Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CC1(C)C(C)(C)OB([C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH:24]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH3:9][O:8][C:6]1[C:5]([O:10][CH3:11])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH:24]=2)[CH:7]=1
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1OC
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1cc(C2=CC(C)(C)CC(C)(C)C2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To a solution of 1-bromo-4,5-dimethoxy-2-nitrobenzene (1.06 g, 4.04 mmol) produced in Example (87a) in 1,2-dimethoxyethane (30 mL) were added 4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane (1.28 g, 4.85 mmol) produced in Example (4b), tripotassium phosphate (1.29 g, 6.06 mmol) and water (1.5 mL). Tetrakis(triphenylphosphine)palladium (230 mg, 0.20 mmol) was then added to the mixture while stirring at room temperature under a nitrogen atmosphere. The mixture was then stirred for 13 hours at an external temperature of 70° C., and stirring was continued for 3 hours at an external temperature of 100° C. Tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.20 mmol) and water (2 mL) were added to the reaction mixture, and it was further stirred for 9 hours at an external temperature of 100° C. and then for 11 hours at an external temperature of 70° C. After cooling the reaction mixture, ethyl acetate was added and the mixture was filtered through Celite. The filtrate was concentrated and extracted with ethyl acetate, and the obtained organic layer was washed with brine. The organic layer was then dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 1.1 g of the title compound as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6]2.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=2)[N:13]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][N:5]([C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=3)[N:13]=1)[CH2:6]2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: CN1C2CCCC1CNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1C2CCCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2
Temperature: 25 °C

Procedure:
A mixture of 9-methyl-3,9-diaza-bicyclo[3.3.1]nonane (0.50 g, 3.56 mmol), 2-chloro-6-nitroquinoline (0.74 g, 3.56 mmol), N,N-diisopropylethylamine (0.92 g, 7.13 mmol) and dioxane (25 ml) was stirred at reflux for 40 h. The mixture was allowed to cool to room temperature. The precipitated product was filtered and was washed with diethylether. The crude product was purified by silica gel column chromatography using a solvent mixture of dichloromethane, methanol and aqueous ammonia (9:1:1%). The pure product was isolated. Yield 300 mg (27%). Mp 166.2° C. LC-ESI-HRMS of [M+H]+ shows 313.1674 Da. Calc. 313.166451 Da, dev. 3 ppm.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][S:5][C:6]=1[C@@H:7]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:8]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14].CN(C1CCCCC1)C1CCCCC1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:29]([O:28][C:26]([NH:25][C@@H:7]1[C:6]2[S:5][CH:4]=[N:3][C:2]=2/[C:11](=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])/[CH2:10][CH2:9][C@H:8]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)/C=C/CC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1scnc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COC(=O)/C=C1\CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2scnc21
Temperature: 140 °C
Yield: 29 %

Procedure:
A mixture of (6S,7S,E)-methyl 7-(4-bromothiazol-5-yl)-7-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)hept-2-enoate (0.217 g, 0.409 mmol), bis(tri-t-butylphosphine)palladium (0) (0.021 g, 0.041 mmol) and methyl dicyclohexylamine (0.096 mL, 0.450 mmol) in dioxane (10 mL) (degassed with nitrogen) was heated at 140° C. under microwave radiation for 1 h under nitrogen. The solvent was removed under vacuum and the product was purified by flash chromatography eluting with ethyl acetate in hexane from 0 to 45% to afford the desired product (53.4 mg, 29%), (M+H=451.20), as well as the isomerized product (double bond moved into the ring) (108.8 mg, 59%) as the major component.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:5][CH:6]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:19]2([CH3:20])[CH:14]([CH:15]([O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])=[CH2:4].C(O)(=O)C(C(C(O)=O)O)[OH:36]>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[O:1]1[C@@:3]([CH2:4][OH:36])([CH2:5][CH:6]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28])[CH2:7][CH2:8][C@H:9]([C@@H:11]2[C@:19]3([CH3:20])[CH:14]([CH:15]([O:21][Si:22]([CH3:23])([CH3:24])[CH3:25])[CH2:16][CH2:17][CH2:18]3)[CH2:13][CH2:12]2)[CH3:10])[CH2:2]1
Reactant: C=C(CO)CC(CC[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C)O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: C[C@H](CCC(C[C@@]1(CO)CO1)O[Si](C)(C)C(C)(C)C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -20 °C
Yield: 94 %

Procedure:
A 20 ml amount of dichloromethane was placed in a 200 ml eggplant-shaped flask, 1.36 ml of titanium tetraisopropoxide was added, then the solution was cooled to -20° C. and stirred. Thereafter, 1.05 g of D(-)-diethyl tartrate dissolved in 5 ml of dichloromethane and the solution stirred at -25° C. for 20 minutes was placed and then, 2.14 g of the compound (4-10), (7R)-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-octene, dissolved in 10 ml of dichloromethane, was added, then the solution was stirred for 30 minutes. Further, 4.3 ml of t-butyldiperoxide was added and the solution was stirred at the same temperature for 30 minutes. The reaction solution was poured into 20 ml of a 10% aqueous solution of tartaric acid, the solution was stirred at that temperature for 30 minutes and at room temperature for 1 hour, then separation was performed and extraction performed from the aqueous layer by dichloromethane. The organic layer was washed by a 10% aqueous solution of tartaric acid and saturated saline and was dried over anhydrous magnesium sulfate. After filtration by Celite, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 50 ml of ether, 18 ml of 1N sodium hydroxide was added, then the solution was stirred under ice cooling for 1 hour. After separation, extraction was performed from the aqueous layer by ether. The organic layer was washed with saturated saline, then was dried over anhydrous magnesium sulfate, then filtered by Celite. The filtrate was concentrated under reduced pressure to obtain 2.40 g of a crude product. This was purified by a silica gel column (IR-60, 200 g, hexane/ethyl acetate=15/1 to 4/1) to obtain the desired product (4-11), (7R, 2R)-1,2-epoxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-octane in an amount of 2.08 g (yield 94%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][N:4]=1.[NH2:8][CH2:9]CCN.[CH3:13][NH:14][C:15]([NH:17][CH2:18][CH2:19]CNCC1C=CSN=1)=[S:16]>>[CH3:13][NH:14][C:15]([NH:17][CH2:18][CH2:19][NH:8][CH2:9][CH2:2][C:3]1[CH:7]=[CH:6][S:5][N:4]=1)=[S:16]
Reactant: CNC(=S)NCCCNCc1ccsn1
Reactant: NCCCN
Reactant: BrCc1ccsn1
Product: CNC(=S)NCCNCCc1ccsn1

Procedure:
In addition, using in the procedure of Example 40(a), 3-bromomethylisothiazole and 1,3-diaminopropane as the starting materials, the product is N-methyl-N'-[3-(3-isothiazolylmethylamino)propyl]thiourea.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:1][CH2:25][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: CCOC(=O)CC(C)Br
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Product: CCOC(=O)CCCNc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 12.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (160 mg, 0.76 mmol) and ethyl 3-bromobutanoate (0.01 mL, 0.91 mmol) to provide 460 (32 mg, 13% yield) as a white powder. LC-MS (M+H=326, obsd.=326). 1H NMR (400 MHz, DMSO-D6) δ 8.53 (ddd, J=1.7, 6.4, 9.7, 2H), 8.03 (d, J=8.6, 1H), 7.27 (m, 2H), 6.88 (dd, J=2.1, 8.7, 1H), 6.14 (s, 2H), 4.47 (t, J=6.9, 2H), 3.97 (q, J=7.1, 2H), 2.33 (t, J=7.4, 2H), 1.95 (p, J=7.3, 2H), 1.12 (t, J=7.1, 3H).
Reaction SMILES: N(CCN)=[N+]=[N-].C(N(CC)CC)C.[CH:14]1[C:19](N=C=S)=[CH:18][C:17]2[C:23]([O:25][C:26]3([C:36]4[CH:37]=[CH:38][C:39]([OH:41])=[CH:40][C:35]=4[O:34][C:28]4[CH:29]=[C:30]([OH:33])[CH:31]=[CH:32][C:27]3=4)[C:16]=2[CH:15]=1)=[O:24]>ClCCl>[CH:14]1[CH:19]=[CH:18][C:17]([C:23]([OH:25])=[O:24])=[C:16]([C:26]2[C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=3[O:34][C:35]3[C:36]=2[CH:37]=[CH:38][C:39]([CH:40]=3)=[O:41])[CH:15]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 21 h
Yield: 99.1 %

Procedure:
Under argon atmosphere, to a solution of 2-azidoethylamine (16) (˜50%, 1H NMR) (synthesized by the method described in Non-Patent Document: R. Srinivasan, L. P. Tan, H. Wu, P. Yang, K. A. Kalesh, S. Q. Yao, Org. Biomol. Chem. 2009, 7, 1821-1828) (200 mg, ˜1.16 mmol) in dichloromethane (5 mL) were successively added triethylamine (70.0 μL, 502 μmol) and fluorescein isothiocyanate isomer I (FITC, 17, commercial product) (90%, HPLC) (100 mg, 231 μmol) at room temperature. After stirring for 21 hours at the same temperature, the reaction solution was concentrated under reduced pressure using an evaporator. The residue was purified by flash column chromatography (silica-gel 30 g, dichloromethane/methanol=9/1) to give 1-(2-azidoethyl)-3-(5-fluoresceinyl)thiourea (18) (109 mg, 229 μmol, 99.2%) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]2.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[F-].[K+]>CN1CCCC1=O>[C:20]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C1Cc2cccc(Br)c2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: [F-]
Agent: [K+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: COC(=O)C1Cc2cccc(-c3ccccc3)c2C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Methyl 4-bromo-2-indancarboxylate (510 mg), tributylphenyltin (881 mg), a tris(dibenzylideneacetone)dipalladium chloroform complex (41 mg) and tri-2-furylphosphine (19 mg) were dissolved in N-methylpyrrolidone (10 ml), and the mixture was stirred at 70° C. for 3 hours and allowed to cool. To the reaction solution was added a saturated potassium fluoride solution and the solution was stirred at room temperature for 30 minutes followed by filtering through Celite. The filtrate was extracted with ether. The organic layers was washed with saturated aqueous sodium bicarbonate and saturated brine and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled away under a reduced pressure. The resultant residue was purified by column chromatography on silica gel (hexane: ethyl acetate=4:1) to obtain methyl 4-phenyl-2-indancarboxylate. The resultant ester was dissolved in methanol to which 1 N sodium hydroxide was added to hydrolyze. Methanol was distilled away under a reduced pressure. To the resultant residue was added 1 N hydrochloric acid. The product was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled away to obtain the title compound (351 mg) (melting point: 97-102° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[CH:5]=[C:4]([Cl:17])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:27]1([C:33]2[CH:37]=[C:36]([CH2:38][NH2:39])[O:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)CCC>[Cl:17][C:4]1[N:3]=[C:2]([NH:39][CH2:38][C:36]2[O:35][N:34]=[C:33]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:37]=2)[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[CH:5]=1
Reactant: CC(C)c1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Reactant: NCc1cc(-c2ccccc2)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)c1cc(Nc2cc(Cl)nc(NCc3cc(-c4ccccc4)no3)n2)n[nH]1
Temperature: 90 °C
Reaction time: 30 h
Yield: 44.6 %

Procedure:
To a solution of 2,6-dichloropyrimidin-4-yl-(5-isopropyl-1H-pyrazol-3-yl)-amine (19.44 g, 71.7 mmol) in 1-butanol (200 mL) was added diisopropylethylamine (23.7 mL, 143 mmol) and 3-phenylisoxazol-5-ylmethylamine (15.0 g, 86.1 mmol). The mixture was stirred at 90° C. for 30 h, then concentrated on a rotary evaporator. The residue was taken up in 100 mL of methanol and boiled until the volume reached around 50 mL. The solution was allowed to cool to room temperature and then placed in the refrigerator overnight. The solid that formed was collected by filtration, while the filtrate was concentrated on a rotary evaporator, heated to boiling in methanol and cooled overnight in the refrigerator. This solid was collected and the filtrate was subjected to methanol recrystallization a third time. The three solids were combined to give the desired product (13.1 g, 45%) as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[O:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][O:10]2)=[CH:4][C:3]=1[F:20].[C:21]([Cu])#[N:22]>CN1C(=O)CCC1>[C:21]([C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[O:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][O:10]2)=[CH:4][C:3]=1[F:20])#[N:22]
Reactant: N#C[Cu]
Reactant: CCCCCC1COC(c2cc(F)c(Br)c(F)c2)OC1
Solvent: CN1CCCC1=O
Product: CCCCC[C@H]1CO[C@H](c2cc(F)c(C#N)c(F)c2)OC1
Temperature: 25 °C

Procedure:
9.1 g (0.026 mol) of 2-(4'-bromo-3',5'-difluorophenyl)-5-pentyl-1,3-dioxane, 3.5 g (0.0039 mol) of CuCN and 78 cm3 of NMP were refluxed for 2 hours on a mantle heater. The reactant was cooled to room temperature, and after adding 10 cm3 of EDA, it was poured in ice water, extracted with hexane and washed with an aqueous EDA solution and water. The hexane was removed, the residue was treated in a silica gel column with chloroform as solvent, and the chloroform was removed. The residue was recrystallized from a mixture of methanol and water to obtain 1.7 g (0.006mol) of trans-2-(4'-cyano-3',5'-difluorophenyl)-5-pentyl-1,3-dioxane. The phase transition temperature of this compound as measured using DSC was as follows. ##STR16## (where, C indicates crystal, and I shows isotropic liquid).
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]3=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[F:29][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]3=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COCC1CN(c2ccc([C@H]3CC[C@H](O)CC3)cc2)C(=O)O1
Solvent: ClCCl
Product: COCC1CN(c2ccc([C@H]3CC[C@@H](F)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.5 g of (RS)3-[4-(trans-4-hydroxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one was dissolved in 10 ml of methylene chloride and treated at room temperature within 30 minutes with a mixture of 2.2 ml of diethylamino-sulfur trifluoride and 5 ml of methylene chloride. After stirring at room temperature for 2 hours the mixture was poured into 50 ml of ice-water and extracted twice with methylene chloride. The organic phase was washed with sodium chloride solution, sodium hydrogen carbonate solution and again with a sodium chloride solution, dried with magnesium sulfate and concentrated. The residue, 0.6 g of yellow honey, was chromatographed on a 30-fold amount of silica gel with methylene chloride-ethyl acetate (19:1) and yielded 80 mg of (RS)-3-[4-(cis-4-fluoro-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one as a colorless oil. 1H-NMR (CDCl3)ppm: 7.47 (d,2H), 7.24 (d,2H), 4.88 (bd,1H), 4.74 (m,1H), 4.04 (t, 1H), 3.91 (m,1H), 3.64 (d,2H), 3.43 (s,3H), 2.53 (m,1H), 2.16 (m,2H), 1.72 (m,6H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1([CH3:20])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][CH2:12][CH2:11]1>C(Cl)Cl>[CH3:6][C:5]([C:17]1[CH:18]=[CH:19][C:14]2[S:13][CH2:12][CH2:11][C:10]([CH3:9])([CH3:20])[C:15]=2[CH:16]=1)=[O:7]
Reactant: CC1(C)CCSc2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
37 g of aluminium chloride were suspended at 0° C. in 200 ml of methylene chloride and the suspension was treated slowly with 22 g of acetyl chloride while stirring vigorously. After 30 minutes, a solution of 49.4 g of 3,4-dihydro-4,4-dimethyl 2H-1-benzothiopyran in 150 ml of methylene chloride was added dropwise thereto. After stirring at 0° C. for 1 hour, the mixture was poured into ice/water and extracted with methylene chloride. The organic phase was washed neutral with 1N sodium hydroxide solution and water, dried and evaporated. The oily crude product was filtered over a short column of silica gel [eluting agent: hexane/ether (9:1)]. There were obtained 51.5 g of 3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl methyl ketone in the form of a colorless oil which solidifies upon standing in a refrigerator.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:5]=C[C:7]=1[C:8]([F:11])([F:10])[F:9].FC(F)(F)C1[N:23]=CC(N)=CC=1>>[F:9][C:8]([F:11])([F:10])[C:7]1[N:23]=[CH:5][C:4]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:3][CH:2]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)c(Cl)c1
Product: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1

Procedure:
The title compound was prepared by a method analogous to the method used to prepare Intermediate 39 using 6-(trifluoromethyl)pyridin-3-amine as the starting material. LCMS (R—SO3−)=226.2.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1([C:15]([OH:17])=[O:16])[CH2:12][C:11]1([Cl:14])[Cl:13]>CN(C)C(=O)C>[Cl:9][C:10]1([C:15]([O:17][CH3:1])=[O:16])[CH2:12][C:11]1([Cl:14])[Cl:13]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1(Cl)CC1(Cl)Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: COC(=O)C1(Cl)CC1(Cl)Cl
Reaction time: 20 h

Procedure:
Potassium carbonate (4.14 grams) and methyl iodide (3.74 ml) were added to a solution of 1,2,2-trichlorocyclopropane carboxylic acid (5.68 grams) and N,N-dimethylacetamide (50 ml). The reaction mixture was stirred for approximately 20 hours and then filtered. Ethyl ether (250 ml) was added to the filtrate and the resultant mixture was washed, dried, and evaporated in vacuo to the desired product, methyl 1,2,2-trichlorocyclopropane carboxylate. Structure of the product was confirmed by NMR.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O.[CH:19](O)(C)C>[Pd]>[CH3:3][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15]
Reactant: CC(C)O
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: Cc1c(C(=O)OC(C)C)[nH]c2ccccc12
Yield: 25 %

Procedure:
Sodium borohydride (0.23 g) was added to a stirred solution of ethyl 3-formylindole-2-carboxylate (0.2 g) and 10% palladium on carbon (0.11 g) in isopropanol (45 ml). The solution was heated at reflux for 4 hours, cooled and filtered through Celite. The solution was partitioned between ethyl acetate and water. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-10% ethyl acetate as eluent to give the desired end product as a white solid (0.05 g, 25%); NMR δ(CD3SOCD3) 1.3 (d, 6H), 2.5 (s, 3H), 5.2 (m, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.4 (m, 1H), 7.6 (d, 1H), 11.3 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 89.1 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate (27 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 34 mg of the titled compound (yield, 83%). 1H NMR (300 MHz, CDCl3): δ 3.28-3.31 (m, 4H), 3.75-3.78 (m, 4H), 4.15 (s, 4H), 6.90-6.97 (m, 3H), 7.24-7.42 (m, 5H), 7.80 (dd, J=9.0 and 6.0 Hz, 1H).