Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.O[C@@H]([C@H]1C(=O)N2C(C([O-])=O)=C(C3SC4=C(C(=O)CC)N=CN4C=3)[C@H](C)[C@H]12)C.[Na+].[Si]([NH:40][S:41]([C:44]1[N:45]=[CH:46][N:47]2[CH:51]=[C:50]([C:52]3[C@H:53]([CH3:76])[C@@H:54]4[C@@H:71]([C@H:72]([OH:74])[CH3:73])[C:70](=[O:75])[N:55]4[C:56]=3[C:57]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=3)=[O:58])[S:49][C:48]=12)(=[O:43])=[O:42])(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C1COCC1>[OH:74][C@@H:72]([C@H:71]1[C:70](=[O:75])[N:55]2[C:56]([C:57]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][C:64]([N+:67]([O-:69])=[O:68])=[CH:65][CH:66]=3)=[O:58])=[C:52]([C:50]3[S:49][C:48]4=[C:44]([S:41](=[O:43])(=[O:42])[NH2:40])[N:45]=[CH:46][N:47]4[CH:51]=3)[C@H:53]([CH3:76])[C@H:54]12)[CH3:73]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(=O)(=O)N[Si](C)(C)C(C)(C)C)c4s3)[C@H](C)[C@H]12
Agent: CCC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S(N)(=O)=O)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic acid (0.26 ml) and 1.5 ml of a 1 M-tetra-n-butylammonium fluoride/THF solution were added under ice cooling to a solution of 197 mg of 4-nitrobenzyl(1S,5R,6S)-2-(7-t-butyldimethylsilylsulfamoylimidazo-[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 6 ml of THF. The solution was stirred at room temperature for 3 hr. The reaction mixture was added to an aqueous sodium hydrogencarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=10:1) to give a crude product of 4-nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-sulfamoylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate. The crude product was dissolved in 5 ml of THF and 5 ml of 1/15 M sodium phosphate buffer (pH 6.6). 10%Pd—C (50 mg) was added thereto. The atmosphere in the reactor was replaced with hydrogen. The system was stirred at room temperature for 30 min. The catalyst was removed by filtration through Celite, followed by washing with water. The filtrate was adjusted to pH 7.0 by the addition of an aqueous sodium hydrogencarbonate solution, and washed with ethyl acetate. Purification was then carried out using Cosmosil 40C18-PREP (30% aqueous methanol) and Dowex 50 (sodium form) in that order to give 40.7 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:7]=1[C:8]#[N:9].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(3-fluorophenoxy)-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9](CC1C=CC=CC=1)[CH2:8]2)=[O:4].C([O-])(O)=O.[Na+].[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:34]([O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:35])[CH2:8]2)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Temperature: 30 °C

Procedure:
2-Benzyl-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (3.9 g) and NaHCO3 (12.3 g) are suspended in CH2Cl2 (50 mL) and the mixture is treated with benzylchloroformate (Z—Cl) (10.8 mL). The mixture is warmed to 30° C. and after 10 min the reaction mixture is added to a mixture of water (150 mL) with NaHCO3 (12.3 g), the organic phase is separated, dried and evaporated. To the residue are added MeOH and the crystalline solid is collected and dried. 3.79 g of the title compound are obtained with MP 59-65° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C@@H:8]([CH2:11][CH3:12])[CH2:9][OH:10].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][C@@H:8]([CH3:7])[CH2:11][CH3:12])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC[C@H](C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC[C@H](C)COS(=O)(=O)c1ccc(C)cc1
Yield: 95.1 %

Procedure:
In 300 ml flask were charged 100 ml of pyridine and 40 g of (S)-2-methylbutanol (98 ee %) (produced by Tokyo Chemical Industry Co., Ltd.), and the mixture was cooled to 15° C. or less. To the mixture was added 104 g of p-toluenesulfonyl chloride at that temperature over 10 minutes. The inner temperature was returned to room temperature, at which the mixture was allowed to react for 2 hours. Water was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed twice with a saturated sodium chloride aqueous solution. The solvent was removed by distillation under reduced pressure to obtain 104.6 g of (S)-2-methylbutyl p-toluenesulfonate. The resulting compound was put in a 1 l flask, and 300 ml of dimethylformamide (hereinafter abbreviated as DMF) and 47.7 g of lithium bromide (monohydrate) were added thereto, followed by allowing the mixture to react at 60° C. for 5 hours. Water was added thereto, and the reaction mixture was extracted with diethyl ether. The extract was washed twice with water, and diethyl ether was removed by distillation to obtain 60.2 g of a crude product. The crude product was purified by distillation to obtain 45.45 g (66.2%) of the titled compound (b.p.: 55° C./100 mmHg).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2([CH2:19][Cl:20])CC[N+](F)(CC2)C1.[Cl-].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:32](=[O:34])[CH3:33])C=[CH:30][CH:31]=1>C(#N)C>[Cl:20][C:19]1[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][C:28]=1[C:32](=[O:34])[CH3:33]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: COc1cccc(C(C)=O)c1
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Cl)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of SELECTFLUOR™ (5.0 g, 14.1 mmol) and sodium chloride (825 mg, 14.1 mmol) in acetonitrile (200 ml), under nitrogen, was added 1-(3-methoxyphenyl)ethanone (1.94 ml, 14.1 mmol) and the reaction mixture was stirred at room temperature for 5 days. To the mixture was added distilled water (200 ml) and the solution was extracted with dichloromethane (2×100 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica) with gradient elution, ethyl acetate:cyclohexane [5:95 to 10:90]. The appropriate fractions were combined and concentrated to give the title compound (1.12 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2OF)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](C3N(C)C=CN=3)[S:17][C:10]=12.[F:39]C1C=C(N)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.[CH2:63]([N:65]1[CH:69]=[C:68](C2SC3C(=NC=CC=3OC3C=CC(N)=CC=3F)C=2)[N:67]=[CH:66]1)[CH3:64]>>[CH2:63]([N:65]1[CH:69]=[C:68]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:39])=[O:28])=[CH:3][C:2]=3[F:1])[CH:15]=2)[N:67]=[CH:66]1)[CH3:64]
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4OF)cc3F)c2s1
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5F)cc4F)c3s2)c1
Yield: 42 %

Procedure:
Following the procedure described above for the compound 30a (example 12, step 2) but substituting amine 9 for the amine 15, title compound 30b was obtained in 42% yield. 1H NMR (DMSO-d6) δ (ppm): 10.55 (s, 1H), 10.05 (s, 1H), 8.41 (d, 1H), 7.97 (m, 1H), 7.95 (s, 1H), 7.85 (dd, 1H), 7.77 (d, 1H), 7.65 (s, 1H), 7.45 (dd, 1H), 7.41 (dd, 1H), 7.26 (m, 1H), 7.16 (m, 1H), 6.57 (d, 1H), 4.03 (q, 2H), 3.60 (s, 2H), 1.38 (t, 3H). MS (m/z): 534.0 (M+H).
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[N:19]=[C:20]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:21]1
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1ccc([N+](=O)[O-])cc1N=C=S
Product: Cc1ccc([N+](=O)[O-])cc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-5-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-5-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[C:11]([Br:26])[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>ClCCl>[Br:26][C:11]1[C:10](=[O:27])[N:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:35](=[O:36])[O:37][C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)[C:14]([CH3:15])=[CH:13][C:12]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CN)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
1-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (1.08 g, 2.48 mmol) was suspended in dichloromethane (7.5 mL). Pyridine was added (0.222 mL, 2.74 mmol). After stirring for 10 minutes at room temperature, a stock solution of 4-nitrophenyl chloroformate (5.0 mL, 0.50 M) in dichloromethane was added dropwise. After stirring for 4.5 hours at room temperature, a stock solution of 4-nitrophenyl chloroformate (2.5 mL, 0.50 M) in dichloromethane was again added dropwise and stirring continued at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) afforded a yellow solid (0.85 g, 57%).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.OS(O)(=O)=O.O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C@@H:33]([N:35]3[CH2:40][CH2:39][C@:38]([CH2:47][CH2:48][CH2:49][OH:50])([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[O:37][C:36]3=[O:51])[CH3:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>CC(C)=O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C@@H:33]([N:35]3[CH2:40][CH2:39][C@:38]([CH2:47][CH2:48][C:49]([OH:3])=[O:50])([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[O:37][C:36]3=[O:51])[CH3:34])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1
Reactant: CC(C)=O
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(=O)O)(c2ccccc2)OC1=O
Reaction time: 8 h
Yield: 79.8 %

Procedure:
CrO3 (1 g) was added to H2SO4 (1 mL) and water was added to bring the total volume to 4 mL. (R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (600 mg, 1.4 mmol) was dissolved in 10 mL acetone, and cooled in an ice bath. The Jones reagent (0.5 mL) was slowly added to the mixture and stirred overnight. Solvent was removed in vacuo, the residue was dissolved in CH2Cl2 (10 mL) and water (10 mL). The layers were separated, and the aq layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanoic acid (500 mg, crude), which was not purified.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>O1CCOCC1.O>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[N:5]=1
Reactant: C1COCCN1
Reactant: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc(N3CCOCC3)n2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a stirred solution of (4,6-dichloro-1,3,5-triazin-2-yl)-(4-trifluoromethoxyphenyl)amine (XIII) (5.0 g, 15.3 mmol) in dioxane (25 mL) was added i-Pr2(Et)N (2.37 g, 18.3 mmol) and morpholine (1.60 g, 18.3 mmol), and the resulting mixture heated at 85° C. for 12 hours. The reaction mixture was cooled to ambient temperature, diluted with water and stirred for 1 h. The white precipitate was filtered and dried under vacuum to give (4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-(4-trifluoromethoxyphenyl)amine (XIV) (5.63 g, 98% yield): GC/MS m/z 375 (M+); 1H NMR (CDCl3) δ 7.55 (d, J=3.7 Hz, 2H), 7.51 (bs, 1H), 7.25 (d, J=2.2 Hz, 2H), 3.74-3.87 (m, 8H).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.C(OCC)(=O)C>[CH2:25]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(OCc2ccccc2)ccc2ccccc12
Temperature: 60 °C
Yield: 86.2 %

Procedure:
450 ml of a dimethylformamide solution containing 100 g (0.58 mole) of 2-hydroxy-1-naphthaldehyde and 96.3 g (0.7 mole) of anhydrous potassium carbonate was stirred with heating at 60° C. To the solution was added dropwise 88.3 g (0.7 mole) of benzyl chloride. After the completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours. Then 870 ml of ethyl acetate heated at 60° C. and 1.2 liters of warm water at 60° C. were added to the mixture and it was extracted at 60° C. and separated. The organic layer was concentrated under reduced pressure to about 550 ml. 440 ml of methanol was added to the concentrate, and the solution was cooled to 5° C. to crystallize. The precipitated crystals were collected by filtration, and washed with methanol to obtain 131 g (0.5 mole) of 2-benzyloxy-1-naphthaldehyde.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:13][CH:12]=2)[CH:7]=[CH:6][N:5]=1)=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:55][C:56]1[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][C:57]=1[C:63]([F:66])([F:65])[F:64]>CN(C=O)C.CCOC(C)=O>[Cl:55][C:56]1[CH:62]=[CH:61][C:59]([NH:60][C:19](=[O:21])[CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:2]([NH2:1])=[O:3])[CH:9]=3)=[CH:16][CH:15]=2)=[CH:58][C:57]=1[C:63]([F:64])([F:65])[F:66]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1cc(Oc2ccc(CCC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1

Procedure:
A solution of 3-(4-{[2-(aminocarbonyl)pyridin-4-yl]oxy}phenyl)-propanoic acid (200 mg, 0.70 mmol), HATU (319 mg, 0.84 mmol), DIPEA (0.24 mL, 1.4 mmol), and 4-chloro-3-(trifluoromethyl)aniline (136 mg, 0.70 mmol) in DMF (5 mL) was stirred overnight at rt. EtOAc was added to the reaction and the mixture was washed with 1N HCl, 1N NaOH, and brine, dried over Na2SO4 and concentrated. Purification by column chromatography (SiO2, 20-100% EtOAc in hexane) followed by recrystallization in EtOAc/hexane provided A-3 (37 mg, 11%). 1H NMR (300 MHz, d6-DMSO) δ: 10.36 (s, 1H), 8.48 (d, J=5.7 Hz, 1H), 8.18 (d, J=2.5 Hz, 1H), 8.09 (bs, 1H), 7.81 (dd, J1=2.5 Hz, J2=8.8, 1H), 7.7 (bs, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.35-7.40 (m, 3H), 7.12-7.16 (m, 3H), 2.97 (t, J=7.3 Hz, 2H), and 2.70 (t, J=7.8 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([OH:3])=[O:2].[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27]C>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([OH:3])=[O:2].[CH3:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:3]
Reactant: CCN1CCCC1CN
Agent: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: CN1CCCC1CNC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 2-aminomethyl-1-ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the urea.
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.N1(C(=O)C)CCNCC1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.[C:37]([N:40]1[CH2:45][CH2:44][N:43]([S:46]([C:49]2[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH2:42][CH2:41]1)(=[O:39])[CH3:38]>>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([S:46]([C:49]2[CH:57]=[CH:56][C:52]([C:53]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([Cl:23])=[C:25]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:26]=3)=[O:54])=[CH:51][CH:50]=2)(=[O:47])=[O:48])[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: CC(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: CC(=O)N1CCNCC1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 646 μL of 1-(piperazin-1-yl)ethanone via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 125 mg of 4-(4-acetylpiperazin-1-ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield 4-(4-acetylpiperazin-1-ylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 499.4 (M)+.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH2:9]([O:16][C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCCC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)CCCC(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of glutaric anhydride (11.4 g, 0.1 mol) and benzyl alcohol (11.4 mL, 1.1 equiv.) in toluene (200 mL) was heated at 70° C. for 2 days. Solvent was evaporated at reduced pressure to give the product which was dried under high vacuum and was pure enough to use in the next step. 1H NMR (CDCl3): δ1.96 (t, J=7.2 Hz, 2H), 2.44 (q, J=7.0 Hz, 4H), 5.13 (s, 2H), 7.33 (s, 5H).
Reaction SMILES: [C:1]([NH2:5])(=O)[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:7].C([O:23][CH2:24][CH2:25][CH:26](Cl)[C:27](=O)[CH3:28])(=O)C>C1COCC1>[CH2:2]([C:1]1[S:7][C:26]([CH2:25][CH2:24][OH:23])=[C:27]([CH3:28])[N:5]=1)[CH3:3]
Reactant: CC(=O)OCCC(Cl)C(C)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCC(N)=O
Solvent: C1CCOC1
Product: CCc1nc(C)c(CCO)s1
Temperature: 25 °C
Yield: 146 %

Procedure:
Propionamide (20 grams, 0.27 moles) and dried THF (150 grams) were added to a 500 ml three-neck flask equipped with a mechanical stirrer, a condenser and a thermometer. The mixture was stirred and 18 grams of phosphorus pentasulfide (0.08 moles) were added over a time period of 30 minutes while keeping the temperature between 20–25° C. The reaction mixture was then refluxed for 2 hours and was thereafter cooled to room temperature. 57.8 grams of 5-acetoxy-3-chloro-2-pentanone were then added, over a time period of 15 minutes, and the reaction mixture was allowed to reflux for 20 hours. Thereafter, the THF was removed by distillation at atmospheric pressure, the reaction mixture was cooled to 25° C., 120 grams of hydrochloric acid (10%) were added, and the mixture was brought back to reflux for 1 additional hour. After cooling to room temperature the reaction mixture was extracted with two portions of 50 grams of dichloromethane to remove excess starting materials. The acidic aqueous phase was turned basic with a 20% aqueous solution of sodium hydroxide and the resulting thiazole was extracted with three portions of 75 grams of dichloromethane. The dichloromethane extracts were combined and dried over sodium sulfate, filtered and evaporated to dryness. The residue was distilled under vacuum at 0.5 mmHg to yield 20 grams of pale yellow oil (43.3% yield) having a purity of 98.9%, as determined by gas chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1)=[O:10].C([O-])([O-])=O.[K+].[K+].[CH3:25][S:26][CH2:27][CH2:28][CH2:29][CH2:30]S(C1C=CC(C)=CC=1)(=O)=O>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:30][CH2:29][CH2:28][CH2:27][S:26][CH3:25])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1)=[O:10]
Reactant: CSc1nccc(C(=O)c2ccc(O)cc2F)n1
Reactant: CSCCCCS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CSCCCCOc1ccc(C(=O)c2ccnc(SC)n2)c(F)c1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
(2-Fluoro-4-hydroxyphenyl)-(2-methylsulfanyl-pyrimidin-4-yl)-methanone (2.26 g, 12.7 mmol), K2CO3 (3.5 g, 25.4 mmol) and 1-methylthio-4-tosylbutane (8.5 g, 44.5 mmol) were stirred in NMP for 1 h at 100° C., cooled to RT, filtered, diluted with water, and extracted into EtOAc. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography on a silica column eluting with hexane:ethyl acetate 9:1 to 3:2 to yield [2-fluoro-4-(4-methylsulfanyl-butoxy)-phenyl]-(2-methylsulfanyl-pyrimidin-4-yl)-methanone (3.42 g).