Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[O-].[Na+].C1COCC1.[CH2:9]([O:16][C:17]1[CH:18]=[C:19](/[CH:24]=[N:25]/[OH:26])[CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:27]=[C:28]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(OCC)(=O)C.O>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:24]2[CH2:27][C:28]([CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[O:26][N:25]=2)[CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1cc(/C=N/O)cc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.4 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 2715 mg) was added dropwise to a THF (4 mL) solution of (E)-1-(3-(benzyloxy)-5-methylphenyl)-N-hydroxymethanimine (400 mg) and di-tert-butyl 2-methylenesuccinate (402 mg) at 0 C, and the obtained mixture was stirred at 0 C for 2 hours and subsequently at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and water was added thereto. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (674 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:23][C:24]=1[C@H:25](O)[CH3:26].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C@@H:25]([C:24]3[S:23][C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=4)=[N:21][C:20]=3[CH3:19])[CH3:26])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@@H](C)O
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@@H](C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with (S)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol [ee=95%; PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to obtain (R)-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless oil. The configuration was tentatively assigned as R according to R. Cadilla et al., PCT Int. Appl. (2002), WO 02/062774 A1 and the generally accepted SN2-type mechanism of the Mitsunobu reaction.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([O:32][CH:33]([CH3:35])[CH3:34])[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:37][S:38]([O:17][C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)[C@H:15]([O:32][CH:33]([CH3:34])[CH3:35])[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:36])(=[O:40])=[O:39]
Reactant: CC(C)OC(C(=O)N1C(=O)OCC1Cc1ccccc1)C(O)c1cccc(OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](OS(C)(=O)=O)c1cccc(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
12.9 g of 4-Benzyl-3-(3-(3-benzyloxyphenyl)-3-hydroxy-2-isopropoxy propionyl]oxazolidin-2-one was dissolved in 30 ml of pyridine, and 3.06 ml of methanesulfonyl chloride was dropwise added thereto under ice-cooling. After stirring was continued at room temperature for 2 hours, the reaction solution was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated, to give 3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-1(R)-(3-benzyloxyphenyl)-2(S)-isopropoxy-3-oxopropyl methanesulfonate. This product was then dissolved in 300 ml of ethanol, and 2 g of 10% palladium carbon was added, and the mixture was stirred overnight under hydrogen atmosphere at room temperature. The reaction solution was filtered, and the filtrate was concentrated. The residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate, The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 5.87 g of the title compound as a colorless oil in the 2:1→3:2 hexane-ethyl acetate fraction.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:29](OCCC(C)C)=O>C(Cl)(Cl)Cl>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[NH:1][N:29]=[CH:12]2
Reactant: CC(C)CCON=O
Reactant: COC(=O)c1cc(C(F)(F)F)cc(C)c1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(C(F)(F)F)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 3, at 0° C. and under nitrogen atmosphere, in chloroform (0.3M) was added acetic anhydride (2.3 equiv.) drop wise and the resulting mixture was stirred for 1 h at r.t. Then potassium acetate (0.2 equiv.) was added followed by addition of isoamyl nitrite (2.2 equiv.) and the resulting mixture was heated at reflux for 16 h. After, the reaction was cooled down to r.t. While cooling, a solid precipitation was observed. The solid was filtrated and dried under vacuum to give the title compound 4. (0.324 g, 75%).
Reaction SMILES: OC([CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)=O.[C:9]([O-:12])(=[O:11])[CH3:10].[Na+].C(OO)(=O)C>C(Cl)Cl.C(O)(=O)C.[C].[Ru]>[C:9]([O:12][CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)(=[O:11])[CH3:10]
Reactant: CC(=O)[O-]
Reactant: O=C1CC(C(=O)O)N1
Agent: [Ru]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OC1CC(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
0.3 of 4-hydroxycarbonylazetidine-2-one, 0.43 g of anhydrous sodium acetate and 100 mg of 5% ruthenium-carbon were suspended in a mixture of 12 ml of methylene chloride and 4 ml of acetic acid and cooled to -3° C., to which 1.1 ml of acetic acid solution containing 40% peracetic acid was carefully dropped, subjected to stirring at 0° C. for 1 hour. The catalyst was separated by suction filtration, then solvent was distilled off under reduced pressure. 20 ml of n-hexane was added thereto. Undissolved matter was filtered off, the filtrate was concentrated under reduced pressure to obtain 0.37 g of the title compound (yield: 82%).
Reaction SMILES: [C:1]1(=O)[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH2:2]1.[C:16]1(N)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22].OP(O)(O)=O>O>[CH:4]1[C:5]2[N:6]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:22]=[C:7]3[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: O=C1CC=Cc2ncc3ccccc3c21
Reactant: Nc1ccccc1N
Agent: O=P(O)(O)O
Solvent: O
Product: c1ccc2c(c1)nc1c3ccccc3c3ccccc3n21
Temperature: 300 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
97.6 g (0.5 mol) of phenanthridone, 60 g (0.55 mol) of o-phenylenediamine and 15 g of 85% strength H3PO4 (remainder water) are mixed and fused under nitrogen. The elimination of H2O starts from 200° C. The temperature is gradually raised to 300° C over the course of 6 hours, whilst stirring, and is additionally kept at 300° to 330° C for 8 hours. In the course of this time, about 12 g of H2O have distilled over. A fractional distillation in an oil pump vacuum is then carried out and 77 g (57.5% of theory) of benzimidazo-[1,2-f]-phenanthridine of boiling point 227° C/0.4 mm Hg and melting point 153° C are obtained as almost colourless crystals (after recrystallisation from 5 parts of ethanol). ##STR31##
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1OC)=[O:5])C.[Na].[OH2:31].[CH2:32](O)C>>[CH3:32][O:31][C:19]1[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:25])[F:27])=[CH:23][C:18]=1[N:17]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:14])[F:15])=[CH:12][C:7]=2[NH:6][C:4]1=[O:5]
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)ccc1Nc1cc(C(F)(F)F)ccc1OC
Reactant: CCO
Reactant: O
Agent: [Na]
Product: COc1ccc(C(F)(F)F)cc1-n1c(=O)[nH]c2cc(C(F)(F)F)ccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To an ice cooled suspension of N-(2-ethoxycarbonylamino-4-trifluoromethylphenyl)-2-methoxy-5-trifluoromethylaniline (140 mmol, 59 g) in 200 ml absolute ethanol is added sodium (174 mmol, 4 g) and the mixture is stirred at 70° C. for four hours. When the reaction is completed the reaction mixture is poured into water which is acidified and the title compound is collected by filtration as white crystals, M.p. 226° C.
Reaction SMILES: CNCCN(C)C.[Li]CCCC.[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>O1CCCC1>[C:21]([C:14]1[O:13][CH:17]=[CH:16][C:15]=1[CH:18]=[O:19])([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=Cc1ccoc1
Reactant: CCOC(=O)Cl
Agent: CNCCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1occc1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 7.02 g (68.7 mmol) of N,N'-trimethylethylene diamine in 100 ml of anhydrous tetrahydrofuran (chilled to -78° C.) was added 44.6 ml (71.4 mmol) of 1.6 M n-BuLi in hexanes. A dark yellow solution was formed. The solution was stirred at -78 C under a blanket of argon for 15 minutes. To the solution was added 6.24 g (64.9 mmol) of distilled 3-furaldehyde and the solution was stirred at -78° C. for 20 minutes. To this solution was added 55.0 ml (71.4 mmol) of 1.3M solution of BuLi in hexanes and the solution was stirred at -78° C. for 3 hours. The anion formed was transfered via cannula onto a solution of 7.75 g (6.8 ml, 71.4 mmol) of ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran (chilled to -78° C.). The resulting solution was allowed to warm to room temperature and stirred overnight (16.33 h). The solution was poured onto 1:10 10% HCl: ice (v/v) and the layers were separated. The aqueous layer was extracted with ether and the organic phases combined, dried over MgSO4, filtered and concentrated in vacuo to yield a brown oil. Purification by flash chromatography (silica gel, 5% ethyl acetate in hexane) yielded the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH:40]=[CH:41][C:42]([OH:44])=[O:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]>O1CCCC1.CO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:27]=3)[C:22]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=CC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-carboxyvinyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (500 mg) is dissolved in a mixed solution of tetrahydrofuran (15 ml) and methanol (5 ml), then thereto is added 10% palladium/carbon (160 mg), and the mixture is stirred at room temperature under hydrogen for 3 hours and 30 minutes. The reaction solution is filtered, and concentrated under reduced pressure to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-carboxyethyl)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (498 mg). MS (m/z): 656 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)=[C:4]([CH2:20][CH3:21])[CH:3]=1.NN>C(Cl)(Cl)Cl.C(O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH2:7])=[C:4]([CH2:20][CH3:21])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCc1cc(Br)ccc1CN
Temperature: 25 °C

Procedure:
2-(4-Bromo-2-ethyl-benzyl)-isoindole-1,3-dione (4 g, 11.7 mmol) and hydrazine (1.8 mL, 58.3 mmol) in chloroform:ethanol (1:1.5, 250 mL) were refluxed for 4 h. The mixture was cooled to room temperature and filtered through a pad of celite. The solution was diluted in water and partitioned. The organic layer was washed with water, saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and then concentrated in vacuo to a yellow oil (2.2 g, 88%). 1H NMR (300 MHz, CDCl3): δ ppm 1.23 (t, J=7.54 Hz, 3H) 1.65 (s, 2H) 2.66 (q, J=7.60 Hz, 2H) 3.84 (s, 2H) 7.19-7.23 (m, 1H) 7.30-7.34 (m, 2H).
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[CH2:15]([O:17][CH2:18][CH3:19])[CH3:16].[C:20]1([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:17]([C:18]1[CH:29]=[CH:28][C:27]([S:11]([C:1]2[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([C:30]3[CH:29]=[CH:28][C:27]([O:26][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:32][CH:31]=3)(=[O:9])=[O:8])[CH:2]=2)(=[O:13])=[O:12])=[CH:32][CH:19]=1)[C:15]1[CH:22]=[CH:21][CH:20]=[CH:25][CH:16]=1
Reactant: CCOCC
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Product: O=S(=O)(c1ccc(Oc2ccccc2)cc1)c1cccc(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)c1
Temperature: 170 °C
Reaction time: 24 h

Procedure:
To a solution of 137.0 grams (0.498 mole) of m-benzenedisulfonyl chloride in 170 grams of diphenyl ether was added 1.0 gram of ferric chloride. The reaction was stirred at 170° C for 24 hours. After the reaction had cooled to room temperature, ethyl ether was added and the mixture was filtered and washed with water. The ether layer was separated, filtered, and dried over Na2SO4. Evaporation of the ether and distillation of diphenyl ether under reduced pressure afforded a crude solid. The crude product then was distilled under high vacuum (0.1mm) with an open flame. The distillate solidified upon cooling and was dissolved in 40 ml of chloroform and 800 ml of ethyl ether. A small amount of insoluble black residue was filtered from the solution. The addition of 800 ml of petroleum ether precipitated 160 grams (63%) of a white powder, mp 70°-75° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[N:11]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[S:22])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>C(O)C>[O:14]1[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][CH2:19][N:20]([C:21]2[S:22][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:23]=2)[C:38]([C:34]2[S:33][CH:37]=[CH:36][CH:35]=2)=[O:39])[CH2:16][CH2:15]1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(c1cccs1)N(CCCN1CCOCC1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Yield: 54 %

Procedure:
A mixture of 2-bromoacetophenone (60 mg, 0.3 mmol) and (3-morpholin-4-yl-propyl)-thiourea (61 mg, 0.3 mmol) in dry ethanol (3 mL) was heated at reflux for 10 min, cooled to room temperature, and concentrated in vacuo. The resulting residue was suspended in dichloromethane (3 mL) followed by the addition of N,N-diisopropylethylamine (105 μL, 0.6 mmol) and thiophene-2-carbonyl chloride (34 μL, 0.32 mmol). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (1.5 mL) and subjected to HPLC purification (Method Y). The resulting free amine was dissolved in MeOH (1 mL) and 1M HCl/ether (50 mL) was added. The precipitate was filtered and dried in vacuo to provide the title compound (67 mg) as an off-white solid as the hydrochloride salt. LC/MS (ESI) m/z 413.9 [M+H]. HPLC retention time (Method A)=2.78 min.
Reaction SMILES: [Mg].BrCCBr.Cl[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH3:14].[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[Cl:13][C:9]1[C:8]([CH3:14])=[C:7]([C:15]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Cl)cccc1Cl
Reactant: O=C1CCCCC1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1C1(O)CCCCC1
Temperature: 25 °C

Procedure:
Under a nitrogen blanket, 96 g (4 moles) of magnesium shavings in 60 ml of absolute THF (tetrahydrofuran) are placed in a receiver. At 65° C., 1 ml of 1,2-dibromoethane is added and then a solution of 644 g (4 moles) of 2,6-dichlorotoluene in 1.5 liters of absolute THF is dripped in over a period of 21/4 hours. The mixture is then stirred under reflux for 4 hours and cooled to room temperature, and 352.8 g (3.6 moles) of cyclohexanone in 250 ml of absolute THF is added under a nitrogen blanket. After the reaction the Grignard reaction mixture is worked up as usual and the solvent is substantially removed by distillation under reduced pressure. The residue is subjected to incipient distillation (30° to 107° C./0.27 mbar). The crude product remaining (676 g), which already consists to the extent of 90% of 1-(3'-chloro-2'-methylphenyl)-cyclohexanol, can be purified further by column chromatography using toluene as eluant.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(Cl)CCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[C:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (4.26 g, 20.00 mmol) and (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (5.48 g, 20.00 mmol) in ClCH2CH2Cl (100 mL) were added triethyl amine (4.2 g, 40.00 mmol) and AgF (2.53 g, 20.00 mmol) in one portion. The mixture was stirred at rt overnight. The mixture was then quenched with sat. NH4Cl and extracted with CH2Cl2. The organic phase was separated, filtered through Celite and dried over Na2SO4. The mixture was then separated and concentrated. The residue was triturated with EtOAc and nHexane, and the precipitates were collected by filtration and the mother liquid was concentrated and further purified by flash column (SiO2, 1-20% of EtOAc in hexanes) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (6.65 g, 68.2%; HRMS (ES+) m/z Calcd for C27H32Cl2N2O2+H [(M+H)+]: 487.1914. found: 487.1910.) and rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (0.86 g, 8.8%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:36][O:37][C:38](Cl)=[O:39].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH3:36][O:37][C:38]([N:22]1[CH2:21][CH2:20][CH:19]([C:18]2[C:12]3[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=4)=[N:14][C:13]=3[C:15]([O:25][CH3:26])=[CH:16][CH:17]=2)[CH2:24][CH2:23]1)=[O:39]
Reactant: COc1ccc(C2CCNCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N1CCC(c2ccc(OC)c3nc(NC(=O)c4ccc(F)cc4)sc23)CC1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a suspension of 0.1 g (0.24 mMol) 4-fluoro-N-[4-methoxy-7-piperidine-4-yl-benzothiazol-2-yl]-benzamide hydrochloride (1:1) in 3 ml THF were added 0.036 ml triethyl amine. At 0° C. 0.020 ml (0.26 mMol) chloro formic acid methyl ester was added dropwise and stirred for 1 h. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. This was extracted three times with 15 ml ethyl acetate, the combined organic phase were dried over sodium sulfate and evaporated to dryness in vacuo. One obtained 0.080 g (76%) 4-[2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazol-7-yl]-piperidine-1-carboxylic acid methyl ester as a white solid. F.p.: 238-239° C.
Reaction SMILES: Br[C:2]1[C:3]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[Zn]C>C1COCC1.[Pd]>[CH3:27][C:2]1[C:3]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(Br)c(C(=O)Nc3ccccc3)n2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: C[Zn]Cl
Solvent: C1CCOC1
Product: Cc1ncc(-c2ccc(S(C)(=O)=O)cc2)nc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 819.5 %

Procedure:
A solution of 3-bromo-6-(4-methylsulfonylphenyl)-N-phenyl-pyrazine-2-carboxamide (89.4 mg, 0.1634 mmol) and palladium; triphenylphosphane (9.441 mg, 0.008170 mmol) in THF (1 mL) was treated with chloro(methyl)zinc (490.2 μL of 2 M, 0.9804 mmol) and left to stir for 16 hours at ambient temperature. The reaction was treated with further chloro(methyl)zinc (490.2 μL of 2 M, 0.9804 mmol) and allowed to heat at 60° C. for 7 hours. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The resultant residue was dissolved in DMSO and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (24.6 mg, 41% Yield). 1H NMR (400.0 MHz, DMSO) δ 2.81 (s, 3H), 3.31 (s, 3H), 7.15-7.19 (m, 1H), 7.39-7.43 (m, 2H), 7.82 (d, J=7.6 Hz, 2H), 8.11 (d, J=8.5 Hz, 2H), 8.56 (d, J=8.5 Hz, 2H), 9.44 (s, 1H) and 10.71 (s, 1H) ppm; MS (ES+) 367.98. LCMS retention time, 3.37 min.