Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[K+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(COC)OC>[C:20]1([S:26]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CSc1ccc(-c2c[nH]c3ccccc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CSc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of 3-(4-methylthiophenyl)indole (7.34 g, 30.7 mmol), prepared as in step 1, in dimethoxyethane (75 mL) was added powdered KOH (85%, 7.01 g, 125 mmol) and benzenesulfonyl chloride (4.25 mL, 33.3 mmol). A white precipitate formed immediately and the reaction mixture became quite warm. The reaction mixture was stirred for 1 hour during which time it cooled to ambient temperature. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. 1-phenylsulfonyl-3-(4-methylthiophenyl)indole (8.89 g, 76% yield) was obtained by chromatography on silica gel (10%, then 20% ethyl acetate/hexanes).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)C(NO)=N.[Cl:12][CH2:13][C:14]([OH:16])=O.Cl.C([N:20]=[C:21]=[N:22]CCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:12][CH2:13][CH:14]1[O:16][N:20]=[CH:21][N:22]1[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)CCl
Reactant: CCN=C=NCCCN(C)C
Reactant: N=C(NO)c1cccc(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(N2C=NOC2CCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
3-Fluoro-N-hydroxy-benzamidine (1.4 g, 9.08 mmol), chloroacetic acid (0.94 g, 9.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.91 g, 9.99 mmol) and 1-hydroxybenzotriazole hydrate (1.35 g, 9.99 mmol) were mixed in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL), washed with aqueous saturated sodium bicarbonate (75 mL), washed with water again (50 mL) and washed with brine (50 mL). The organic phase was dried over sodium sulfate and concentrated to give a solid. The solid was dissolved in N,N-dimethylformamide (10 mL) and the reaction mixture stirred at 120° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (3×50 mL) and washed with brine (50 mL). The organic phase was dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with 10 to 30% ethyl acetate in hexanes to give the product as a yellow oil (1.15 g, 60%). 1H NMR (300 MHz, CDCl3): δ 7.91 (dd, 1H), 7.82 (m, 1H), 7.5 (m, 1H), 7.25 (m, 1H), 4.78 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][N:12]([CH2:14][C:15]1[CH:32]=[CH:31][C:18](/[CH:19]=[N:20]/[C:21]2[CH:29]=[CH:28]C=C3[C:22]=2[CH2:23][O:24]C3=O)=[CH:17][CH:16]=1)[CH3:13].C[O-].[Na+].O.[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:38][CH3:39]>>[CH3:11][N:12]([CH2:14][C:15]1[CH:32]=[CH:31][C:18]([CH:19]2[CH:7]([C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:23](=[O:24])[C:22]3[C:38]([C:37]([O:41][CH2:42][CH3:43])=[O:40])=[CH:39][CH:28]=[CH:29][C:21]=3[NH:20]2)=[CH:17][CH:16]=1)[CH3:13]
Reactant: CN(C)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(OC)cc1)C(c1ccc(CN(C)C)cc1)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-methoxybenzaldehyde (231 mg, 1.7 mmol) and (E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one (500 mg, 1.7 mmol) in ethyl propionate (30 mL) was added sodium methanolate (120 mg, 5.2 mmol) and the mixture was stirred at 25° C. for 4 h. Then the resulting mixture was added water (10 mL) and evaporated under reduced pressure, extracted with EtOAc (4×100 ml), and concentrated to dryness. A crude product was obtained (250 mg) and was used for next step reaction without further purification. LC-MS (ESI) m/z: 459 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=4)[NH2:24])[N:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C[Si]([N:36]=[C:37]=[O:38])(C)C.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:22]=[C:23]([NH:24][C:37]([NH2:36])=[O:38])[CH:25]=[CH:26][CH:27]=4)[N:19]=[C:18]([C:28]([F:31])([F:29])[F:30])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cccc(N)c3)s2)c1
Reactant: C[Si](C)(C)N=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cccc(NC(N)=O)c3)s2)c1
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of the 3-(5-(5-(3-(methylsulfonyl)phenyl)-thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)aniline in anhydrous DCM (1.0 mL) and THF (3.0 mL) was added trimethylsilyl isocyanate (112 mg, 0.85 mmol) and triethyl amine (29 mg, 0.28 mmol). The reaction mixture was stirred under nitrogen atmosphere for overnight. A 1.0 M solution of tetra-butylammonium fluoride (1.42 mL, 1.42 mmol) in THF was added and the mixture was stirred at room temperature for overnight. The solvent was evaporated in vacuo and the resulting residue was purified by HPLC, providing the urea product (70 mg, 49%). 1H-NMR (Acetone-d6): δ 8.56 (s, 1H), 8.13 (m, 1H), 7.98 (m, 1H), 7.91 (m, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.49 (m, 1H), 7.20 (m, 1H), 7.17 (m, 1H), 6.44 (br, 2H), 3.18 (s, 3H). MS (ES): 507 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[N:45]1[CH:50]=[CH:49][N:48]=[C:47]([NH2:51])[N:46]=1.[H-].[Na+]>CN(C=O)C.CO>[N:45]1[CH:50]=[CH:49][N:48]=[C:47]([NH:51][C:37](=[O:39])[C:36]([NH:35][C:33]([C:32]2[CH:31]=[C:30]([C:27]3[CH:28]=[CH:29][C:19]4[O:18][C:17]([C:14]5[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=5)=[C:21]([C:22]([NH:23][CH3:24])=[O:25])[C:20]=4[CH:26]=3)[CH:44]=[CH:43][CH:42]=2)=[O:34])([CH3:41])[CH3:40])[N:46]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Reactant: Nc1nccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4nccnn4)c3)cc12
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
DIEA (28 μL, 0.158 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (25 mg, 0.053 mmol), 1,2,4-triazin-3-amine (11 mg, 0.105 mmol) in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg, 0.263 mmol) was added and the reaction was allowed to stir overnight. The mixture was treated with a drop of MeOH and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (7.4 mg, 25%). 1H NMR (500 MHz, CD3OD) δ ppm 8.58-8.63 (1 H, m), 8.22-8.26 (1 H, m), 7.93-8.00 (3 H, m), 7.85-7.93 (2 H, m), 7.66-7.75 (2 H, m), 7.59 (1 H, t, J=7.63 Hz), 7.27 (2 H, t, J=8.85 Hz), 2.98 (3 H, s), 1.72 (6 H, s). LC-MS retention time: 1.56 min; m/z (MH+): 553. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=9.65 min, purity=97%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=9.58 min, purity=97%.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9](O)=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[H-].[Na+].[O-]C1C=CC=CC=1.[H][H].Cl[CH2:33][CH2:34][NH2:35]>CN(C=O)C>[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@@H:14]1[CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([CH2:33][CH2:34][NH2:35])[CH:8]=[CH:7][C:6]=3[C@H:5]1[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: NCCCl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(CCN)cc4CC[C@H]3[C@@H]1CCC2=O

Procedure:
Estrone (5.0 g, 18.5 mmole) was dissolved in 80 mL of anhydrous DMF. Sodium hydride (4.4 g, 185 mmole) was slowly added to the solution to generate reactive phenoxide in situ. Care was taken to avoid rapid evolution of hydrogen gas. 4.3 g (55 mmole) chloroethylamine was added to the solution and the mixture was allowed to react at 60° C. for 4 hrs. The product was precipitated with a large volume of water and the precipitate collected. For purification, the crude solid was dissolved in methylene chloride, and washed with water. Evaporation of methylene chloride yielded 3-aminoethyl estrone which after washing with ethyl ether gave 3.0 g (52%) of product m.p. 140° C. (decomp.), 3-aminoethyl estrone hydrochloride, m.p. 180° C. (decomp.), 1HNMR (ppm): δ3.01 (2,t,CH2CH2NH2), 2.78 (2,t,CH2,CH2NH2), 4.00 (2,t,COCH2).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=O.[OH-].[K+].O.NN>C(O)COCCO>[NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1
Reactant: Nc1ccccc1C(=O)c1ccsc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Nc1ccccc1Cc1ccsc1

Procedure:
14.8 g of 3-(amino-benzoyl)thiophene, 23.8 g of solid potassium hydroxide and 19.6 g of hydrazine hydrate are heated to the boil at reflux in 180 cc of diethylene glycol for 3 hours. After diluting the reaction mixture with ice water, extraction is effected with ether. The ether phase is washed thrice with water, is dried with sodium sulphate and concentrated. 3-(2-amino-benzyl)thiophene is obtained in the form of a light yellow oil having a B.P. of 121°-123° 10.05 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[N:18]=1)[CH3:11].[CH3:31][N:32]([CH2:34][C:35](O)=[O:36])[CH3:33].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C.BrC1N=C(O[C@@H](C2C(Cl)=CC=C(F)C=2Cl)C)C(N)=NC=1>CN(C=O)C>[NH2:30][C:14]1[N:15]=[CH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:35](=[O:36])[CH2:34][N:32]([CH3:33])[CH3:31])[CH2:26][CH2:25]3)[CH:23]=2)=[N:18][C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1nc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CN(C)CC(=O)O
Agent: C[C@@H](Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@@H](Oc1nc(-c2cnn(C3CCN(C(=O)CN(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to procedure 63 using 3-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrazin-2-ylamine coupled with dimethylamino-acetic acid in the presence of HOBt/EDC/triethylamine in DMF as described in procedure 5 using 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine as the starting material. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.49 (m, 1H), 7.36 (t, 1H), 6.47 (q, 1H), 6.15 (s, 2H), 4.39 (m, 1H), 4.16 (m, 1H), 3.16 (m, 2H), 3.02 (m, 1H), 2.75 (m, 1H), 2.19 (s, 6H), 2.01 (m, 2H), 1.88 (s, 1H), 1.75 (d, 3H); LCMS: 536 [M+1]; c-Met Ki: 0.015 μM.
Reaction SMILES: [CH:1]1(Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:8]=[N+:9]=[N-:10].[Na+].CS(C)=O>>[CH:1]1([N:8]=[N+:9]=[N-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: BrC1CCCCC1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCCCC1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
Cyclohexyl bromide (2.74 mL, 0.023 mol) was added to a stirred solution of 0.5M sodium azide in DMSO (50 mL, 0.025 mol) at room temperature, under an atmosphere of nitrogen. The reaction mixture was heated to 75° C. behind a blast shield and stirred for 5 h. The reaction mixture was then cooled with an ice-bath, quenched by the addition of water (75 mL) and extracted with diethyl ether (3×125 mL). The combined organic layers were washed with brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a crude oil (2.4 g) which was used without further purification.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[N:21](CCC#N)[C:20]3[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=3[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[C:31](OCC)(=O)[CH3:32].CO>C(O)(C)C.C(=O)(O)[O-].[Na+].C(N(CC)CC)C>[CH2:1]([CH:8]1[CH2:13][CH:12]2[N:11]([CH2:14][CH2:15][CH2:16][C:17]3[NH:21][C:20]4[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=4[N:18]=3)[CH:10]([CH2:31][CH2:32]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCn1c(CCCN2CCC(Cc3ccccc3)CC2)nc2ccccc21
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CO
Product: c1ccc(CC2CC3CCC(C2)N3CCCc2nc3ccccc3[nH]2)cc1

Procedure:
A mixture of 0.4 g of 3-{2-[3-(4-benzyl-piperidin-1-yl)-propyl]-benzoimidazol-1-yl}-propionitrile, 20 mL of isopropanol and 2 mL of 0.4 M sodium in isopropanol was heated to reflux for 2 h. Conversion was complete by TLC (80:20:1 ethyl acetate:methanol:triethylamine). The mixture was cooled, diluted with 10 mL of saturated sodium bicarbonate and concentrated. The residue was partitioned between 3×100 mL of chloroform and 50 mL of water. After drying over magnesium sulfate and concentration under reduced pressure, the residue was purified by preparative TLC eluting with 400:100:25 ethyl acetate:methanol:triethylamine. The major band (UV visualization) was 2-[3-(4-benzyl-piperidin-1-yl)-propyl]-1H-benzimidazole (220 mg): MS (m+1)=334.2; 1H NMR (400 MHz, CDCl3) 7.4 (d, 2H), 7.32 (m, 2H), 7.25 (m, 1H), 7.2 (m, 4H), 3.1 (m, 4H), 2.65 (m, 2H), 2.6 (m, 2H), 2.1 (m, 2H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m, 1H), 1.5 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@H:11]([CH2:21][N:22]3[N:26]=[N:25][C:24]([CH2:27][CH2:28]O)=[N:23]3)[O:10][C:9]2=[O:30])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@H:11]([CH2:21][N:22]3[N:26]=[N:25][C:24]([CH2:27][CH2:28][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:23]3)[O:10][C:9]2=[O:30])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COc1cccc([C@H]2[C@H](Cn3nnc(CCO)n3)OC(=O)N2c2ccc(Cl)cc2)c1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc([C@H]2[C@H](Cn3nnc(CCN4CCOCC4)n3)OC(=O)N2c2ccc(Cl)cc2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (4S,5S)-3-(4-chlorophenyl)-5-((5-(2-hydroxyethyl)-2H-tetrazol-2-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one (47 mg, 0.11 mmol) in DCM is cooled to 0° C. and treated with methanesulfonyl chloride (10 μL, 0.13 mmol) followed by triethylamine (36 μL, 0.26 mmol). After 30 min., the reaction is quenched with water and extracted with DCM, then dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product is then dissolved in DMF (1 mL) and treated with excess morpholine (48 μL, 0.55 mmol) and heated to 100° C. overnight. The cooled reaction is then quenched with water, basified to pH 10 and extracted with EtOAc. The crude product is purified by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)) to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 7.47-7.43 (m, 2H), 7.34-7.29 (m, 3H), 7.04 (app t, J=2.0 Hz, 1H), 7.00-6.98 (app d, J=7.7 Hz, 1H), 6.90 (ddd, J=8.3, 2.6, 0.9 Hz, 1H), 5.61 (d, J=5.0 Hz, 1H), 5.33 (dd, J=14.6, 5.6 Hz, 1H), 5.25 (dd, J=14.6, 4.1 Hz, 1H), 4.99 (ddd, J=5.6, 5.1, 4.2 Hz, 1H), 3.78 (s, 3H), 3.55 (t, J=4.6 Hz, 4H), 2.99-2.93 (m, 2H), 2.59-2.55 (m, 2H), 2.40-2.37 (m, 4H); HPLC-MS calculated C24H27ClN6O4 (M+H+) 499.2, found 499.2.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([CH:17]1[O:22][CH2:21][CH2:20][NH:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([CH:17]1[O:22][CH2:21][CH2:20][N:19]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc(CC2CNCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCOC(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compound could be made in the following manner: 1.5 eq. of 4-Bromobenzyl bromide and 1 eq. of 2-Benzyl-morpholine in acetonitrile could be stirred at room temperature and 3 eq. of potassium carbonate could be added. The reaction could be stirred at room temperature overnight. The solution could be filtered through Celite and concentrated in vacuo to afford a brown solid. Purification could be done by flash chromatography to afford product.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[C:12]([CH3:19])[CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[S:18])[N:3]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:1][CH3:2])=[C:12]([CH3:19])[CH:11]=1
Reactant: Cc1cc(Cl)ccc1N=C=S
Reactant: CCNCCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCC(=O)O)C(=S)Nc1ccc(Cl)cc1C
Yield: 36.6 %

Procedure:
3-Ethylaminopropionic acid (19.8 g) was reacted with 4-chloro-2-methylphenylisothiocyanate (20 g), triethylamine (20 g), and methylene chloride (250 mL) according to the procedure described in step 2 of Example 1 to give 12 g of 3-[3-(4-chloro-2-methylphenyl)-1-ethyl-thioureido]propionic acid. The product (12 g) was dissolved in acetone (245 mL). Conc. HCl (5 mL) was added and the mixture was heated at reflux for 18 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in methylene chloride (100 mL), and washed with 1N NaOH. The organic phase was dried over anhydrous magnesium sulfate, then evaporated to dryness. The solid was recrystallized from ethanol. The title compound (8 g) was obtained as a white solid., m.p. 133°-136° C.
Reaction SMILES: [N+:1]([C:4]12[CH2:19][C:18]([CH3:23])([C:20](O)=[O:21])[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:32]>C(Cl)Cl.Cl>[N+:1]([C:4]12[CH2:19][C:18]([CH3:23])([C:20]([F:32])=[O:21])[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C(=O)F)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 9-nitro-9,10-dihydro-11-methyl-9,10-ethanoanthracene-11-carboxylic acid (hereafter called Core C) (500 mg, 1.6 mmol) and pyridine (0.25 mL, 3.0 mmol) in 10 mL of DCM was added a solution of cyanuric fluoride (400 mg, 3.0 mmol) dropwise. After stirring 30 min, the reaction was diluted with 1N HCl, and extracted 2×DCM. The DCM extracts were dried over MgSO4. The solution was filtered, concentrated by rotary evaporator to give 482 mg (98%) of 9-nitro-9,10-dihydro-11-methyl-9,10-ethanoanthracene-11-carboxylic acid fluoride Core D. MS found: (M+H)+=312.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]1[CH:9]=[C:10]([C:14](=O)[CH3:15])[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:2][CH2:3][CH2:4][CH2:5][N:6]=[C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=1)[CH3:15]
Reactant: NCCCCl
Reactant: CC(=O)c1cccc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=NCCCCl)c1cccc(F)c1
Reaction time: 8 h

Procedure:
In step 8-1, 3-chloropropan-1-amine hydrochloride (4.1 g, 32 mmol) was added to a suspension of 1-(3-fluorophenyl)ethanone (4.4 g, 32 mmol) and sodium carbonate (3.7 g, 35 mmol) in water (15 mL). The reaction mixture was stirred overnight and the resulting solution was then extracted with ethyl acetate (3×150 mL). The organic layer was dried with sodium sulfate, and the ethyl acetate removed to yield 3-chloro-N-(1-(3-fluorophenyl)ethylidene)propan-1-amine (8-1) as a light yellow oil. m/z=214.0 [M+1].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1C=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=1C(O)=O.S(OC)(O[CH3:20])(=O)=O.[C:23]([O:26][CH2:27]C)(=[O:25])[CH3:24]>>[CH3:27][O:26][C:23](=[O:25])[C:24]1[CH:11]=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:5][C:4]=1[O:3][CH3:20]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 500 ml round bottom flask was charged witih 5.35 grams of 60% sodium hydride dispersion and the solid was washed twice with hexane and decanted (under nitrogen). The residue was suspended in 200 mL of dimethylformamide (DMF), cooled to 0° C. and was treated with 11 grams (60 mmol) of 2-hydroxy-5-nitrobenzoic acid. The reaction mixture was stirred for 1 hour at 0° C. The mixture was then treated with 17 mL (180 mmol) dimethyl sulfate and was allowed to warm to room temperature while stirring for 1.5 hours. An additional 17 mL of dimethyl sulfate was added and the reaction was stirred overnight at room temperature. The mixture was diluted with 1.5 L ethyl acetate and was washed with 400 ml of 0.75 M aqueous sodium hydroxide (NaOH) solution followed by 400 mL of saturated bicarbonate solution, 400 mL of water and 500 mL of saturated brine. The organic phase was dried and evaporated. There was obtained 11.6 grams of the desired product as yellow flakes. The material was generally used without purification.