Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=3)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:39][C:40]1[C:41]([OH:51])=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1>ClCCl>[Cl:39][C:40]1[C:41]([OH:51])=[C:42]([S:47]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=2)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(-c3ccc(F)cc3)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
tert-Butyl 3-(((4′-fluorobiphenyl-4-yl)methylamino)methyl)benzylcarbamate (1.8 g, 4.28 mmol, 1.0 eq) was dissolved in dichloromethane and cooled 0° C. Triethylamine (1.85 mL, 12.8 mmol, 3.0 eq) was added slowly over 5-10 minutes and the mixture was stirred for 10 minutes at 0° C. 3,5-Dichloro-2-hydroxybenzene-1-sulfonyl chloride (1.2 g, 4.7 mmol, 1.1 eq) was dissolved in DCM and added slowly to the above mixture at 0° C. After 2 h, the reaction mixture was concentrated under vacuum at low temperature and the white precipitate that formed was removed. The solution was purified by silica gel (60-120) column chromatography using 15-20% ethyl acetate/hexane as the eluent to afford the desired product (2.3 g, 85%). 1H NMR (400 MHz, CD3OD) δ 1.45 (d, 9H), 4.11-4.15 (d, 2H) 4.49-4.52 (d, 4H), 7.07-7.19 (m, 8H), 7.42-7.44 (d, 2H), 7.56-7.59 (m, 3H), 7.65-7.66 (d, 1H). MS (ESI): 644.0 (M−H)−.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:17](=O)(O)[O-].[Na+]>CO>[CH3:17][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([Cl:16])=[N:15][C:7]=1[NH2:6]
Reactant: O=C([O-])O
Reactant: Nc1nc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1N
Temperature: 70 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Concentrated sulfuric acid (25 mL) and 2-amino-6-chloro-nicotinic acid (4.3 g, 25 mmol) described in Production Example 4-1-1A (or 4-1-1B) were added to methanol (50 mL) while cooling with ice followed by stirring for 5 hours at 70° C. After allowing to cool on standing, the reaction mixture was neutralized with sodium bicarbonate (90 g). The resulting solid was filtered to obtain the title compound (3.2 g, 17 mmol, 68%) as a pale brown solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=O)(C)(C)C.[CH2:27](O)[CH3:28].[ClH:30]>>[ClH:30].[NH2:8][CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:25])[CH3:26])=[CH:20][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:27][CH3:28])=[O:18]
Reactant: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(OCCCC(=O)[O-])c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCCOc1cc(C(C)C)ccc1CCN
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-[2-(2-tert-Butoxycarbonylaminoethyl)-5-isopropyl-phenoxy]butyrate (0.283 g) was deissolved in 10 mL of 35% hydrogen chloride ethanol solution, and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure to give 0.235 g of ethyl 4-[2-(2-aminoethyl)-5-isopropylphenoxy]butyrate hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[C:8]([CH3:14])=[C:7]([CH3:15])[C:6]=1[O:16][CH3:17])[OH:4].O=[C:19]([CH3:55])[CH2:20][O:21][C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:17][O:16][C:6]1[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([O:12][CH3:13])=[C:10]([CH3:11])[C:5]=1[CH:3]([OH:4])[CH2:2][NH:1][CH:19]([CH3:55])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[NH:29][C:28]2=[O:52])=[CH:53][CH:54]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Reactant: COc1c(C)c(C)c(OC)c(C(O)CN)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: COc1c(C)c(C)c(OC)c(C(O)CNC(C)COc2ccc(CC3SC(=O)NC3=O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
A solution of 1.23 g of 2-amino-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)ethanol [prepared as described in Preparation 14] and 3.0 g of 5-[4-(2-oxopropoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in Preparation 20] in 300 ml of benzene was heated under reflux for approximately 4 hours, during which time the water produced throughout the reaction was eliminated as a benzene azeotrope. The reaction mixture was then freed from benzene by distillation under reduced pressure. The residue was dissolved in a mixture of 100 ml of absolute methanol and 100 ml of absolute ethanol, after which 8.5 g of sodium borohydride were added to the solution. The resulting mixture was then heated under reflux for one hour. At the end of this time, the reaction mixture was freed from the alcohol by distillation under reduced pressure. The residue was then mixed with water and then it was extracted with ethyl acetate. The ethyl acetate layer was then washed twice with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and 50 ml of trifluoroacetic acid were then added to the residue, whilst ice-cooling. The resulting mixture was then stirred at room temperature for one hour. At the end of this time, the trifluoroacetic acid was distilled off under reduced pressure and the residue was mixed with water. The aqueous mixture thus obtained was then neutralized with an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed twice with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 160 mg of the title compound, having an Rf=0.3 (thin layer chromatography on silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:11][C:12]1[CH:13]=[C:14]([N:19]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>[Pt].[Pt].C[Si](C)(C)O[Si](C)(C=C)C=C.C[Si](C)(C)O[Si](C)(C=C)C=C.C[Si](C)(C)O[Si](C)(C=C)C=C.C1(C)C=CC=CC=1>[CH3:27][C:22]1[CH:21]=[C:20]([N:19]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][CH2:33][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:34][CH:35]=2)[C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Agent: [Pt]
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1)(OCC)OCC
Temperature: 25 °C

Procedure:
40 mL of toluene, 6.0 g of triethoxysilane, and 0.54 mmol of a toluene solution of tris-(tetramethyldivinyldisiloxane) diplatinum (0) were placed in a three-neck flask. While stirring at room temperature, 20 mL of a toluene solution of 9.9 g of 4-[N,N-bis-(3,4-dimethylphenyl)amino]styrene was dropped into the flask. Upon completion of addition of drops, the mixture was stirred for 3 hours at 70° C. The solvent was removed under reduced pressure, and a lemon-yellow oil of 4-[N,N-bis-(3,4-dimethylphenyl)amino][2-(triethoxysilyl)ethyl]benzene was obtained. The yield was 13.4 g (yield rate of 90.1%). This refined material was subjected to the same process as in Practical Example 1, and platinum was measured in the same manner. The platinum concentration of this refined material was 1.9 ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[NH:8]1[CH2:18][CH2:17][CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:15]([O:14][C:12]([CH:11]1[CH2:17][CH2:18][N:8]([CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:9][CH2:10]1)=[O:13])[CH3:16]
Reactant: CC(C)(C)CC=O
Reactant: CCOC(=O)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
3,3-Dimethylbutyraldehyde (5.26 ml, 42.0 mmol) was added to a solution of ethyl isonipecotate (6.6 g, 42.0 mmol) in methanol/acetic acid (99:1, v/v, 50 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (3.43 g, 54.6 mmol) was added, and the mixture was stirred at room temperature for 4 days then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 25% EtOAc:75% cyclohexane) to yield the title compound (7.16 g, 71%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:7]1[C:2]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 76 %

Procedure:
A procedure similar to that of the method described in step C.1 is carried out, starting from 1.2 g (5.9 mmol) of 2-chloro-3,5-dinitropyridine, 1.03 g (7.07 mmol) of ethyl 5-aminovalerate and 0.9 g (8.84 mmol) of triethylamine in 20 ml of dioxane. This gives 1.4 g of expected product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([Li])CCC.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl.C(N(CC)CC)C>COCCOCCOC>[CH3:15][Si:16]([CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])([CH3:19])[CH3:18]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cccc(CO)c1
Agent: [Li]CCCC
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Cc1cccc(CO)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylbenzylalcohol (6.10 g, 50 mmol) in anhydrous diglyme (200 ml) at -78° C. was added 1.5M butyllithium (100 ml) over 20 min. The resulting mixture was allowed to warm to -20° C. and stirred for 30 min. Then a mixture of trimethylchlorosilane (19.0 g, 175.0 mmol) and triethylamine (5.05 g, 50 mmol) was added and the final solution was stirred at room temperature for 3 hours. The reaction mixture was treated with ice water (200 ml), extracted three times with diethyl ether (100 ml) and the extracts washed twice with water, brine, dried over MgSO4 and concentrated. The crude product was dissolved in 90% aqueous methanol (200 ml) and refluxed for 1 hour. Then the solvents were removed and 3-trimethylsilylmethylbenzylalcohol was purified by fractional distillation.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:11])=[CH:2]1.ClN1[C:26](=[O:27])[CH2:25][CH2:24]C1=O.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:27]1[C:2]2=[C:3]([C:10]([O:12][CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:11])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[N:1]2[CH2:24][CH2:25][CH2:26]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(OCCN1CCCCC1)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCCN1CCCCC1)c1c2n(c3ccccc13)CCCO2

Procedure:
2-(1-Piperidyl)ethyl 1 H-indole-3-carboxylate was treated initially with N-chlorosuccinimide (1.5 equivalents) for 2 h, then with 3-bromo-1-propanol (3 equivalents) for 21 h, followed by anhydrous potassium carbonate in acetone, using the method described in Example 1b. The crude product was purified using the same chromatography conditions as in Example 1b to afford the title compound. (E4) as a pale yellow oil (15%). This was converted to its oxalate salt and crystallised from acetone mp 174°-177° C.
Reaction SMILES: C1(O)C=CC=CC=1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.[OH:14][C:15]1[CH:31]=[CH:30][C:18]([CH:19]=[C:20]2[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]2=[O:29])=[CH:17][CH:16]=1>ClCCl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[CH3:27][C:23]1([CH3:28])[O:24][C:25](=[O:26])[C:20](=[CH:19][C:18]2[CH:30]=[CH:31][C:15]([O:14][CH:13]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)=[CH:16][CH:17]=2)[C:21](=[O:29])[O:22]1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=Cc2ccc(OC3CCCCO3)cc2)C(=O)O1

Procedure:
Protection of the phenol with dihydropyran was carried out based on the method given in Miyashita et al. (1977) J. Org. Coed. 42: 3772. Compound 1.1 (500 g, 2 mol) was dissolved in dichloromethane (4 L). 3,4-Dihydro-2H-pyran (250 g, 3 mol) was added to the suspension followed by PPTS (5 g, 20 mmol). The reaction mixture heated to a gentle reflux (3.5 h). HPLC showed ˜90% completion of the reaction. The reaction was concentrated under reduced pressure to ˜2 L of volume. 1 L of acetone was added, and 2 L of solvent was removed under reduced pressure. 1 L of acetone was added, and 1 L of solvent was removed under reduced pressure. 0.5 L of acetone was added, and 0.5 L of solvent was removed under reduced pressure. The resulting slurry of very fine, light yellow crystals was filtered and rinsed sequentially with two 500 mL portions of acetone. The product was dried in a vacuum oven at 50° C. until no further solvent collected in the traps. Compound 52.1 (528 g) was obtained as fine, light yellow crystals. 1H NMR(400 MHz)(DMSO-d6) δ 8.29 (s, 1H); 8.18 (d, 2H, J=8.9 Hz); 7.13 (d, 2H, J=8.9 Hz); 5.67 (m, 1H); 3.70 (m, 1H); 3.60 (m, 1H). 1.9-1.5 (m, 12H). MS ESI (pos.) m/e: 355.1 (M+Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@H:30]1[C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@H:30]1[C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]=[CH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2ccc(-c3onc(C)c3C=CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and (trans)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([NH2:16])=[N:14][CH:15]=1)=[O:8].C(N(CC)CC)C.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>C(Cl)(Cl)Cl>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:38])[F:39])[CH:29]=3)(=[O:36])=[O:35])[CH:3]=[CH:4][C:5]=2[CH3:18])=[CH:15][N:14]=1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(N)nc1
Temperature: 25 °C

Procedure:
To a solution of 5-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 28 (85 mg, 0.349 mmol) in CHCl3 (2 mL) was added triethylamine (0.453 mmol) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.064 mL, 0.401 mmol). The reaction mixture was heated to reflux for 12 h, cooled to rt and concentrated in vacuo. The crude residue was adsorbed on SiO2 and purified by flash chromatography (CH2Cl2/MeOH 99:1) on SiO2 to afford N-(2-aminopyrimidin-5-yl)-2-methyl-5-(3-(trifluoromethyl)phenylsulfonamido)benzamide 29. MS m/z found 452 [MH+]; calc. for C19H16F3N5O3S=451.09.
Reaction SMILES: CN.[C:3](N1C=CN=C1)([N:5]1C=CN=[CH:6]1)=[O:4].[CH2:15]([C@:17]1([C:42]#[N:43])[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)[N:23]=2)[C:18]1=[O:41])[CH3:16].O>O1CCCC1>[C:42]([C@@:17]1([CH2:15][CH3:16])[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:40][CH2:39][N:38]([C:3]([NH:5][CH3:6])=[O:4])[CH2:37][CH2:36]4)=[CH:33][CH:34]=3)[N:23]=2)[C:18]1=[O:41])#[N:43]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)C1=O
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCN(C(=O)NC)CC4)cc3)n2)C1=O
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of 2 M methylamine in tetrahydrofuran (0.28 mL) were added 1,1′-carbonyldiimidazole (91 mg) and tetrahydrofuran (3.0 mL) in an ice bath, and the mixture was stirred at the same temperature for 10 min. To the reaction mixture was added (3R)-3-ethyl-2-oxo-1-(2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)pyrrolidine-3-carbonitrile (200 mg) obtained in Example 220, and the mixture was stirred at 70° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). To a solution of the obtained purified product (290 mg) in ethanol (3 mL) was added 1 M hydrochloric acid (0.64 mL), and the mixture was stirred at room temperature for 5 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized (ethanol/diisopropyl ether) to give the title compound (220 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[C:21]([C:22]4[CH:23]=[C:24]([C:30]5[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][C:31]=5[CH3:40])[CH:25]=[CH:26][C:27]=4[O:28][CH3:29])=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=3)[C@H:10]2[CH3:45])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:46]1[CH2:49][CH2:48][CH2:47]1>C1COCC1>[N:46]1([C:18]2[N:17]=[C:16]([CH2:15][N:11]3[C@@H:10]([CH3:45])[C@@H:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)[O:13][C:12]3=[O:14])[C:21]([C:22]3[CH:23]=[C:24]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][C:31]=4[CH3:40])[CH:25]=[CH:26][C:27]=3[O:28][CH3:29])=[CH:20][N:19]=2)[CH2:49][CH2:48][CH2:47]1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Reactant: C1CNC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(N4CCC4)nc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Yield: 100 %

Procedure:
To methyl 3′-[4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-(methylsulfonyl)pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (81 mg, 0.121 mmol) in THF (1.6 mL) was added azetidine (40.7 μL, 0.604 mmol). The reaction was subjected to microwave irradiation at 100° C. for 15 min. The reaction was concentrated, then dissolved in ethyl acetate and washed with water (2×), brine, dried (Na2SO4), filtered, concentrated. The crude reaction was purified by column chromatography to yield methyl 3′-[2-(azetidin-1-yl)-4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (78 mg, 0.121 mmol). LCMS calc.=647.2. found=647.4.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]([CH3:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:13][N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:15][CH:14]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CN(C)Cc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CN(C)Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of methyl 2-((4-aminobenzyl)(methyl)amino)acetate (0.680 g, 3.27 mmol) in pyridine (15 ml) was cooled to 0° C., and methane sulfonylchloride (0.280 ml, 3.59 mmol) was added. The mixture was warmed to RT and stirred for 1 hour. The solvent was removed, and the crude was portioned between DCM and water. The aqueous phase was basified with solid K2CO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and the solvent was evaporated. The crude was filtered on SCX cartridge (DCM/MeOH 1/1; MeOH/conc.aq.NH4OH 90/10). The basic fraction was evaporated to dryness to give methyl 2-(methyl(4-(methylsulfonamido)-benzyl)amino)acetate (0.750 g, 2.62 mmol, 80% yield, MS/ESI+ 287.2 [MH]+).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:32].[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCN5CCOCC5)cc4)cc3)n(C)c(=O)c12
Yield: 67.7 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (366 mg), 4-(2-chloroethyl)morpholine hydrochloride (192 mg) and potassium carbonate (356 mg) in DMF (5 ml) was stirred at 60° C. for 62 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration to provide the title compound as colorless solid (337 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[OH:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[OH:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20](=[CH:12][C:9]3[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=3[CH3:11])[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: O=C1Cc2ccc(O)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(O)ccc32)c(C)c1CCC(=O)O
Yield: 40.1 %

Procedure:
3-(2-carboxyethyl)-2,4-dimethyl-5-formylpyrrole (82 mg), 63 mg 6-hydroxy-2-oxindole, and 48 μL piperidine in 2 mL of ethanol were heated at 90° C. for two days. The reaction mixture was cooled, concentrated, and purified by silica gel column chromotography eluting with ethyl acetate-hexane-acetic acid to give 55 mg (40%) of the title compound as an dark brown solid.