Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:9]2=[O:13])=[CH:15][CH:16]=1
Reactant: O=C1NCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 14B (0.82 g, 3.00 mmol) in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran, 4.5 mL, 4.5 mmol) via syringe under nitrogen followed by ethyl 2-bromoacetate (0.33 mL, 3.00 mmol). The reaction mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated and then diluted with ethyl acetate. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography eluting with ethyl acetate/hexane (20:80) to obtain the title compound. MS (APCI+) m/z 359.9 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11]
Reactant: COc1ccccc1CC(N)=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methoxyphenyl acetamide (13.0 g, 78.6 mmol) was dissolved in methylene chloride (10.0 mL). Subsequently, 1.0M boron tribromide in methylene chloride solution (157 mL, 157 mmol) was slowly added dropwise under ice-cooling, and the mixture was stirred for one hour at room temperature. Subsequently, water was slowly added thereto under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was extracted with chloroform, followed by washing the organic layer with brine, drying over anhydrous sodium sulfate. The reaction mixture was subjected to concentration under reduced pressure and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (1.8 g, 11.9 mmol, 15%).
Reaction SMILES: Cl.[C:2]1([C:8]2[O:12][N:11]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)[N:22]=[C:21]1N1CCOC(C2ON=C(C3C=CC=CC=3)N=2)C1.C(N(CC)CC)C>O1CCCC1>[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)[N:22]=[C:21]1[N:15]1[CH2:16][CH2:17][O:18][CH:13]([C:10]2[N:9]=[C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:12][N:11]=2)[CH2:14]1
Reactant: Cn1c(N2CCOC(c3nc(-c4ccccc4)no3)C2)nc(-c2ccncn2)cc1=O
Reactant: c1ccc(-c2nc(C3CNCCO3)no2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCOC(c3noc(-c4ccccc4)n3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of the resulting 2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholine hydrochloride (intermediate 28) in tetrahydrofuran (6.0 ml) was added with 2-chloro-3-methyl-6-(pyrimidine-4-yl)pyrimidin-4-one (intermediate 1 260 mg, 2.34 mmol) and triethylamine (1.81 ml, 13.0 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The solution was partitioned between water and chloroform, and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluent; 5% methanol in chloroform) to afford 1-methyl-2-[2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholin-4-yl]-1H-[4,4′]bipyrimidinyl-6-one (compound 2 in Table 1, 749 mg, 64%, 2 steps) as solid
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.02 g, 3 mmol) in DCM (30 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (541 mg, 3 mmol), EDC (633 mg, 3.3 mmol), and TEA (1.05 mL, 7.5 mmol). This mixture was stirred at room temperature for 18 h. The reaction mixture was washed with H2O (20 mL), dried over Na2SO4, filtered, concentrated and purified with CombiFlash to afford 0.7052 g (50%) of the title compound. LC-MS m/z 466 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:23]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:23])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)c1cccc(Br)c1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NCC(=O)c1ccc(Cl)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To an ice-cooled mixture of the product from Step A (4.6 g, 23 mmol) and diisopropylethylamine (4.46 g, 34.5 mmol) in dichloromethane (50 mL) was added 2-bromo-4′-chloroacetophenone (5.48 g, 23 mmol). The reaction mixture was stirred at room temperature for 3 hours and then diluted with dichloromethane (100 mL). The mixture was washed with water and brine, dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, 20 to 40% ethyl acetate/hexanes) purification provided the 2-(1-(3-bromophenyl)ethylamino)-1-(4-chlorophenyl)ethanone (6.0 g, 74%): 1H NMR (CDCl3, 300 MHz) δ 7.80 (dd, J=6.7, 2.0 Hz, 2H), 7.52 (t, J=1.7 Hz, 1H), 7.43-7.37 (m, 3H), 7.29-7.17 (m, 2H), 3.93 (d, J=1.4 Hz, 2H), 3.80 (q, J=6.6 Hz, 1H), 1.42 (d, J=6.6 Hz, 3H). ESI MS m/z=352 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[CH2:28][CH2:27]2)[N:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 28 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and ethanesulfonyl chloride (Aldrich), to give [4-amino-2-(1-ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone. HRMS, observed: 420.1704; Calcd for (M+H)+: 420.1700.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:7]=2)[CH:3]=1.C(NC1C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1)(=O)C.N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[N+:37]=[N-:38])[C:12]([O:14][CH3:15])=[O:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[N:7]=2)[CH:3]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)Cc1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(=[N+]=[N-])c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetate (1.95 g, 5.49 mmol) and 4-acetamidobenzenesulfonyl azide (1.52 g, 6.32 mmol) in acetonitrile (11 mL) at 0° C. was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.04 mL, 6.87 mmol) dropwise over 20 min. The ice bath was removed and stirring continued at room temperature for 1 h. The reaction was partitioned between water and ethyl acetate. The organics were washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated. The resulting residue was purified by column chromatography (8%→25% ethyl acetate/n-hexane) to give 1.39 g (66%) as a yellow oil. 1H-NMR (CDC13, 500 MHz) δ 8.01 (s, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 5.64 (s, 2H), 3.89 (s, 3H), 3.64 (t, J=8.2 Hz, 2H), 0.93 (t, J=8.4 Hz, 2H), −0.03 (s,9H; 13C NMR (126 MHz, CDCl3) δ ppm 165.9, 143.2, 128.7, 125.3, 123.1, 122.7, 122.5, 116.5, 116.4, 81.8, 67.9, 52.1, 17.8, −1.4.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18]C)=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH3:32])=[N:10]2)=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH3:32])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SC)=NC1c1ccc(C#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SC)=NC1c1ccc(C#N)cc1

Procedure:
Ethyl 4-(4-cyanophenyl)-6-methyl-2-(methylsulfanyl)-1-[3-(trifluoromethyl)phenyl]-1,4-dihydro-5-pyrimidinecarboxylate (example 7; 100 mg, 0.22 mmol) and sodium methoxide (117.6 mg, 2.18 mmol) are dissolved in 5 ml methanol and stirred at reflux temperature for 3 h. The reaction is quenched with 10 ml of water and the aqueous phase is extracted with 10 ml methylene chloride (2×). After drying with sodium sulfate, the solvent is removed in vacuo and the product is purified by column chromatography (silica gel; eluent: cyclohexane-ethyl acetate, gradient 90:10 to 50:50).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][CH:13](O)[C:14]#[CH:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl.O>[CH3:15][CH:14]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]#[CH:12]
Reactant: C#CC(C)O
Reactant: Oc1cccc2ccccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: C#CC(C)Oc1cccc2ccccc12
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of 1-naphthol (200 mg, 1.38 mmol) and but-3-yn-2-ol (146 mg, 2.07 mmol) in anhydrous DCM (10 mL) under a N2 atmosphere and at 0° C. was added Ph3P (435 mg, 1.66 mmol) portion wise. The reaction mixture was stirred for 10 min and then DEAD (360 mg, 2.07 mmol) (70% solution in toluene) was slowly added. The resulting reaction solution was stirred at the room temperature for 24 h and then diluted with water (50 mL) and extracted with chloroform (3×50 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered concentrated in vacuo and the residue was purified by flash column chromatography using ethyl acetate/n-hexane (a gradient of 5-10%) to furnish 1-[(1-methyl-2-propyn-1-yl)oxy]naphthalene (176 mg, 65%) as a viscous oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[NH:18])=[CH:12][CH:11]=1)=[O:4].CN(C)/[CH:22]=[C:23](\[F:35])/[C:24]([C:26]1[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=1)=O>COCCO>[CH3:1][NH:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:19]=[C:24]([C:26]3[N:30]([CH:31]([CH3:32])[CH3:33])[C:29]([CH3:34])=[N:28][CH:27]=3)[C:23]([F:35])=[CH:22][N:18]=2)=[CH:12][CH:11]=1)=[O:4]
Reactant: CNC(=O)[C@H]1CCCN1c1ccc(NC(=N)N)cc1
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Solvent: COCCO
Product: CNC(=O)[C@H]1CCCN1c1ccc(Nc2ncc(F)c(-c3cnc(C)n3C(C)C)n2)cc1
Temperature: 200 °C
Yield: 39.9 %

Procedure:
(R)-1-(4-Guanidino-phenyl)-pyrrolidine-2-carboxylic acid methylamide (Method 59; 0.22 g, 0.82 mmol) and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 14; 0.15 g, 0.63 mmol) were added to 2-methoxyethanol (4 ml) and heated at 200° C. for 2 hours in the microwave. Solvent was removed in vacuo and chromatographed. The product was passed purified by HPLC, and the required fractions were combined and basified with K2CO3 (0.5 g), extracted with DCM (2×50 ml), dried and solvent removed in vacuo to yield a yellow solid (110 mg, 40%). NMR (400.132 MHz, CDCl3) 8.21 (d, 1H), 7.56 (d, 1H), 7.34 (d, 2H), 6.79 (s, 1H), 6.60 (d, 2H), 6.56 (s, 1H), 5.56 (septet, 1H), 3.99 (t, 1H), 3.64 (t, 1H), 3.20 (q, 1H), 2.80 (d, 3H), 2.58 (s, 3H), 2.29-2.24 (m, 2H), 2.06-1.89 (m, 2H), 1.45 (d, 6H); m/z 438.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:13]([CH2:14][CH:15]=[C:16]2[C:17](=[O:19])[CH3:18])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:23])[CH:6]=[CH:5]1.[CH3:25][Si:26]([CH3:29])([CH3:28])Cl>N1C=CC=CC=1>[CH3:25][Si:26]([CH3:29])([CH3:28])[O:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:13]([CH2:14][CH:15]=[C:16]2[C:17](=[O:19])[CH3:18])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:23])[CH:6]=[CH:5]1
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Solvent: c1ccncc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@]12C
Temperature: 0 °C

Procedure:
30 g. of 11β-hydroxy-1,4,16-pregnatriene-3,20-dione is combined in 300 ml. of absolute pyridine with 30 ml. of trimethylchlorosilane and agitated for 24 hours at room temperature. The mixture is then stirred into ice water, the thus-precipitated sediment is vacuum-filtered, washed out with water, and taken up in methylene chloride. After evaporation, 36.5 g. of crude 11β-trimethylsilyloxy-1,4,16-pregnatriene-3,20-dione is obtained. A sample recrystallized from diisopropyl ether melts at 196°- 197.5° C.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+].Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23]1>CS(C)=O.CO>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23]1)(=[O:5])[NH2:6]
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: O=C(O)CC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: NC(=O)c1ccc(C(F)(F)F)cc1N1CCC(CC(=O)O)CC1
Reaction time: 4 h

Procedure:
0.46 g of 2-fluoro-4-(trifluoromethyl)benzamide are added to a suspension of 1.8 g K2CO3 and 0.8 g of piperidin-4-yl acetic acid hydrochloride In 12 ml of DMSO, the mixture obtained is stirred for 4 h at 150°, solvent is evaporated, the evaporation residue obtained is suspended in MeOH and filtrated. The filtrate obtained is concentrated and subjected to chromatography on silica gel. [1-(2-Carbamoyl-5-trifluoromethyl-phenyl)-piperidin-4-yl]-acetic acid is obtained. 300 mg of EDC are added to a solution of 260 mg of [1-(2-carbamoyl-5-trifluoromethyl-phenyl)-piperidin-4-yl]-acetic acid, 230 mg of 3,5-bis-trifluoromethyl-benzenesulfonamide, 200 mg of DIEA and 90 mg of DMAP in 4 ml of DMF. The mixture obtained is stirred for 3 days at RT, solvent is evaporated in vacuo and the evaporation residue obtained is treated with EtAc. The mixture obtained is washed with 1 N HCl, saturated aqueous NaHCO3 solution and brine, dried, concentrated in vacuo and subjected to chromatography on silica gel. 2-{4-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-ethyl]-piperidin-1-yl}-4-trifluoromethyl-benzamide is obtained.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:23]O>>[CH:5]1([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CO
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
Thionyl chloride (1 mL) was added to a stirred mixture of 3-cyclohexyl-1H-indole-6-carboxylic acid (30.4 g, 0.125 mol) in methanol (300 mL). The mixture was stirred at reflux for 18 hours, treated with decolorizing carbon, and filtered. The filtrate was concentrated to about 150 mL at which point crystallization occurred. The filtrate was cooled to room temperature and filtered. The solid was washed with cold methanol followed by diethyl ether to provide the desired product as a pale purple solid (22.2 g, 69% yield). ESI-MS m/z 258 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.35 (m, 4H), 1.63 (s, 1H), 1.78 (m, 3H), 2.06 (d, J=8.05 Hz, 2H, 3.90 (m, 1H), 7.08 (d, J=1.83 Hz, 1H), 7.62 (s, 1H), 7.65 (s, 1H), 7.74 (d, J=1.46 Hz, 1H), 7.77 (d, J=1.46 Hz, 1H), 8.08 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].C[Si]([N:20]=[C:21]=[O:22])(C)C.ClCCl>CN(C)C=O>[NH2:20][C:21]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14])=[O:22]
Reactant: C[Si](C)(C)N=C=O
Reactant: NC(=O)c1sc(-c2ccccc2)cc1N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)Nc1cc(-c2ccccc2)sc1C(N)=O

Procedure:
3-Amino-5-phenyl-2-thiophenecarboxamide (0.5 g), trimethylsilylisocyanate (3 mL), dichloromethane (15 mL) and dimethylformamide (3 mL) were heated at reflux for 3 days.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(O[CH:12]=[C:13]([C:19](=[O:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)(C)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:12]=[C:13]([C:19](=[O:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: Nc1ccccc1Br
Solvent: CC(C)O
Product: CCOC(=O)C(=CNc1ccccc1Br)C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
To a solution of 2-bromoaniline (2 g, 11.63 mmol) in Isopropanol (15 mL) stirred under nitrogen at room temperature was added neat ethyl 2-(ethoxymethylene)-3-oxobutanoate (2.165 g, 11.63 mmol) in one charge. The reaction mixture was stirred at room temperature for 20 min, at which time LCMS showed only a trace amount of product. The reaction mixture was heated to 75° C. and stirred for 20 min. LCMS showed complete conversion. The mixture was cooled to room temperature and concentrated under vacuum, during which time a large amount of material precipitated out. Filtration followed by a hexanes wash afforded ethyl 2-(((2-bromophenyl)amino)methylene)-3-oxobutanoate (3.8 g, 10.96 mmol, 94% yield) that was apx. 90% pure to be used in the next step. LCMS: (M+H)+: 312.0.
Reaction SMILES: C([O:3][C:4](=[O:10])[CH:5](Cl)[C:6]([CH3:8])=O)C.[CH:11]([NH2:13])=[O:12].[OH-].[Na+].Cl>CCOC(C)=O>[CH3:8][C:6]1[N:13]=[CH:11][O:12][C:5]=1[C:4]([OH:3])=[O:10]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ncoc1C(=O)O
Temperature: 120 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
Ethyl-2-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120° C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separae. The organic layer was discarded while the aqueous was acidified with conc. (32%) aqueous HCl to pH 2 (ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The collected solid was placed in the oven at 40° C. over night under reduced pressure to give 4-methyl-1,3-oxazole-5-carboxylic acid (498 g, 64.5%).
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O=O.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.CN(C=O)C.[Cu]I>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)([CH3:15])[CH3:14]
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1c[nH]c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-iodouracil (8 g, 30 mmol) in redistilled triethylamine (500 mL) and dry DMF (10 mL) was degassed with oxygen-free nitrogen for 15 minutes. Bis(triphenylophosphine)palladium (II) chloride (0.5 g), copper (I) iodide (0.5 g) and trimethylsilylacetylene (10 g, 102 mmol) were then added and the mixture was heated with stirring at 50° C. for 24 hours. The cooled reaction mixture was filtered, the filtrate evaporated to dryness and the residue dissolved in dichloromethane (500 mL). The organic solution was washed with a 2% aqueous solution of disodium EDTA (3×250 mL), water (3×200 mL), dried (Na2SO4) and evaporated to dryness. The residue was triturated with ethanol to give the first crop of the title compound. The solid filtered from the reaction mixture was also found to contain the required product but in a more impure form and so was worked up as above in a separate batch to give a second crop.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][CH2:52][NH2:53]>>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([NH:53][CH2:52][CH2:51][O:50][CH3:49])=[O:6]
Reactant: COCCN
Reactant: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(F)c(C(=O)NCCOC)cc1[N+](=O)[O-]

Procedure:
2-Fluoro-N-(2-methoxy-ethyl)-4-methylamino-5-nitro-benzamide was prepared by following General Procedure F starting from 2-fluoro-4-methylamino-5-nitro-benzoic acid (75 mg), HBTU (159 mg), DIEA (92 uL), and 2-methoxyethylamine (26 mg). The crude product was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([N:30]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:39])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:42][N:41]=[N:40][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([N:30]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:39])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2c(C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.