Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH:15]=O)[CH:10]=1>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[CH:15]=[N:7]/[S@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])[CH:10]=1
Reactant: O=Cc1cc(Cl)ccn1
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Liu, G. et al., J. Org. Chem., 64:1278 (1999). To a solution of S-(−)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in dichloromethane (14.13 mL) was added sequentially copper(II) sulfate (2.481 g, 15.54 mmol) and 4-chloropicolinaldehyde[1.0 g, 7.06 mmol, prepared according to a modified described by Negi (Synthesis, 991 (1996))]. The white suspension was stirred at rt. After 3 h, the brown suspension was filtered through CELITE®, eluting with DCM, to give a clear brown filtrate. Concentration gave a brown oil weighing 1.85 g. Purification by normal phase chromatography gave 1.31 g of 1A as a clear, yellow oil. MS (ESI) m/z: 245.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[Br:12]Br.O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:12])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: Nc1c(O)cc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To an ice-cold solution of 2-amino-5-nitro phenol (40.0 g, 259.52 mmol) in DCM (1.0 L), was added bromine (13.38 mL, 259.52 mmol) drop wise. The resulting reaction mixture was stirred at room temperature for 45 min. After the completion of the reaction (TLC monitoring), water was added and extracted with EtOAc (3×1.0 L). The combined organics was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude (55.0 g, 92%) was carried forward to the next step without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]([NH:12][CH2:13][C@H:14]1[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[O:11]>ClCCl>[CH3:8][O:9][C:10](=[O:11])[NH:12][CH2:13][C@H:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1
Reactant: COC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)NC[C@@H]1CNCCO1

Procedure:
To a 4:1 solution of dichloromethane and TFA (0.1 M) was added (R)-tert-butyl 2-(((methoxycarbonyl)amino)methyl)morpholine-4-carboxylate. After 1 h the solution was then concentrated in vaccuo to give crude (S)-methyl(morpholin-2-ylmethyl)carbamate which was used in the next step without further purification. LCMS (m/z) (M+H)=175.0, Rt=0.11 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]=1.[CH2:17]([Zn]CC)C.ICI>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]12[CH2:17][CH:12]1[CH:13]([OH:16])[CH2:14][CH2:15]2
Reactant: OC1C=C(c2ccc3ccccc3c2)CC1
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Product: OC1CCC2(c3ccc4ccccc4c3)CC12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-(naphthalen-2-yl)cyclopent-2-enol (2.32 g, 11.0 mmol) in dichloromethane (80 mL) was treated with diethylzinc (1.0 M in hexane; 54.6 mL, 54.6 mmol, 5.0 eq.). After 10 min, the reaction mixture was cooled to 0° C., treated with a solution of diiodomethane (4.51 mL, 55.5 mmol, 5.0 eq) in dichloromethane (20 mL) dropwise over 10 min and allowed to warm to ambient temperature. After 2 h, the reaction mixture was quenched with saturated aqueous ammonium chloride (40 mL). The reaction mixture was extracted with dichloromethane (3×40 mL). The combined organic phases were dried over magnesium sulphate, concentrated in vacuo to afford the desired compound in a quantitative yield as a white solid which was not further purified. 1H NMR (400 MHz, CDCl3) δ ppm 0.94-1.01 (1H, m, CH), 1.27-1.41 (2H, m, CH2), 1.98-2.02 (1H, m, CH), 2.10-2.20 (2H, m, CH2), 2.24-2.33 (1H, m, CH), 4.71-4.80 (1H, m, CH), 7.23-7.26 (1H, m, ArH), 7.40-7.48 (2H, m, ArH), 7.64 (1H, s, ArH), 7.72-7.84 (3H, m, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([N:25]=CC4C=CC(OC)=CC=4)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1>[NH2:25][C:18]([C:35]1[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:42][CH:43]1[CH2:44][CH2:45]1)[C:10](=[O:46])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(C=NC(c2ccc(Cl)nc2)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)c2cncn2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.4 %

Procedure:
To a solution of the title compound of Example 45, the slower moving enantiomer of 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-[(4-methoxy-benzylidene)amino]-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (1.41 g, 1.74 mmol) in THF (200 ml) was added 2N hydrochloric acid (20 ml) slowly. The reaction mixture was stirred at ambient temperature for 1.5 hour after which time it was cooled to 0° C. An aqueous solution of potassium carbonate was added followed by addition of ethyl acetate. After separation, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (1:99:0.1 to 2:98:0.1) as the eluents to afford the title compound as a white solid ( 0.844 g, 1.59 mmol, 90% yield). It is the faster eluting enantiomer of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one with >99% optical purity.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@H:12]2[CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[N:3]1.O.NN>C(O)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@H:12]2[CH2:14][NH2:15])=[N:3]1
Reactant: Cn1cc2c([C@H]3C[C@H]3CN3C(=O)c4ccccc4C3=O)cccc2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1cc2c([C@H]3C[C@H]3CN)cccc2n1

Procedure:
A crudely purified product of cis-2-{[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}-1H-isoindole-1,3(2H)-dione was dissolved in ethanol (6.5 mL), and hydrazine monohydrate (3 mL) was added. The mixture was heated under reflux for 20 min. The solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound as a crudely purified product.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1cccc(Cl)c1
Product: COc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1-c1c(Cl)cnn1C
Yield: 49.2 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (30 mg, 0.13 mmol) was treated with 3-Chlorophenyl isocyanate (17 μL, 0.14 mmol) in a similar manner to Example 1.53, providing 25 mg (46%) of Compound 91: LCMS m/z (%)=391 (M+H35Cl, 100), 393 (M+H37Cl, 70). 1H NMR (400 MHz, acetone-d6) δ: 8.51 (s, 1H), 8.41 (s, 1H), 7.84 (t, 1H), 7.71 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.49 (s, 1H), 7.49 (d, J=2 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 7.29 (t, 1H), 7.16 (d, J=8 Hz, 1H), 7.01 (d, J=8 Hz, 1H), 3.84 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[O:10]1CCC[CH2:11]1>>[CH3:9][C:4]1[N:3]=[C:2]2[NH:1][C:11](=[O:10])[O:8][C:7]2=[CH:6][CH:5]=1
Reactant: Cc1ccc(O)c(N)n1
Reactant: C1CCOC1
Product: Cc1ccc2oc(=O)[nH]c2n1

Procedure:
1.24 g (10 mmol) of 2-amino-3-hydroxy-6-methylpyridine are introduced into a three-necked round-bottomed flask. The contents are placed under argon. 20 ml of anhydrous tetrahydrofuran and then 2.43 g (15 mmol) of 1,1-carbonyldiimidazole are added. The mixture is heated to reflux for 6 hours. The reaction medium is evaporated. The crystals obtained are washed with water, filtered off and redissolved in hot methanol. The solution is filtered and re-evaporated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[CH:30]=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:41])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([Br:41])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nccn4cc3-c3ccccc3)cc2)CCC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(Br)n4cc3-c3ccccc3)cc2)CCC1
Yield: 127.2 %

Procedure:
To a solution of compound 4-1 (100 mg, 0.227 mmol) in CHCl3 (5 mL) was added NBS (40 mg 0.227 mmol.) and the mixture was heated to reflux for 2 hrs. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HCl(aq) and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 150 mg of 4-3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[CH:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([CH3:36])[CH:27]=1.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:35])[F:34])=[C:28]([CH3:36])[CH:27]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Cc1cc(Br)ccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
3,4-bis(Benzyloxy)-6-ethynylpyridazine (Intermediate 5; 3.0 g, 9.48 mmol), copper(I) iodide (0.181 g, 0.948 mmol) and bis(triphenylphosphine)-palladium(II) dichloride (0.333 g, 0.474 mmol) were combined. The reaction vessel was purged with nitrogen, followed by the addition of 4-bromo-2-methyl-1-(trifluoromethyl)benzene (2.493 g, 10.43 mmol), 1,8-diazabicycloundec-7-ene (8.66 g, 56.9 mmol) and tetrahydrofuran (32 ml) before the resulting mixture was allowed to stir at room temperature overnight. The reaction was quenched with brine and extracted into ethyl acetate (×2) and the combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to afford a dark brown gum. The gum was purified by column chromatography (silica, 0-50% ethyl acetate in petrol) to afford 3,4-bis(benzyloxy)-6-((3-methyl-4-(trifluoromethyl)phenyl)-ethynyl)pyridazine as a dark brown oil (1.22 g, 27%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH2:5]2.C([Li])CCC.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2([OH:69])[C@H:35]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:34]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:33]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@@H:32]([CH2:60][O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[O:31]2)=[CH:26][C:23]=1[CH:24]=[O:25].[Li]>C1COCC1.C1(C)C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2([OH:69])[C@H:35]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@@H:34]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:33]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C@@H:32]([CH2:60][O:61][CH2:62][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[O:31]2)=[CH:26][C:23]=1[C:24]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH2:5]2)=[O:25]
Reactant: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Reactant: Brc1ccc2c(c1)CCC1(CCC1)O2
Agent: [Li]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C(=O)c1ccc2c(c1)CCC1(CCC1)O2
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a stirred solution of 6-bromospiro[chromane-2,1′-cyclobutane] (0.563 g, 2.23 mmol) in THF (3 mL) at −78° C. was added n-butyl lithium (1.45 mL, 2.23 mmol) and stirred for 1 h. Compound obtained in step III (0.3 g, 0.45 mmol) in toluene (3 mL) was cooled to −78° C. and lithium salt prepared above was added to this at −78° C. This reaction mixture was stirred for 1 h, quenched with sat. NH4Cl (10 mL) and extracted with ethyl acetate (2×20 mL). The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, concentrated and purified by silica gel column chromatography to furnish [2-methoxy-5-[(3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)-2-hydroxytetrahydropyran-2-yl]phenyl]-spiro[chromane-2,1′-cyclobutane]-6-yl-methanone (0.250 g).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>>[CH:15]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1)=[CH:16][CH3:17]
Reactant: C=CCBr
Reactant: Oc1ccc2oc3ccccc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC=COc1ccc2oc3ccccc3c2c1

Procedure:
A solution of 2-hydroxydibenzofuran (2.0 grams) was treated with allyl bromide (1.2 mL) and potassium carbonate (1.5 grams). The mixture was stirred over night at 60°. The reaction was partitioned between methylene chloride and water. The organic was washed once with water and dried over sodium sulfate. The organic layer was filtered and concentrated to an oil which was chromatographed over silica gel to afford the title compound.
Reaction SMILES: [Cl:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](O)[CH:4]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:5]1[CH:4]=[C:3]([C:2]([Cl:1])([F:20])[F:19])[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 85.6 %

Procedure:
This compound was prepared as described in Example 19: 75 g (0.235 mol) of product of Example 5, 50.29 g (55 ml, 0.469 mol) of 2,6-lutidine and 252.66 g (214 ml, 2.3 mol) of phosphorus oxychloride were reacted affording 68 g of a black oil. Crude was purified by kugelrohr distillation at 200 Pa, pot temperature 110° C., to give 48 g (60%) of product as a yellow oil; nD25 1.4466.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol (353 mg, 1.05 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (200 mg, 1.05 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (302 mg, 1.58 mmol) and 1-hydroxy-1H-benzotriazole (161 mg, 1.05 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (166 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:34])([CH:31]([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][N:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[C:29](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:34])[CH:31]([F:33])[F:32])=[CH:24][CH:23]=2)[N:26]=[N:27]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]nnn1-c1ccc(OCC(F)(F)C(F)F)cc1
Product: C[C@@H](n1nnn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1

Procedure:
In the same manner as in Reference Example 5, starting from 1.39 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.63-g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-5(1H,4H)-tetrazolone, 1.27 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-5(1H,4H)-tetrazolone was obtained as a colorless oil.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[C:14]2[O:15][C:16]3[C:21]([C:22]4([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([C:4]([N:25]2[CH2:26][CH2:27][C:22]3([C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[C:14]=4[O:15][C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc2c1Oc1ccccc1C21CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1Oc1ccccc1C21CCN(C(=O)C2CC2)CC1
Reaction time: 8 h

Procedure:
A solution of cyclopropane carboxylic acid chloride (1.2 ml.) in methylene chloride (10 ml.) is added dropwise with stirring to a mixture of 4-methoxyxanthene-9-spiro-4'-piperidine (2.0 g.) and triethylamine (1.6 ml.) in methylene chloride (40 ml.) at 5° C. The mixture is allowed to reach room temperature and stirred overnight. The mixture is washed with 3 N hydrochloric acid, 3 N sodium hydroxide solution and water, dried MgSO4 and the methylene chloride evaporated to dryness, to give 1'-cyclopropylcarbonyl-4-methoxyxanthene-9-spiro-4'-piperidine (I.R. amide band 1620 cm.-1 ; t.l.c.--single spot) which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[CH:3]=1.[Cl:11]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH2:10][Cl:11])=[CH2:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cc(Cl)ccn1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: C=C(CCl)c1cc(Cl)ccn1
Temperature: 25 °C
Yield: 17.1 %

Procedure:
A mixture of 4.3 g of 4-chloro-2-isopropenylpyridine, 3.8 g of N-chlorosuccinimide and 10 ml of carbon tetrachloride was stirred in an oil bath at 150° to 160° C. for hour. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane-ethyl acetate 20:1) to obtain 0.90 g of the objective compound.
Reaction SMILES: CON(C)[C:4](=[O:30])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:29])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:8][CH2:7]1.O1CCC[CH2:33]1.C[Mg]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:29][N:20]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4](=[O:30])[CH3:33])[CH2:7][N:8]=1)=[CH:19]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22]
Reactant: CON(C)C(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 10 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
N-Methoxy-N-methyl-2-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetamide (0.20 g) was dissolved in absolute tetrahydrofuran (20 mL), and a 12% methylmagnesium bromide tetrahydrofuran solution (1.4 mL) was added under ice-cooling. The mixture was stirred at 10° C. for 5 hr under ice-cooling, acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=35:65-50:50), and the obtained colorless oil was crystallized from ethyl acetate-hexane-to give the title compound (121 mg, yield: 67%) as colorless crystals. MS:434(MH+). melting point 123-124° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([CH3:16])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Mg]Cl>C1COCC1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni]>[C:2]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[Mg]Cl
Reactant: Clc1ccccc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Solvent: C1=CCCC=CCC1
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1
Reaction time: 15 h
Yield: 96.3 %

Procedure:
The general procedure from Example 16 was followed using chlorobenzene (1.126 g, 10.0 mmol) and o-tolylmagnesium chloride (15 mL, 15.0 mmol) with Ni(COD)2 (83.4 mg, 0.303 mmol) and (Me3C)2PH(O) (50.0 mg, 0.303 mmol) in 20.0 mL of THF. After 15 h at room temperature, the reaction mixture was quenched with 10 mL of H2O. The mixture above was extracted with 3×50 mL of diethyl ether. The combined ether extracts were dried over MgSO4, filtered, and the ether and THF removed from the filtrate by rotary evaporation. The resulting residues were chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 1.62 g (96% yield) of 2-phenyltoluene. It was >95% pure by 1H NMR. 1H NMR (500 MHz, CDCl3): δ 7.62-7.47 (m, 9H), 2.50 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 142.0, 141.9, 135.2, 130.3, 129.7, 129.1, 128.0, 127.2, 126.7, 125.7, 20.4. ppm.