][OH:45])[C:26]([OH:28])=[O:27]
Reactant: NO
Reactant: O=C(O)C(=O)CC(O)(Cc1c[nH]c2ccccc12)C(=O)O
Agent: CC(=O)C(=O)O
Agent: Cl
Agent: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Product: O=C(O)C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Temperature: 35 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Indole-3-pyruvic acid (73.8 g, 352 mmol) was added to and dissolved in 917 g of an aqueous solution of 1.6 wt % sodium hydroxide. A temperature of the reaction mixture was maintained at 35° C. As the pH value was maintained at 11.1 using an aqueous solution of 30% sodium hydroxide, 310.2 g (1761 mmol) of an aqueous solution of 50% pyruvic acid was dripped over 2 hours. The reaction was further continued for 4.5 hours to yield a reaction mixture containing 4-hydroxy-4-(3-indolylmethyl)-2-ketoglutaric acid. As the pH value was maintained at 7 with the addition of the aqueous solution of 30% sodium hydroxide, 367.2 g (2114 mmol) of an aqueous solution of 40% hydroxylamine hydrochloride was added thereto, and stirred at 5° C. for 17.5 hours. The pH value of the reaction mixture was adjusted to 2 using concentrated hydrochloric acid, and organic matters were extracted with ethyl acetate. An organic layer was washed with saturated aqueous NaCl solution, and concentrated to yield residue. The residue was recrystallized from 60 mL of 28% aqueous ammonia and 350 mL of 2-propanol to yield 43.4 g of diammonium salt of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid (142 mmol, yield 40% versus indole-3-pyruvic acid) as crystal.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:46]([C:69]([F:72])([F:71])[F:70])=[N:47][N:48]([C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([C:69]([F:70])([F:72])[F:71])=[N:47][N:48]([C:50]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:49]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3C(F)(F)F)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)-3-(trifluoromethyl)-1-trityl-1H-pyrazole and used in the consecutive step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:20]=[C:19]([CH2:21][C@H:22]4[O:26]C(C)(C)[O:24][C:23]4=[O:29])[O:18][N:17]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[K+].Cl>CO>[Br:1][C:2]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:20]=[C:19]([CH2:21][C@@H:22]([OH:26])[C:23]([OH:29])=[O:24])[O:18][N:17]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CC1(C)OC(=O)[C@@H](Cc2nc(-c3nnc(N4CCC(Oc5cc(F)ccc5Br)CC4)s3)no2)O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H](O)Cc1nc(-c2nnc(N3CCC(Oc4cc(F)ccc4Br)CC3)s2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (5R)-5-[(3-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazol-2-yl}-1,2,4-oxadiazol-5-yl)methyl]-2,2-dimethyl-1,3-dioxolan-4-one (200 mg, 0.36 mmol) in MeOH (5 mL) was added KOH (61 mg, 1.08 mmol). The resulted solution was stirred at rt overnight, adjusted to pH 1 with HCl solution (1 mol/L), and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude product was purified by preparative HPLC to afford the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+].CO>[C:1]1([C:7]2[O:11][C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1nnc(-c2ccccc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
A mixture of methyl 3-(5-phenyl-1,3,4-oxadiazol-2-yl)propanoate (600 mg, 2.0 mmol) in 1 M of aqueous NaOH (10 mL) and Methanol (10 mL) was stirred at room temperature overnight. The reaction solution was adjusted to pH 5 and extracted with ethyl acetate three times. The combined organic layers were dried, filtered and concentrated to yield the desired product (0.50 g, 83%). LCMS calculated for C11H11N2O3 (M+H): 219.1. Found 219.1.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10]O)[C:4]=1[OH:12].[H][H]>CO>[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[OH:12]
Reactant: Cc1cc(CO)c(O)c(CO)c1
Reactant: [H][H]
Solvent: CO
Product: Cc1cc(C)c(O)c(C)c1

Procedure:
108 g of o-cresol, 215 g of 38 wt% formalin, 50 g of sodium hydroxide, and 200 g of water were reacted for 96 hours at 25° C., and the reaction mixture was then neutralized with acetic acid, to obtain 126 g of 2,6-bis(hydroxymethyl)-4-methylphenol. (Yield: 75 mol%) The obtained 2,6-bis(hydroxymethyl)-4-methylphenol was reacted in 250 ml of methanol in the presence of 0.375 wt% of platinum-alumina catalyst and hydrogen for 4 hours at 180° C. at 179 kg/cm2 -G, and 15 g of 2,4,6-trimethylphenol was obtained. (Yield: 45 mol%) The yield on the basis of the raw material was 34 mol%.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=O.[CH3:7][O:8][C:9](=[O:13])[CH2:10][CH2:11][NH2:12].[BH3-]C#N.[Na+]>CO>[CH3:7][O:8][C:9](=[O:13])[CH2:10][CH2:11][NH:12][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1]
Reactant: COC(=O)CCN
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCNCC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.5 g 2,2-Dimethyl-propionaldehyde, 2.18 g 3-Amino-propionic acid methyl ester and 50 ml MeOH was stirred at room temperature for 30 min. 1.5 g NaCNBH3 was added in small portion. The mixture was stirred for another 3 hrs. The solvent was removed in vacuum. 50 mL Water was added to the residue and the mixture was basified to PH10 by 1N NaOH. The solution was extracted by EtOAc (30 mL×3). The organic phase was washed by 20 mL water, dried over Na2SO4. Removed the solvent gave 0.66 g target molecule as clear oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([NH:22][C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37]>CN(C=O)C>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([NH:22][C:21]2[C:12]([NH:11][S:8]([C:5]3[CH:6]=[N:7][C:2]([NH:37][CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(Cl)nc2)cc(OC)c1
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(NCCN(C)C)nc2)cc(OC)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
6-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-pyridine-3-sulfonamide (100 mg, 0.21 mmol), prepared using procedures similar to those used in Example 8, KHCO3 (40 mg, 0.40 mmol), N1,N1-dimethylethane-1,2-diamine (225 μL, 2.0 mmol) and dry DMF (1.0 mL) were combined and heated to 130° C. with stirring overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give N-(3-(3,5-dimethoxy-phenylamino)-quinoxalin-2-yl)-6-(2-(dimethylamino)ethylamino)pyridine-3-sulfonamide (21.0 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (br s, 1H), 8.63 (d, 1H), 8.07 (dd, 1H), 7.40 (m, 1H), 7.34 (m, 1H), 7.28 (d, 2H), 7.14 (m, 4H), 6.47 (d, 1H), 6.12 (m, 1H), 3.75 (s, 6H), 3.35 (m, 2H), 3.14 (m, 2H), 2.74 (s, 6H). MS (EI) m/z for C25H29N7O4S: 524.1 (MH+).
Reaction SMILES: [H-].[Na+].C(NC(C)C)(C)C.[C:10]([OH:15])(=[O:14])[CH:11]([CH3:13])[CH3:12].C([Li])CCC.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCCCCC.O.O1CCCC1>[CH3:12][C:11]([CH3:13])([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([OH:15])=[O:14]
Reactant: CC(C)C(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(C)(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a mixture of 1.23 g (41.0 mmol) of 80% sodium hydride and 50 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere, was added 3.88 g (38.3 mmol) of diisopropylamine and then 3.3 g (37.5 mmol) of isobutyric acid. After heating at reflux for 5 minutes and cooling to 0° C., 15 mL (37.5 mmol) of 2.5M n-butyllithium in hexane was added. The mixture was warmed to 35° C. for 30 min, cooled to 0° C. and 6.40 g (37.5 mmol) of benzyl bromide added. The mixture was stirred for 30 minutes at 0° C., then warmed to 35° C. for one hour and recooled to 0° C. Water was added and the aqueous layer extracted with diethyl ether, acidified with 6N aqueous HCl and extracted with diethyl ether. The organic layer was dried and concentrated to provide 4.0 g of crude product. Chromatography on silica gel using 10% methanol/methylene chloride afforded 1.0 g of pure 2,2-dimethyl-3-phenylpropionic acid, m/e 185 (M+Li).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4]SC.[CH:10]1C(C(O)=O)=CC=C(N)[CH:11]=1.N[C@H](C(O)=O)CC1C=CC=CC=1.N1CCC[C@H]1C(O)=O>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:10][CH3:11])[CH3:4]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CSCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
L-methionine 2 g; PABA 0.2 g; L-phenylalanine 2 g; L-proline 2 g;