Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[C:16]([CH:17]=[CH2:18])=[CH:15][N:14]=[C:13]([C:19]3[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]4[O:26][C:25]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=4[CH:38]=3)[N:12]=1)[NH:6]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:11]4[N:12]=[C:13]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[N:14]=[CH:15][C:16]=4[CH2:17][CH2:18][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C=Cc1cnc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1cc2c(F)cccc2[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ncc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 5-(4-(4-fluoro-1H-indol-2-yl)-5-vinylpyrimidin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.08 mmol) in DMAc (1 mL), K3PO4 (100 mg, 0.37 mmol) was added under N2 protection. The reaction mixture was stirred at 90° C. overnight. Then the mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC to give the product of 5-(11-fluoro-5,6-dihydropyrimido[4′,5′:3,4]pyrido[1,2-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (10 mg, yield: 20.0%). 1H-NMR (CDCl3, 400 MHz) δ 8.75 (s, 1H), 8.36 (s, 1H), 8.00˜8.10 (m, 2H), 7.75 (s, 1H), 7.53 (s, 1H), 7.15˜7.25 (m, 4H), 6.84 (t, J=8.8 Hz, 1H), 6.01 (br s, 1H), 4.41 (t, J=6.4 Hz, 2H), 3.50 (s, 3H), 3.34 (t, J=6.4 Hz, 2H), 3.05 (d, J=4.8 Hz, 3H), 2.83 (s, 3H). MS (M+H)+: 614
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[NH2:12])[CH:2]=[CH2:3].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]2[N:21]=[C:22]([S:24](Cl)(=[O:26])=[O:25])[N:23]=[C:16]2[N:15]=1.[OH-].[Na+].C>N1C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]2[N:21]=[C:22]([S:24](=[O:25])(=[O:26])[NH:12][C:6]3[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:1][CH:2]=[CH2:3])[N:23]=[C:16]2[N:15]=1
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Reactant: C=CCOc1cccc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: C=CCOc1cccc(Cl)c1NS(=O)(=O)c1nc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
0.77g of 2-amino-3-chlorophenyl allyl ether in 12ml of dry pyridine were treated with 1.03g of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulphonyl chloride and stirred at ambient temperature overnight. The pyridine was removed by evaporation with final traces eliminated by means of a vacuum pump. An oily brown product was obtained which was stirred with 30ml of 1M sodium hydroxide for 20 minutes to give a brown solution. Charcoal (20-30mg) was added and the mixture stirred for 10 minutes and then filtered through Celite ("Celite" is a trade mark). The filtrate was cooled, acidified with 10% hydrochloric acid to pH 1-2 to produce a solid which was then filtered off, washed with water and dried in vacuo to give 1.2g (a yield of 73%) of 5,7-dimethyl-2-(N-[2-allyloxy-6-chlorophenyl]-sulphamoyl)-1,2,4-triazolo[1,5-a]pyrimidine (Compound No. 1).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9]([NH2:11])=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.Br.Br[CH2:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=1[CH3:26])=O.O>CCO>[F:1][C:2]1[C:7]([NH:8][C:9]2[S:10][CH:14]=[C:15]([C:17]3[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=3[CH3:26])[N:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1nc(C)c(C(=O)CBr)s1
Reactant: NC(=S)Nc1cccnc1F
Agent: Br
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccnc3F)n2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
According to the general procedure 1, N-(2-fluoropyridin-3-yl)thiourea (prepared from 3-amino-2-fluoropyridine (Asymchem), following procedure D) is added to a solution of N-[5-(bromoacetyl)-4-methyl-1,3-thiazol-2-yl]acetamide, hydrobromide salt (Intermediate 1) and TEA (3 eq) in EtOH. The mixture is stirred for 2 h at RT. After addition of water, the desired product is filtrated off and washed with water. N-{2-[(2-fluoropyridin-3-yl)amino]-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl}acetamide is isolated as a pale yellow solid (57%). The hydrochloride salt of a batch of N-{2-[(2-fluoropyridin-3-yl)amino]-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl}acetamide (200.00 mg; 0.57 mmol; 1.00 eq.) is prepared. It is suspended in MeOH (10.00 ml) and hydrogen chloride (2.29 ml; 1.25 M; 2.86 mmol; 5.00 eq.) in methanol is added. The mixture is stirred during 20 minutes at RT and filtered. The yellow powder obtained is washed with diethyl ether and dried under vacuo, affording compound (43) in 79% yield. 1H NMR (DMSO-d6, 300 MHz) δ 2.13 (s, 3H), 2.47 (s, 3H), 3.15 (s, 2H), 7.01 (s, 1H), 7.36 (m, 1H), 7.77 (m, 1H), 8.94 (m, 1H), 10.39 (s, 1H), 12.07 (s, 1H). M− (ESI): 347.8; M+ (ESI): 349.8. HPLC, Rt: 3.0 min (purity: 100%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([O:12]C)=[O:11])=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1>O1CCOCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]([F:15])([F:16])[F:17])[C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cnc(Cl)cc1C(F)(F)F

Procedure:
9.6 g (0.047 mol) of methyl 4-trifluoromethylpyridin-3-ylcarboxylate, dissolved in 50 ml of dichloromethane, are treated with 30% hydrogen peroxide/urea adduct and 17 ml of trifluoroacetic anhydride. The reaction solution is stirred at temperature of 20° C. for 20 hours and then washed once each with dilute sodium hydroxide solution and half-saturated sodium chloride solution. The product obtained is 3-methoxycarbonyl4-trifluoromethyl-3-pyridine N-oxide; 1H NMR (CDCl3, ppm): 8.55, s, 1H; 8.31, d, 1H; 7.6, d, 1H; 3.98, s, 3H. 4.85 g (0.022 mol) of the above product are then added to a mixture of 5 ml of phosphorus oxychloride and 4.3 ml of ethyidiisopropylamine in 15 ml of 1,2dichloroethane, and the mixture is heated to a temperature of 60° C. After about 2 hours, another 2 ml of phosphorus oxychloride and 2.8 ml of ethyidiisopropylamine are added, and the mixture is stirred at this temperature for 20 hours. The reaction mixture is subsequently added to ice-water, adjusted to pH 3 using 30% NaOH and then extracted with dich ioromethane. Filtration through a little silica gel gives an approximately 5:1 product mixture of the two 6-chloro- and 2-chloro-4-trifluoromethylpyridin-3-yl methyl esters, which can be separated by HPLC into the pure components. Thus, pure methyl 6-chloro-4-trifluoromethylpyridin-3-ylcarboxylate is obtained as the main product; 1H NMR (CDCl3, ppm): 8.91, s, 1H; 7.68, s, 1H; 3.98, s, 3H, and pure methyl 2-chloro-4-trifluoromethylpyridin-3-ylcarboxylate is obtained as the byproduct; 1H NMR (CDCl3, ppm): 8.64, d, 1H; 7.52, d, 1H; 4.01, s, 3H. In the presence of 0.073 g of potassium hydroxide, 0.22 g of pure methyl 6-chloro-4-trifluoromethylpyridin-3-ylcarboxylate are hydrolysed at room temperature in a 1:1 mixture of 6 ml of dioxane/water. Recrystallization gives the pure 6-chloro-4-trifluoromethyinicotinic acid: m.p. 115-117° C.; 1H NMR (CDCl3, ppm): 9.12, s, 1H; 7.24, s, 1H.
Reaction SMILES: [NH4+:1].C([O-])(=O)C.ClC(Cl)(Cl)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:13][C:12]=1[C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)=[O:9].O>CS(C)=O>[Cl:33][C:29]1[CH:28]=[C:27]([C:26]2[C:12]3[C:11](=[CH:16][CH:15]=[C:14]([C:17](=[O:25])[C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:13]=3)[NH:10][C:8](=[O:9])[N:1]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: [NH4+]
Reactant: O=C(c1ccc(F)cc1)c1ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c2cccc(Cl)c2)c1
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc2[nH]c(=O)nc(-c3cccc(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
Acetic acid, ammonium salt (0.135 mol) was added at room temperature to a mixture of intermediate 4 (0.0675 mol) in DMSO (300 ml). The mixture was stirred at 60° C. for 4 hours, then brought to room temperature and poured out into water. The precipitate was filtered, washed with water, taken up in warm CH3CN, filtered, washed again with CH3CN, then with diethyl ether and dried under a vacuo, yielding 18.5 g (72%) of intermediate 5. The mother layer was purified by column chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH:NH4OH 95/5/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1.8 g (7%) of 4-(3-chlorophenyl)-6-(4-fluorobenzoyl)-2(1H)-quinazolinone (intermediate 5), mp. 226° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C@H:27]4[CH2:28][CH2:29][O:25][CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: N[C@H]1CCOC1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N[C@H]3CCOC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-tetrahydrofuran-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84-2.02 (m, 1H) 2.09-2.27 (m, 1H) 2.43 (s, 3H) 3.63 (dd, J=8.84, 4.04 Hz, 1H) 3.73 (td, J=8.08, 5.81 Hz, 1H) 3.83-3.95 (m, 2H) 4.42-4.58 (m, 1H) 7.66 (d, J=7.83 Hz, 1H) 7.73 (s, 1H) 7.77 (br. s., 1H) 8.18 (br. s., 1H) 8.44 (d, J=6.82 Hz, 2H) 8.78 (d, J=6.32 Hz, 1H) 8.92 (s, 1H) 13.18 (br. s., 1H). MS m/z [M+H]+ 390.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:14]=[C:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][N:21]=2)[N:16]1[CH2:25][C:26](O)=[O:27]>>[Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[C:4]([NH:7][C:26](=[O:27])[CH2:25][N:16]2[C:17]3[C:22](=[N:21][CH:20]=[CH:19][CH:18]=3)[CH2:23][CH2:24][C:15]2=[O:14])[S:5][CH:6]=1
Reactant: Cc1n[nH]c(-c2c(Cl)csc2N)n1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Product: Cc1n[nH]c(-c2c(Cl)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1

Procedure:
The title compound was prepared from 4-chloro-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine (69 mg, 321 umol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (82 mg, 397 umol) using protocol A. The residue was purified by HPLC. Method [8] Retention time 3.40 min by HPLC (M+=403 and 405) and (M+Na=425 and 427). 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J=5.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.49 (dd, J=8.4 and 5.4 Hz, 1H), 6.86 (s, 1H), 5.46 (broad s, 2H), 4.95 (s, 2H), 3.49 (m, 2H), 3.01 (m, 2H), 2.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[C:13]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=1[Cl:11])[C:13]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=1[Cl:11]
Reactant: Fc1ccc(CS)c(Cl)c1
Reactant: C#Cc1cccc(Cl)c1Cl
Agent: [Na]
Product: Fc1ccc(C(/C=C\c2cccc(Cl)c2Cl)SC(/C=C\c2cccc(Cl)c2Cl)c2ccc(F)cc2Cl)c(Cl)c1

Procedure:
A solution of 2,3-dichlorophenylacetylene (0.02 mol), 2-chloro-4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,3-dichlorostyryl-2-chloro-4-fluorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N:10]1[CH:14]=[C:13]([C:15](O)=[O:16])[C:12]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=2[N+:27]([O-])=O)=[N:11]1.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]2[C:12]3[C:13](=[CH:14][N:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[Cl:1])[N:11]=3)[C:15](=[O:16])[NH:27][C:19]=2[CH:20]=1
Reactant: COc1ccc(Cl)c(-n2cc(C(=O)O)c(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])n2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: COc1ccc(Cl)c(-n2cc3c(=O)[nH]c4cc(N)ccc4c3n2)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
A mixture of 1-(2-chloro-5-methoxyphenyl)-3-(2,4-dinitrophenyl)-1H-pyrazole-4-carboxylic acid (3.20 g), 90% calcium chloride (200 mg) and 90% ethanol (150 ml) was stirred at 90° C. for 10 minutes, reduced iron (5.12 g) was added thereto, and then was stirred at 90° C. for 4 hours. The reaction mixture was cooled, filtered through Celite, the Celite layer was washed ethyl acetate. The filtrate and washings were combined, added water thereto and then extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (1.20 g).
Reaction SMILES: CO[C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:12]2[CH2:18][CH:17]([CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:22])=[CH:6][CH:5]=1.O[Li].O.O[NH:38][C:39](=[NH:41])[CH3:40].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([N:11]([CH:12]2[CH2:18][CH:17]([CH:19]([CH3:20])[CH3:21])[CH2:16][CH2:15][NH:14][C:13]2=[O:22])[CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]3[O:33][N:41]=[C:39]([CH3:40])[N:38]=3)=[CH:5][CH:6]=2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CC(=N)NO
Reactant: COC(=O)c1ccc(CN(C2CC(C(C)C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(CN(C3CC(C(C)C)CCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-(5-isopropyl-2-oxo-azepan-3-yl)-amino]-methyl}-benzoic acid methyl ester (0.30 g, 0.60 mmol) was saponified to the acid using LiOH.H2O (0.04 g, 0.90 mmol). The acid (0.10 g, 0.21 mmol) was dissolved in THF (3 ml) and added dropwise to a solution of 1,1-carbonyl diimidazole (CDI, 0.04 g, 0.23 mmol) in THF (0.5 ml). After 30 min, N-hydroxy-acetamidine (0.04 g, 0.23 mmol) was added. A further two equivalents each of CDI and N-hydroxy-acetamidine were added during a further 48 h stirring at r.t. The reaction mixture was concentrated and crude, coupled amidine was purified over silica gel (gradient ethyl acetate to ethyl acetate/methanol 15%): white solid 0.09 g (73%); MS: m/e=535.5 (MH+). Purified amidine (0.08 g, 0.15 mmol) cyclised in the presence of tetrabutylammonium fluoride (1 M, THF 5 ml) over 36 h at r.t. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organice extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The concentrated, crude product was purified using preparative RP(C18) chromatography: lyophilisate 15 mg; MS: m/e=517.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[Br:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Br:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:17][CH:18]=2)=[S:10])=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)CCCBr
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
Thiourea 4 (200 mg, 0.61 mmol, 1 equiv.) was stirred in CH2Cl2 (10 mL) under N2 atmosphere. 4-Bromobutyryl chloride (169 mg, 0.92 mmol, 1.5 equiv.) was added, followed by triethylamine (85 μL, 0.61 mmol, 1 equiv.). The orange solution was stirred at rt for 1.5 h and diluted with CH2Cl2 (10 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×10 mL), 10% aqueous sodium hydroxide (1×50 mL), and saturated brine (1×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting pale yellow foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 4-bromo-N-{4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-butyramide (138 mg, 48%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:17]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[O:8][N:9]=2.[Li]CCCC.CON(C)[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>C1COCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C:7]2[O:8][N:9]=[C:5]3[CH:4]=[CH:3][C:2]([C:26]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:35])=[CH:17][C:6]=23)[CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Reactant: COc1ccc(C(=O)N(C)OC)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.13 m) was added at −70° C. to THF (300 ml ) under N2 flow. A solution of BuLi (0.143 mol) was added dropwise. The mixture was stirred at −70° C. for 10 minutes. A solution of N,4-dimethoxy-N-methyl-benzamide (0.117 mol) in THF (100 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour, poured out on ice/EtOAc and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried under a vacuo, yielding 19.5 g (41%) of [3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-methoxyphenyl)- methanone (intermediate 10).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8](Cl)=[N:7][C:6]=1[Cl:13])[CH3:2].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)#[N:16]>>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)=[N:7][C:6]=1[Cl:13])[CH3:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Product: CCOC(=O)c1cc(F)c(Oc2ccc(C#N)cc2)nc1Cl
Yield: 49.9 %

Procedure:
2,6-Dichloro-5-fluoro-nicotinic acid ethyl ester (3.5 g, 15.0 mmol) and 4-cyano-phenol (1.78 g, 15.0 mmol) were coupled using the procedure of Example 17(a) to afford 2.4 g of the required product. 1H NMR (DMSO-d6): δ 1.35 (3H, t), 4.4 (2H, q), 7.58 (2H, d), 8.0 (2H, d), 8.4 (1H, d).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:30]([O:34][C:35](=[O:44])[NH:36][CH:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:44])[NH:36][CH:37]1[CH2:38][CH2:39][CH:40]([NH:43][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[CH:16]=[C:8]([O:7][C:6]3[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:9]=2)[CH2:41][CH2:42]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: N#Cc1ccc(Oc2cc(OCc3cccc([N+](=O)[O-])c3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3cccc([N+](=O)[O-])c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 72.8 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-(3-nitro benzyloxy)benzoic acid 1.1 g (2.81 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.6 g, 2.81 mmol) were used to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.35 (2H, s), 6.78 (1H, d), 7.04 (1H, s), 7.12 (2H, d), 7.22 (1H, s), 7.46 (1H, s), 7.72 (1H, t), 7.9 (3H, d), 8.2 (1H, d), 8.34 (2H, m).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Product: CCCCNC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
A solution of 1.0 g of n-butyl isocyanate in 5 ml of tetrahydrofuran was added to a solution of 1.76 g of 1-benzylpiperazine in 20 ml of tetrahydrofuran with ice cooling. The mixture was stirred at room temperature for 2 hours and, then, concentrated under reduced pressure to give 2.8 g of crude 1-benzyl-4-butylaminocarbonylpiperazine. The intermediate was submitted to the next step without purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[F:16][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][NH:1][C:24](=[O:26])[CH3:25])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[I:15]
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A suspension of (5S)-5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 16.0 g, 47.6 mmol) in CH2Cl2 (150 mL) was treated with triethylamine (TEA, 9.62 g, 13.2 mL, 95.2 mmol, 2.0 equiv) at 25° C., and the resulting reaction mixture was cooled down to 0-5° C. before being treated with acetic anhydride (Ac2O, 7.29 g, 6.75 mL, 71.4 mmol, 1.5 equiv) and 4-N,N-dimethylaminopyridine (DMAP, 58 mg, 0.5 mmol, 0.01 equiv) at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showed that the reaction was complete, the reaction mixture was quenched with H2O (100 mL). The two layers were separated, and the aqueous layer was then extracted with CH2Cl2 (2×50 mL), and the combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1010, 17.36 g, 17.99 g theoretical, 96.5%) as white powders, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1010: 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H, NHCOCH3), 3.25 (t, 2H, J=5.4 Hz), 3.56 (dd, 1H, J=6.4, 9.2 Hz), 3.95 (t, 1H, J=9.1 Hz), 4.58 (m, 1H), 5.16 (t, 1H, J=5.7 Hz, OH), 7.02 (dd, 1H, J=2.4, 8.2 Hz), 7.38 (dd, 1H, J=2.4, 10.8 Hz), 7.66 (t, 1H, J=7.5, 8.4 Hz), 8.08 (t, 1H, J=5.8 Hz, NHCOCH3); C12H12FIN2O3, LCMS (EI) m/e 379 (M++H).