Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)=[CH:4][C:3]2[CH2:18][CH2:19][CH2:20][C:2]1=2.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:5]4[S:1][C:2]5[CH2:20][CH2:19][CH2:18][C:3]=5[CH:4]=4)=[N:10][C:9]=13)=[O:17])[CH2:25]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3cc4c(s3)CCC4)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4cc5c(s4)CCC5)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
A mixture of 2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzo[d]oxazole-4-carboxylic acid (90 mg, 0.32 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (86 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (0.27 mL, 1.92 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight, and then was quenched with a saturated solution of sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and semi-preparative HPLC to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzoxazole-4-carboxamide (55 mg, 41%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.01 (d, J=7.5 Hz, 1H), 8.16 (dd, J=8.0, 1.0 Hz, 1H), 7.65 (s, 1H), 7.61 (dd, J=8.0, 1.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 4.60-4.50 (m, 1H), 3.10 (d, J=10.0 Hz, 2H), 3.03-3.00 (m, 2H), 2.86-2.82 (m, 2H), 2.65-2.52 (m, 4H), 2.54 (s, 3H), 2.18-1.96 (m, 3H), 1.62-1.46 (m, 3H), 1.25-1.18 (m, 2H); MS (ESI+) m/z 422 (M+H); HPLC>99% (AUC), tR=13.28 min.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][CH:8]1[CH2:12][S:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]1O)=[O:6])[CH3:3].C(Cl)Cl.CCN(CC)CC.S(Cl)(C)(=O)=O>CCOCC>[CH2:16]([O:15][C:13]([C:10]1[S:11][CH2:12][CH:8]([NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:19])[CH3:3])=[O:6])[CH:9]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C1SCC(NC(=O)OC(C)(C)C)C1O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C1=CC(NC(=O)OC(C)(C)C)CS1
Temperature: 0 °C

Procedure:
Into an ice cooled stirring solution containing the crude alcohol obtained in Step C, 75 ml of CH2Cl2, and 10.5 ml (74 mmole) of Et3N was added 2.9 ml (37 mmole) of mesyl chloride while maintaining the system under a positive argon atmosphere. The reaction was stirred an additional 5 minutes at 0° C. and then 3 hours at 25° C. The reaction was poured into a separatory funnel containing 200 ml Et2O and successively washed with 70 ml water, 1N HCl until the aqueous wash tested acidic; 15 ml water and 50 ml brine, and dried over MgSO4. Removal of the solvent at reduced pressure afforded 6.5 g of a brown oil which was purified by flash chromatography (eluting with 15% and then 20% EtOAc/Hexanes) to yield 3.97 g of product. This material exhibited the following optical rotation [α]Damb =+122.8° at a concentration of 0.5M in ethanol. The highest rotation observed for the R enantiomer under similar conditions was -128.1°.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[C:13]([C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[CH:12][N:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)NN=Cc1c[nH]c(C(C)(C)C)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)c1ncc2cn[nH]c(=O)n12

Procedure:
A 6.15 gm. portion of 3-(2-tert-butyl-4-imidazolylmethylene)carbazic acid ethyl ester in 40 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 186°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[S:33]([C:29]2[S:28][CH:32]=[CH:31][N:30]=2)(=[O:35])=[O:34])[CH:7]=1
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11a, and thiazole-2-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 7.96 (d, 1H), 7.88 (d, 2H), 7.60 (d, 1H), 7.26 (d, 2H), 7.13 (m, 1H), 7.04 (m, 1H), 6.95 (m, 1H), 6.91 (s, 1H), 4.54 (s, 2H), 4.48 (s, 2H), 3.64 (s, 3H), 2.81 (t, 2H), 2.52 (t, 2H); MS 509 (M+1).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:37][CH2:38][CH2:39][CH2:40]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:40][CH2:39][CH2:38][Br:37])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCBr
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCBr)cc(C(=O)OCc2ccccc2)c1
Yield: 79.5 %

Procedure:
A mixture of 5.0 g (0.01 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester, 10.2 ml (0.1 mol) of 1,3-dibromopropane and 7.0 g (0.05 mol) of potassium carbonate in 75 ml of acetone and 15 ml of DMF wasstirred at reflux for 22 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure to an oil. Purification by HPLC using 5% ethyl acetate-hexane gave 4.91 g (79% yield, mp 57°-58°) of 3-(3-bromopropoxy)-5-(octadecyloxy)benzoic acid phenylmethyl ester. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1)=[O:5])[CH3:2].[Br:16]Br>>[Br:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:15]2
Reactant: BrBr
Reactant: CCOC(=O)C1CNc2ccccc2C1
Product: CCOC(=O)C1CNc2ccc(Br)cc2C1

Procedure:
Analogously to Example 33b), starting from 410 mg of 3(R,S)-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline and 0.11 ml of bromine, 6-bromo-3(R,S)-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline is obtained: Rf (D)=0.15; MS: (M)+ =285.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:11]Br>[Fe].O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1ccccc1C(=O)O
Agent: [Fe]
Solvent: O
Product: Cc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
2-Methylbenzoic acid (40.0 g, 0.290 mol) was added to a suspension of Br2 (160 mL) and iron powder (3.20 g, 0.057 mol) under N2 atmosphere in an ice bath. The mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was poured into water and the reddish solid was collected by filtration. The solid was dried under vacuum at 50° C. The solid was dissolved in 400 mL of methanol before 640 mL of 0.1N aqueous HCl was added at room temperature. The mixture was stirred and a white solid was produced. This solid was recrystallized from ethanol to afford 5-bromo-2-methyl-benzoic acid (12.0 g, 19%). 1H NMR (300M Hz, CDCl3) δ 8.17 (d, J=2.1, 1H), 7.56 (dd, J=8.1, 2.1, 1H), 7.15 (d, J=8.1, 1H), 2.59 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH:27][NH2:28])=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].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>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH:27][NH:28][C:4]([C:3]2[C:2]([NH2:1])=[N:10][CH:9]=[C:8]([Br:11])[CH:7]=2)=[O:6])=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)c2cc(Br)cnc2N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-amino-5-bromo-nicotinic acid (1.2 g, 5.53 mmol) in DMF (30 mL) were added 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 6.173 mmol), HATU (2.35 g, 6.184 mmol) and DIPEA (4 mL, 23.56 mmol) at RT. The reaction mixture was stirred for 18 h at RT. The reaction mixture was poured into ice-water (30 mL), extracted with ethyl acetate (3×50 mL), organic layer was washed with brine dried over anhydrous sodium sulphate concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel. The column was eluted with 60% EtOAc in petroleum ether to afford the title compound as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH2:6])=[O:5].Cl[C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([NH:23][C:24]([C:26]3([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[O:30])[CH2:28][CH2:27]3)=[O:25])=[C:18]([F:39])[CH:17]=2)[CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:6][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:21]([F:22])=[CH:20][C:19]([NH:23][C:24]([C:26]3([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)=[O:30])[CH2:28][CH2:27]3)=[O:25])=[C:18]([F:39])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:5]
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)CC1
Reactant: CN(C)CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN(C)CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 100 °C
Yield: 48 %

Procedure:
2-(Dimethylamino)acetamide (0.100 g, 0.974 mmol), N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.15 g, 0.325 mmol) (as prepared in Example 1), cesium carbonate (0.159 g, 0.487 mmol), and xantphos (0.018 g, 0.032 mmol) were combined in dry dioxane (2.5 mL) and argon was bubbled through the mixture for 5 minutes. Palladium acetate (5.47 mg, 0.024 mmol) was added and the solution was degassed for an additional 5 minutes. The reaction flask was fitted with a reflux condenser and a balloon of argon and heated at 100° C. for 15 hours. The mixture was cooled to room temperature and then diluted with ethyl acetate (75 mL) and water (45 mL). The water layer was removed and extracted again with ethyl acetate (25 mL). The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate. Evaporation of the solvent yielded a lavender-colored oil which was purified by silica gel chromatography (0 to 7% methanol in dichloromethane) to give N-(4-(2-(2-(dimethylamino)acetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.0823 g, 48% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 9.97 (s, 1H), 9.79 (s, 1H), 8.20 (d, 1H), 8.09 (dd, 1H), 7.65 (d, 1H), 7.57 (m, 3H), 7.16 (m, 2H), 6.76 (dd, 1H), 3.06 (s, 2H), 2.25 (s, 6H), 1.63 (m, 2H), 1.57 (m, 2H); MS (ESI) ink: 528.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][NH:23][C:22]4=[O:26])[N:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[C:29](B(O)O)=[CH:30][C:31]([F:34])=[N:32][CH:33]=1.ClCCl.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:16]1[C:11]([C:9]2[S:8][C:7]3[C:2]([C:29]4[C:28]([Cl:27])=[CH:33][N:32]=[C:31]([F:34])[CH:30]=4)=[CH:3][CH:4]=[CH:5][C:6]=3[CH:10]=2)=[N:12][C:13]([NH:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])=[N:14][CH:15]=1
Reactant: O=C1NCCN1CCNc1ncc(Cl)c(-c2cc3cccc(Br)c3s2)n1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C1NCCN1CCNc1ncc(Cl)c(-c2cc3cccc(-c4cc(F)ncc4Cl)c3s2)n1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
In a microwave vial, combine 1-{2-[4-(7-bromo-benzo[b]thiophen-2-yl)-5-chloro-pyrimidin-2-ylamino]-ethyl}-imidazolidin-2-one (500 mg, 1.1 mmol), 5-chloro-2-fluoropyridine-4-boronic acid (578 mg, 3.3 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (90 mg, 0.11 mmol), 2-(di-tert-butylphosphino)biphenyl (20 mg, 0.066 mmol) and sodium carbonate (350 mg, 3.3 mmol) in THF (3 mL) and water (1.5 mL). Bubble nitrogen through the mixture for 5 min. Heat the mixture to 100° C. for 10 min. Concentrate the organic layer to dryness in vacuo. Slurry the resulting solid into dichloromethane/methanol and purify by column chromatography (1% 2 N ammonia/methanol solution in dichloromethane to 10% 2 N ammonia/methanol solution in dichloromethane) to afford the title compound. For further purification, dissolve the product in DMSO and purify by reverse phase column chromatography (50% acetonitrile in water (with 0.03% HCl) to 95% acetonitrile in water (with 0.03% HCl) to afford the title compound (146 mg, 26%). MS (ES) m/z 503 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=O)[CH3:15])=[N:9]2)=[CH:4][CH:3]=1.[C:19](N1C=CN=C1)([N:21]1C=CN=C1)=O.CN>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([NH:21][CH3:19])=[O:18])[CH3:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Product: CNC(=O)C(C)Oc1ncn(-c2ccc(Br)cc2)n1
Yield: 80 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 37, 2.3 g of carbonyldiimidazole and 2 ml of 40% aqueous methylamine. The product was recrystallized from ethanol to obtain 2.5 g of the desired product, m.p. 176°-178°.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[CH:3]=1.[BH4-].[Na+].O.O.C(O)(=O)C(O)=O>COCCOCCOC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCN1CCN(C2=Cc3cc(Cl)ccc3Sc3ccccc32)CC1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Sc3ccccc32)CC1
Temperature: 100 °C

Procedure:
750 mg of 3-[2-[4-(2-chloro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone, 0.6 g of sodium borohydride and 30 ml of diglyme are treated dropwise under an argon atmosphere at 20°-30° C over a period of 15 minutes with 2.7 g of oxalic acid dihydrate in 15 ml of diglyme. The mixture is heated for 4 hours at an internal temperature of 100° C and subsequently evaporated under reduced pressure. The residue is treated with chloroform and 2-N sodium hydroxide solution. After equilibration, the aqueous phase is separated and washed twice with chloroform. The combined chloroform extracts are washed with water, dried over potassium carbonate and active carbon, filtered and evaporated under reduced pressure. There is obtained 3-[2-[4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone in the form of a brown oil. The maleate of melting point 173°-175° C is prepared by treatment with maleic acid in ethanol/ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][S:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:48])C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][S:29]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[O:48])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)c1ccc(SCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 4-[[1-[3-methoxy4-[N′-(2-methyl phenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylthio]benzoate (264 mg, 0.482 mmol) in CH2Cl2 (5.2 mL) was added m-CPBA (118.8 mg, 0.482 mmol) at 0° C., and the mixture was stirred at room temp for 1 hr. The mixture was diluted with CHCl3, and quenched with sat. Na2S2O3. The separated organic layer was washed with sat. NaHCO3, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure to afford methyl 4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2 pyrrolidinyl]methylsulfinyl]benzoate as a crude amorphous solid. To a stirred solution of this crude compound in THF (4 mL) and H2O (1mL) was added LiOH (34.6 mg, 1.45 mmol), and the stirring was continued overnight at room temp. The mixture was diluted with CHCl3, washed with 1 N HCl, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-CHCl3-MeOH to afford 193.2 mg (73%) 24 as a white crystalline powder. IR (KBr) 3338, 2956, 1708, 1529, 1299, 1207, 1155 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.70–2.06 (m, 4H), 2.24 (s, 3H), 2.90 (dd, J=8.3, 13.2 Hz, 1H), 3.02–3.08 (m, 1H), 3.16–3.25 (m, 1H), 3.41–3.60 (m, 3H), 3.84 (s, 3H), 4.40 (br s, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.87 (s, 1H), 6.94 (d, J=7.3 Hz, 1H), 7.11–7.17 (m, 2H), 7.75–7.81 (m, 3H), 7.98–8.05 (m, 1H), 8.10 (d, J=8.3 Hz, 2H), 8.46 (s, 1H), 8.56 (s, 1H); MS (FAB) m/z 550 (M++1), 572 (M++Na); Anal. Calcd for C29H31N3O6S.3/2H2O: C, 60.40; H, 5.94; N. 7.29. Found: C, 60.15; H, 5.82; N, 6.90.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)[CH:11]=[N:10][C:9]=2[O:15][C@@H:16]([CH3:21])[C:17]([F:18])([F:20])[F:19])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@H](Oc1ncc(N)nc1-c1ccc(Cl)cc1)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: C[C@H](Oc1ncc(NC(=O)c2cccnc2)nc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
6-(4-Chloro-phenyl)-5-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyrazin-2-ylamine (0.100 g, 315 μmol) was dissolved in dried pyridine (1.0 mL), nicotinoyl chloride hydrochloride (61.6 mg, 346 μmol) was added and the suspension was stirred at 140° C. for 10 minutes in the microwave. The solvent was evaporated and the crude material was purified by flash chromatography (silica gel, 10 g, 0% to 50% CH2Cl2/MeOH/NH3 9/1/0.1) to give 0.121 g (91%) of the title compound as white solid; LC-MS (UV peak area/ESI) 100%, 423.0821 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:39](=[CH:43]\[CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)/[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31](/[C:39](=[CH:43]\[CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)/[C:40]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 0 °C
Yield: 51.1 %

Procedure:
A solution of triphenylphosphine (120 mg, 0.46 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (92 mg, 0.52 mmol). The reaction mixture was stirred at 0° C. until the reaction mixture became homogeneous. The resulting light purple reaction mixture was then treated with (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acrylic acid (100 mg, 0.30 mmol), and the reaction mixture was stirred at 0° C. for 20 min. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-aminothiazole (46 mg, 0.46 mmol) and pyridine (0.044 mL, 0.55 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded the (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-acrylamide (63 mg, 50%) as a yellow oil: EI-HRMS m/e calcd for C18H19ClN2O3S2 (M+) 410.0526, found 410.0529.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>O.CO>[C:1]([CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(CC#N)cccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of KCN (474 mg, 7.2 mmol) in water (1 mL) was slowly added to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (1 g, 3.6 mmol) in methanol (20 mL). This mixture was allowed to stir for 4 h at 50° C. The reaction mixture was concentrated to remove methanol, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (Na2SO4), concentrated and purified by flash column chromatography (25% EtOAc in hexanes) to give the title compound as 0.5 g of an oily liquid (62%). 1H NMR (CDCl3, 600 MHz): δ 3.9 (s, 2H), 3.97 (s, 3H), 7.65 (t, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H).