Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:18][C:12]1[NH:11][CH:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(Br)c1-c1cccc(F)c1
Yield: 33.4 %

Procedure:
To a solution of 38.3 g (164 mmol) of ethyl 4-(3-fluoro-phenyl)-1H-pyrrole-3-carboxylate in 380 ml of tetrahydrofuran are added, over 30 minutes, 32.1 g (181 mmol) of N-bromosuccinimide (CAS 128-08-5), and the mixture is then stirred for 3 hours at reflux. After cooling, 200 ml of aqueous 5% sodium thiosulfate solution are added and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give 17.1 g of ethyl 5-bromo-4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate in the form of a white powder after recrystallizing from diisopropyl ether, filtering off and drying.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:28])[C@H:15]1[CH2:19][C@@H:18]([OH:20])[CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:12][O:13][C:14](=[O:28])[C@H:15]1[CH2:19][C@@H:18]([O:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
4-Dimethylaminopyridine (1.21 g) and p-toluenesulfonyl chloride (1.51 g) were added to a solution of N-tert-butoxycarbonyl-cis-4-hydroxy-D-proline methyl ester (A, 971 mg) in dichloromethane (20 mL). After stirrng at room temperature for 4 hr, the solvent was removed in vacuo. The residue was diluted with ethyl acetate, and washed with 10% citric acid, water, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform:ethyl acetate=1:50, v/v) to give the title compound (1.65 g) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:35])[CH:11]([NH:23][C:24](=[O:34])[C@H:25](Br)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:36](O)(=[S:38])[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([NH:9][C:10](=[O:35])[CH:11]([NH:23][C:24](=[O:34])[C@@H:25]([C:36](=[S:38])[CH3:37])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(NCCc1ccccc1)C(NC(=O)[C@H](Br)Cc1ccccc1)C(=O)NCCc1ccccc1
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=S)[C@@H](Cc1ccccc1)C(=O)NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Yield: 92 %

Procedure:
Prepare by the method of Example 1.4 using N,N′-diphenethyl-2-((R)-2-bromo-3-phenylpropionylamino)malonamide (0.11 g, 0.21 mmol), thioacetic acid (0.05 mL, 0.62 mmol), and cesium carbonate (0.10 g, 0.31 mmol) in dimethylformamide (8 mL). Purify by chromatography on silica gel eluting with 1/1 hexane ethyl acetate to give the title compound (92%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH3:32][C:33]1[S:34][CH:35]=[C:36](/[CH:38]=[CH:39]/[C:40]2[C:41]([OH:51])=[N:42][N:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:44]=2)[N:37]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][O:29][C:5]1[CH:4]=[C:3]([CH2:2][O:51][C:41]2[C:40](/[CH:39]=[CH:38]/[C:36]3[N:37]=[C:33]([CH3:32])[S:34][CH:35]=3)=[CH:44][N:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:42]=2)[CH:28]=[CH:27][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=2)[O:12][C:13]=1[CH3:14]
Reactant: Cc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(C)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.49 g), 4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (1.05 g), potassium carbonate (1.01 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl {4-[4-({2-methoxy-4-[({4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (1.25 g, yield 53%) as pale-yellow crystals. melting point: 153-155° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:24]3[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccncc2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccncc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(pyridin-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 417.01 g/mol.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([CH2:10][C:11](=[O:22])[NH:12][C:13]2[S:14][C:15]3[CH2:16][CH2:17][CH2:18][NH:19][C:20]=3[N:21]=2)[CH2:7][C@@H:6]1[NH:23][C:24]([C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:25].I[CH:33]([CH3:35])[CH3:34]>C1COCC1>[CH:33]([CH:18]1[CH2:17][CH2:16][C:15]2[S:14][C:13]([NH:12][C:11]([CH2:10][N:8]3[CH2:9][C@H:5]([O:4][CH3:3])[C@@H:6]([NH:23][C:24]([C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)=[O:25])[CH2:7]3)=[O:22])=[N:21][C:20]=2[NH:19]1)([CH3:35])[CH3:34]
Reactant: CC(C)I
Reactant: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCCN3)C[C@@H]1NC(=O)c1ccc(Cl)s1
Agent: Cl
Solvent: C1CCOC1
Product: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCC(C(C)C)N3)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
94.3 A suspension of 60 mg 5-chloro-thiophene-2-carboxylic acid {(3S,4S)-4-methoxy-1-[(4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylcarbamoyl)-methyl]-pyrrolidin-3-yl}-amide dihydrochloride in 3 ml THF was treated with 0.03 ml TEA and 0.01 ml 2-iodopropane. After stirring at r.t. overnight, the reaction mixture was again treated with 0.03 ml TEA and 0.03 ml 2-iodopropane and heated to 70° C. overnight. Then, it was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 51 mg 5-chloro-thiophene-2-carboxylic acid {(3S,4S)-1-[(5-isopropyl-4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylcarbamoyl)-methyl]-4-methoxy-pyrrolidin-3-yl}-amide as yellow solid. MS 498.4 ([M+H]+)
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[Cl:20][C:21]1[NH:26][C:25](=[O:27])[NH:24][C:23](=[O:28])[CH:22]=1>>[Cl:20][C:21]1[N:26]([CH2:3][C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:25](=[O:27])[NH:24][C:23](=[O:28])[CH:22]=1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Product: O=c1cc(Cl)n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)[nH]1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 92 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 6-chloropyrimidine-2,4(1H,3H)-dione. M/e+ 387 for C18H13Cl2N4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 9.35 (bs, 1H), 8.44 (d, J=6.23 Hz, 1H), 7.66 (d, J=9.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.29 (m, 2H), 6.90 (t, J=6.9 Hz, 1H), 5.74 (d, J=8.0 Hz, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([SH:11])[N:3]=1.O1C[CH2:15][CH2:14][CH2:13]1>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([S:11][CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: C1CCOC1
Reactant: Nc1nc(S)c2nc[nH]c2n1
Product: CCCSc1nc(N)nc2[nH]cnc12

Procedure:
2-Amino-6-propylthio-9H-purine was prepared by nucleophilic displacement of the iodo group on 1-iodopropane (Aldrich Chemical Co.) by 2-amino-6-mercapto-9H-purine (Aldrich Chemical Co.) in tetrahydrofuran.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([PH:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])([CH3:10])[CH3:9].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:8]([P:12](=[O:17])([C:13]([CH3:16])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[PH](=O)C(C)(C)C
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)P(=O)(c1ccccc1)C(C)(C)C

Procedure:
A 50 mL of reactor equipped with magnetic stir bar was charged with 186 mg (0.20 mmol) of {[(t-Bu)2P(OH)]2PdCl}2, 1.57 g (10.0 mmol) of bromobenzene, 1.62 g (10.0 mmol) of di-tert-butylphosphine oxide and 1.38 g (10.0 mmol) of K2CO3 in 20.0 mL of 1,4-dioxane. The resulting mixture was refluxed for 23 h to afford di-tert-butylphenylphosphine oxide. 31P NMR (CDCl3, 121 MHz): δ51.9 ppm.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[CH3:5][CH:6]([CH3:15])[CH2:7][C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11]>O.C(O)(=O)C>[CH3:5][CH:6]([CH3:15])[CH2:7][C:8](=[O:14])[CH:9]([N+:1]([O-:3])=[O:2])[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=N[O-]
Reactant: COC(=O)CC(=O)CC(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C(=O)CC(C)C)[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (232 g, 3.36 mol) in water (560 mL) was added drop-wise over 1.5 hours to a solution of methyl 5-methyl-3-oxohexanoate (400 g, 2.53 mol) in glacial acetic acid (510 mL) at 20 to 25° C. Stirring was continued at room temperature for 2 hours. Water (1.3 L) was added, and the reaction mixture was stirred for an additional 18 hours. The mixture was then extracted with ethyl acetate (3×2.5 L), and the combined organic layers were washed sequentially with water (2.5 L), with aqueous sodium bicarbonate solution (2.5 L), and with saturated aqueous sodium chloride solution (1.0 L). After drying over sodium sulfate, the organic extracts were concentrated in vacuo to afford the product as a yellow liquid, which was used directly in the next step. Yield: 456 g, 2.24 mol, 89%.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[NH2:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:10]=1
Reactant: CCOC(=O)c1ncc(C(F)(F)F)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(C(F)(F)F)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Intermediate 1) (0.5 g, 2.126 mmol) in dry ethanol (5 ml), 2M NaOH (5.32 ml, 10.63 mmol) was added. The yellow solution was stirred at RT. After 5 minutes, the reaction mixture was poured into water (15 ml) and the pH adjusted to pH 6 by addition of 1M HCl. The yellow precipitate formed was filtered under vacuum and dried to yield the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.65 (1H, s), 8.3 (1H, s), 7.86 (2H, br s)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[H][H]>C(O)C.[Pd]>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1CNCC(c2ccc(OC(F)(F)F)cc2)C1

Procedure:
14 g (45 mmol) of methyl 5-[4-(trifluoromethoxy)phenyl]pyridine-3-carboxylate in ethanol (500 ml) were admixed with 17 g of moistened palladium/carbon catalyst (10% palladium, 50% water), and then hydrogenated at 60° C. and a 50 bar hydrogen atmosphere overnight. The reaction solution was filtered, the filter residue was washed with ethanol and the filtrate was concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 600:1→10:1). Yield: 8 g (59% of theory)
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:13][C:12]1[C:7]2[NH:6][C:3](=[O:4])[CH2:2][O:14][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2cccc(O)c2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
TEA (3.34 ml, 2 equiv.) and after chloroacetyl chloride (1.15 ml, 1.2 equiv.) were added dropwise to a solution of commercially available 2-aminobenzene-1,3-diol (1.5 g, 11.99 mmol) in 20 ml of DMF. After one hours of stirring at room temperature, K2CO3 (3.3 g, 2 equiv.) was added and the reaction was stirred at room temperature overnight. The solvent was evaporated and to the residue water was added. After filtration, the solid material was washed with MeOH and diethyl ether giving 410 mg of a grey solid. Yield=21% 1HNMR (DMSO, 200 MHz) δ 3.47 (1H, bs), 4.47 (2H, s), 6.44 (2H, m), 6.72 (1H, t, J=8 Hz)
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:32]([N:35]([CH2:43]OC)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:34])[CH3:33]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[C@@H:15]([C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH2:43][N:35]([CH:32]([CH3:34])[CH3:33])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(C(=O)OC(C)(C)C)C(C)C
Reactant: O=C(Cc1ccc(Cl)s1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
1.0M of titanium tetrachloride in DCM (30.9 mL, 30.9 mmol) was added dropwise to a solution of (R)-4-benzyl-3-(2-(5-chlorothiophen-2-yl)acetyl)oxazolidin-2-one (9.43 g, 28.1 mmol) in DCM (170 mL) at −78° C., followed by N,N-diisopropylethylamine (9.78 mL, 56.2 mmol). The resulting dark blue mixture was stirred at −78° C. for 1 hour. tert-Butyl isopropyl(methoxymethyl)carbamate (11.4 g, 56.2 mmol) was then added. The mixture was stirred at −78° C. for 1 hour, and then allowed to warm up to room temperature. The mixture was stirred at room temperature for 2 hours, quenched with saturated NH4Cl (300 mL), and extracted with DCM (3×200 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc/hexane (0-20%) to give tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(5-chlorothiophen-2-yl)-3-oxopropyl(isopropyl)carbamate (10.2 g, 72%). MS (APCI+) [M+H]+ 507.2. 1H NMR (CDCl3, 400 MHz) δ 7.36-7.22 (m, 5H), 6.79 (d, J=4.0 Hz, 1H), 6.75 (d, J=4.0 Hz, 1H). 4.67-4.62 (m, 1H), 4.15-4.09 (m, 4H), 3.45-3.38 (m, 2H), 2.80-2.72 (m, 1H), 1.49 (s, 9H), 1.12 (d, J=6.0 Hz, 3H), 1.05 (d, J=6.0 Hz, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:8]2[C:9](=[CH:10][N:11]=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[C:7]=2[OH:22])[S:12][N:13]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2snc(-c3ccccc3F)c2c1O
Product: O=C(O)CNC(=O)c1ncc2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(2-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 348.1 (M+1).
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19](COCC[Si](C)(C)C)[C:16]2=[N:17][CH:18]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>CN(C)C=O>[CH2:1]([NH:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][NH:19][C:16]2=[N:17][CH:18]=1)=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCCc3ccccc3)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)Nc1cnc2[nH]ccc2n1
Yield: 26.8 %

Procedure:
A solution of 1-phenethyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.22 g, 0.53 mmol), tetrabutylammonium fluoride (1 M in THF, 3 mL, 3 mmol) and ethylene diamine (0.3 mL, 5 mmol) in 5 mL of N,N-dimethylformamide was stirred at 80° C. for 14 h, then concentrated. The resulting residue was triturated with methanol then ether to afford 0.040 g (26%) of 1-phenethyl-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as an off-white solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>ClCCl>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:39](=[O:40])[C:38]([C:30]2[CH:29]=[C:28]([C:27]([F:26])([F:44])[F:45])[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=2)([CH3:43])[CH3:42])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C(=O)Nc1ccccc1S(=O)(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A solution of 233 mg (1.0 mmol) 2-aminophenyl phenyl sulfone and 0.25 ml (1.5 mmol) N-ethyldiisopropylamine in 2 ml dichloromethane was cooled in an ice bath and a solution of 350 mg (1.1 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 1 ml dichloromethane was added dropwise. The reaction mixture was stirred at room temperature overnight, evaporated and the residue was purified by flash chromatography to give 490 mg (95%) of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:6]([CH:8]=1)[NH2:7].[CH2:15]([N:19]=[C:20]=[S:21])[CH2:16][CH2:17][CH3:18]>C(O)C>[CH2:15]([NH:19][C:20]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[S:21])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN=C=S
Reactant: Nc1cc(Cl)ccc1N1CCOCC1
Solvent: CCO
Product: CCCCNC(=S)Nc1cc(Cl)ccc1N1CCOCC1

Procedure:
Reaction of 5-chloro-2-morpholinoaniline (2.8 g) (2.8 g) with n-butyl isothiocyanate (1.5 g) in ethanol (20 ml) at room temperature for 60 days yielded 1-(n-butyl)-3-(5-chloro-2-morpholinophenyl)thiourea (m.p. 150°-152° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH2:9])[CH2:3][CH2:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20].CCN(CC)CC>CCOC(C)=O>[F:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: NCCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 2-morpholinoethanamine (0.90 g, 6.91 mmol), 1,2-difluoro-4-nitrobenzene (1.10 g, 6.91 mmol) and Et3N (1.40 g, 13.82 mmol) in EtOAc (10 mL) was refluxed under N2 for 24 h, then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as yellow oil (1.57 g, 84%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([OH:14])=[N:12][CH:13]=1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1.CC(=O)OCC>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH3:15])[C:11](=[O:14])[N:12]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[CH:13]=1
Reactant: BrCC1CC1
Reactant: Cc1cc(Br)cnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cn(CC2CC2)c1=O
Temperature: 70 °C
Yield: 66 %

Procedure:
Potassium carbonate (1.32 g, 9.57 mmol) was added to 5-bromo-3-methyl-2-hydroxypyridine (600 mg, 3.19 mmol) and bromomethylcyclopropane (861 mg, 6.38 mmol) in DMF (6 mL). After heating at 70° C. for 3 h, EA extractive work up and silica gel chromatography (PE: EA=30:110:1), the title compound (510 mg, yield: 66.0%) was obtained as a white solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.39 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 3.77 (d, J=6.8 Hz, 2H), 2.15 (s, 3H), 0.65-0.60 (m, 2H), 0.40-0.37 (m, 2H). LCMS: 242.1; 244.1 (M+H)+
Reaction SMILES: [C:1]([N:16]([CH3:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:23]([CH:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:30]O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[OH-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:23]([CH:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:30][O:20][C:19](=[O:21])[CH2:18][CH2:17][N:16]([C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCC(CO)CCCCCC
Reactant: CCCCCCCCCCCCCC(=O)N(C)CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCC(=O)N(C)CCC(=O)OCC(CCCCCC)CCCCCCCC
Yield: 74.2 %

Procedure:
N-Myristoyl-N-methyl-β-alanine (55 g; manufactured by Kawaken Fine Chemicals Co., Ltd.) and 45 g of 2-hexyldecanol were charged in a 500-ml flask, and thereto was added 2 g of p-toluenesulfonic acid as the catalyst. The mixture was subjected to a reaction at 130° C. for 5 hours. After completion of the reaction, the reaction mixture was neutralized with 1.6 g of an aqueous solution (50%) of sodium hydroxide, the aqueous layer was removed therefrom, the residue was washed with 100 g of deionized water and dehydrated under the condition of 60 mmHg and 95-105° C., and the insoluble substances were filtered off with a filter paper to give 70 g of an oily product as the filtrate.