Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](O)(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:3][CH:4]=1
Reactant: CCCCCCCC(=O)O
Reactant: c1ccc(-c2cnco2)nc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCC(=O)c1ncc(-c2ccccn2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
(189) A solution of 2-(oxazol-5-yl)pyridine (111 mg, 0.76 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.84 mmol, 0.33 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.52 mmol, 3.0 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.76 mmol, 145 mg) was added, and the solution was stirred for 10 min at 0° C. A separate flask was charged with octanoic acid (2 equiv, 1.52 mmol, 219 mg, 0.24 mL) in anhydrous CH2Cl2 (4.2 mL), and to this solution cooled to 0° C. under N2 was added oxalyl chloride (5 equiv, 7.6 mmol, 0.96 g, 0.66 mL). After stirring at rt for 2 h, the solution was concentrated under reduced pressure and dissolved in anhydrous THF (1.5 mL). The solution of octanoyl chloride was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)octan-1-one (189) (107 mg, 0.39 mmol, 52% yield) as a light brown powder: mp 56° C; 1H NMR (CDCl3, 250 MHz) d 8.63 (br d, J=4.8 Hz, 1H), 7.85-7.74 (m, 3H), 7.28 (br t, J=5.1 Hz, 1H), 3.08 (t, J=7.3 Hz, 2H), 1.84-1.67 (m, 2H), 1.47-1.17 (m, 8H), 0.85 (br t, J=6.6 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.5, 157.3, 153.1, 150.0, 146.2, 137.0, 127.8, 124.1, 120.3, 39.1, 31.6, 29.0, 28.9, 24.0, 22.5, 14.0; IR (KBr) umax 2926, 2849, 1694, 1601, 1499, 1470, 1426, 1382 cm−1; MALDI-FTMS (DHB) m/z 273.1595 (C16H20N2O2+H+ requires 273.1597).
Reaction SMILES: [CH:1]([C:3](Cl)([CH3:9])[CH2:4][CH:5]([Cl:8])[C:6]#[N:7])=O.[ClH:11]>[Cu].[Ta]>[Cl:11][C:6]1[C:5]([Cl:8])=[CH:4][C:3]([CH3:9])=[CH:1][N:7]=1
Reactant: Cl
Reactant: CC(Cl)(C=O)CC(Cl)C#N
Agent: [Cu]
Agent: [Ta]
Product: Cc1cnc(Cl)c(Cl)c1
Yield: 64.8 %

Procedure:
18 g of the 4-formyl-2,4-dichlorovaleronitrile obtained in Example 3(a) and 0.1 g of copper powder are heated in a tantalum autoclave for 5 hours to 150° C. after the introduction of 10 g of dry HCl gas under pressure. After they have cooled, the contents of the autoclave are subjected to steam distillation, affording 10.5 g of 2,3-dichloro-5-methylpyridine in the form of colourless crystals with a melting point of 46°-47° C. 1H-NMR spectrum (100 MHz in CDCl3) in ppm: 8.13 (d, 1H, H on C-6); 7.59 (d, 1H, H on C-4); 2.34 (s, 3H, --CH3).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:24]([CH:25]2[CH2:30][CH2:29][S:28][CH2:27][CH2:26]2)[N:23]=[C:22]([CH3:31])[CH:21]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:24]([CH:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)[N:23]=[C:22]([CH3:31])[CH:21]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:11])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCSCC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(C2CCSCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as brown liquid which was used in the next step without further purification. MS (ESI): m/z=470.0 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1.[F-:20].[Cs+]>CS(C)=O>[F:20][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1
Reactant: [F-]
Reactant: O=C(O)c1nn(-c2cc(I)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(O)c1nn(-c2cc(F)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 200 °C
Yield: 69.8 %

Procedure:
To a solution of (1aR,5aR)-2-(4-iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (174 mg, 0.47 mmol) in DMSO (2.5 mL) was added cesium fluoride (500 mg, 3.29 mmol). The mixture was heated under microwave irradiation at 200° C. for 60 min. The mixture was purified by preparative HPLC to give the title compound as a white solid (85 mg). LCMS m/z=260.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[Br:14]Br>>[Br:14][CH2:12][C:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1Cl
Product: O=C(CBr)c1cc([N+](=O)[O-])ccc1Cl
Yield: 96 %

Procedure:
Procedure A was performed with 2′-chloro-5′-nitro-acetophenone (4.0 g, 20 mmol) and bromine (1.13 ml, 22 mmol). The crude product was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (0:1 to 1:4) to afford the desired 2-bromo-2′chloro-5′-nitroacetophenone (5.4 g, 19.2 mmol).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][SH:29]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:29][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: CN(C)CCS
Product: Cc1ccc(NC(=O)Nc2ncc(SCCN(C)C)s2)c(C(=O)C2CCCC2)c1
Yield: 30.1 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(2-dimethylamino-ethylsulfanyl)-thiazol-2-yl]-urea (130 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-dimethylamino-ethanethiol (210 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[N+:25]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1N

Procedure:
Prepared from (3-nitro-4′-trifluoromethoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B9) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white solid (371 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][N:6]=[CH:5]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl.[Cu]Cl.CN1CCCC1=O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([OH:12])=[N:7][N:6]=[CH:5]3)=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: Oc1nncc2cc(Br)ccc12
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Oc1nncc2cc(Oc3ccc(F)cc3)ccc12
Temperature: 120 °C

Procedure:
A 100-mL round-bottom flask under argon was charged with 6-bromophthalazin-1-ol (0.5 g, 2 mmol), 4-fluorophenol (0.4 mL, 4 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.04 mL, 0.2 mmol), cesium carbonate (1 g, 4 mmol), and 1-methyl-2-pyrrolidinone (4 mL), followed by copper (I) chloride (0.1 g, 1 mmol). The reaction mixture was heated at 120° C. for 20 h. The reaction mixture was cooled, diluted with dichloromethane, and washed with water. The pH of the aqueous layer was adjusted to ˜7 with saturated aqueous NaHCO3 and extracted with DCM (2×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash chromatography eluting with 1%, 2%, 3%, and 5% MeOH/CHCl3 gave the title compound. MS (ES+): 257.1 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH:16]([C:20]([OH:22])=O)[CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C=O)C.C(N(CC)CC)C.[NH2:35][CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45])=[O:38]>C(Cl)Cl.O>[Cl:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:37](=[O:38])[CH2:36][NH:35][C:20]([CH:16]1[O:17][CH2:18][CH2:19][N:14]([CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:15]1)=[O:22]
Reactant: NCC(=O)c1ccccc1Cl
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
Oxalyl chloride (0.765 mL, 8.73 mmol) was added to a suspension of 4-(phenylmethyl)-2-morpholinecarboxylic acid (1.288 g, 5.82 mmol) and DMF (0.090 mL, 1.165 mmol) in CH2Cl2 (80 mL) at 0° C. over 10 minutes. The reaction mixture was stirred at 25° C. for 2 h, and then concentrated. The residue was dissolved in CH2Cl2 (80 mL), then triethylamine (2.029 mL, 14.56 mmol) and 2-amino-1-(2-chlorophenyl)ethanone (1.2 g, 5.82 mmol) were added to the brown solution at 0° C. The mixture was stirred at 25° C. for 3 hours, and at this time, water (150 mL) was added. The mixture was extracted with EtOAc (3×100 mL), and the combined organics were dried with anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 50% EtOAc in petroleum ether to afford the title compound (350 mg) as a pale yellow solid. LC-MS (ES) m/z=373 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([O:17][CH:18]([CH3:20])[CH3:19])[CH2:15][C:14](=[O:21])[CH2:13][CH:12]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N-:29]=[N+]=[N-].[Na+]>C(#N)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@:6]3([C@@H:12]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[CH2:13][C:14](=[O:21])[NH:29][CH2:15][C@H:16]3[O:17][CH:18]([CH3:20])[CH3:19])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)OC1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)O[C@@H]1CNC(=O)C[C@H](c2cccc(Cl)c2)[C@@]12C(=O)Nc1cc(Cl)ccc12
Yield: 9.8 %

Procedure:
In a manner similar to the method described in example 2 (method A), rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-(1-methylethoxy)-spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (138.0 mg, 0.33 mmole) was treated with NaN3 (54.0 mg, 0.83 mmole) in the presence of TiCl4 (1.0 M in CH2Cl2, 0.33 mL) (Aldrich) in acetonitrile (10 mL) at reflux for 6 hrs, followed by chiral chromatograph to give (3S,4S,5R)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-(1-methylethoxy)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (14.0 mg): HRMS (ES+) m/z Calcd for C22H22Cl2N2O3+H [(M+H)+]: 433.1080, Found: 433.1080; (3R,4R,5S)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-(1-methylethoxy)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (14.0 mg): HRMS (ES+) m/z Calcd for C22H22Cl2N2O3+H [(M+H)+]: 433.1080, Found: 433.1080;
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:18])[CH3:4].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C.C(Cl)Cl>CNC1(NC)C=CN=CC1>[C:19]([O:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:18])[CH3:4])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: CNC1(NC)C=CN=CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Yield: 99.1 %

Procedure:
(R)-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (19 g, 0.073 mol), acetic anhydride (10 g, 0.1 mol), triethylamine (30 g, 0.3 mol), 4,4-dimethylaminopyridine (200 mg, 0.002 mol) and methylene chloride (500 mL, 8 mol) were stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified flash chromatography to afford the title compound as a yellow oil (21 g, 100% yield).
Reaction SMILES: COC(=O)[NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:6]=1[C:13]#[C:14][Si](C)(C)C.[O-]CC.[Na+].Cl>C(O)C.[Cl-].[Na+].O>[Br:12][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][C:9]=1[CH3:11])[NH:4][CH:14]=[CH:13]2
Reactant: COC(=O)Nc1cc(C)c(Br)cc1C#C[Si](C)(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc2[nH]ccc2cc1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
(4-Bromo-5-methyl-2-trimethylsilanylethynyl-phenyl)-carbamic acid methyl ester (506 mg, 1.49 mmol) was dissolved in ethanol (6 ml). Sodium ethoxide (20% solution in ethanol, 1.17 ml, 2.97 mmol) was added and the mixture was stirred at 70° C. overnight. The reaction solution was poured into ice water, and 1 N hydrochloric acid and saturated brine were added to this mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give 5-bromo-6-methyl-1H-indole (207 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.CO.C(Cl)Cl>C1COCC1.CCO.[Ni]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:14]2[N:13]=[CH:12][N:11]=[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:15]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ncn2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Nc2cc(Oc3ccc(N)cc3)ncn2)cc1

Procedure:
(4-Methoxy-phenyl)-[6-(4-nitro-phenoxy)-pyrimidin-4-yl]-amine (Stage 47.2; 1.06 g, 3.13 mmol) dissolved in THF/EtOH (1:2; 27 mL) is hydrogenated in the presence of Raney-Ni (0.2 g) during 36 h. After filtering off the catalyst and washing with EtOH (20 mL), the solvent is evaporated under reduced pressure and flash chromatographed (silica gel, 4.5×26 cm, MeOH/CH2Cl2=5:95) giving a white solid: M+H=309.1; 1H-NMR (400 MHz, DMSO-d6): 9.23 (s, 1H, NH-pyrimidinyl), 8.22 (s, 1H, pyrimidine), 7.40/6.85/6.79/6.57 (d/d/d/d, 9.0 Hz, 8H, phenyl-oxo/phenyl-OMe), 5.81 (s, 1H, pyrimidinyl), 5.07 (s, 2H, NH2), 3.72 (s, 3H, CH3—O); Rf (MeOH/CH2Cl2=1:9): 0.44; HPLC (System 1): 3.45 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOC(C)=O.[Pd]>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCCC=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: ClCCCC(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 100.1 %

Procedure:
To a solution of 4-chloro-1,1-diphenyl-1-butene (200 mg, 0.82 mmol) in EtOAc (8.0 mL) was added Pd/C (10%, 50 mg). The reaction mixture was stirred under H2 atmosphere for 15 h at 20° C. The reaction mixture was filtered through celite and the filterate was concentrated to give the analytically pure 4-Chloro-1,1-diphenylbutane (201 mg, 99%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ1.70-1.81 (m, 2H), 2.16-2.25 (m, 2H), 3.54 (t, 2H, J=6.5 Hz), 3.91 (t, 1H, J=7.8 Hz), 7.15-7.31 (m, 10H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][S:9]([N:12]2[CH2:17][C@H:16]([CH3:18])[NH:15][C@H:14]([CH3:19])[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH2:20].CCO.C([O-])([O-])=O.[Na+].[Na+].[C:30]1(B(O)O)[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1>C1(C)C=CC=CC=1.CCOC(C)=O.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:30]1([C:2]2[CH:7]=[C:6]([CH2:8][S:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[NH:15][C@H:14]([CH3:19])[CH2:13]3)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=2[NH2:20])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: OB(O)C1=CCCCC1
Reactant: C[C@@H]1CN(S(=O)(=O)Cc2ccc(N)c(Br)c2)C[C@H](C)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc(N)c(C3=CCCCC3)c2)C[C@H](C)N1
Temperature: 80 °C
Yield: 85.9 %

Procedure:
A solution of 356 mg (0.983 mmol) of 2-bromo-4-(cis-3,5-dimethyl-piperazine-1-sulfonylmethyl)-phenylamine (as prepared in the previous step) in toluene (8 mL) and EtOH (4 mL) was treated with 3.93 mL (7.86 mmol) of 2.0 M aqueous Na2CO3 and 186 mg (1.47 mmol) of cyclohex-1-enylboronic acid. The mixture was degassed via sonication, placed under Ar, treated with 170 mg (0.147 mmol) of Pd(PPh3)4, and heated to 80° C. for 4.3 h. The mixture was cooled to RT, diluted with EtOAc (10 mL), and washed with saturated aqueous NaHCO3 (1×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 0-4% MeOH—CH2Cl2 afforded 307 mg (86%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 7.01 (dd, 1H, J=8.0, 2.0 Hz), 6.99 (d, 1H, J=2.0 Hz), 6.57 (d, 1H, J=8.0 Hz), 5.77-5.72 (m, 1H), 4.07 (s, 2H), 3.85 (br s, 2H), 3.55-3.47 (m, 2H), 2.88-2.77 (m, 2H), 2.26-2.13 (m, 6H), 1.81-1.73 (m, 2H), 1.72-1.64 (m, 2H), 0.99 (d, 6H, J=6.0 Hz).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([NH:12]O)[CH2:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C[Mg+].[Br-].CCOCC.C([O-])(O)=O.[Na+].[C:36](NO)([CH3:39])([CH3:38])[CH3:37]>C(=S)=S.CC(C)=O>[C:36]([NH:12][C@@H:8]1[CH2:7][C:6]2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=[C:2]([F:1])[C:11]=2[O:10][CH2:9]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COc1ccc(F)c2c1C[C@@H](NO)CO2
Reactant: CC(C)(C)NO
Agent: C[Mg+]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: S=C=S
Solvent: CC(C)=O
Product: COc1ccc(F)c2c1C[C@@H](NC(C)(C)C)CO2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(R)-8-Fluoro-3-hydroxylamino-5-methoxy-3,4-dihydro-2H-1-benzopyran (6.30 g, 29.6 mmol), anhydrous sodium sulfate (20 g) and acetone (500 mL) were refluxed under nitrogen for 4 days until TLC indicated a complete reaction. The salt was filtered off, ether (300 mL) was added to the filtrate and the solution, still containing finely suspended salt, was filtered through a sintered glass filter (grade 4). The clear filtrate was concentrated in vacuo. Dry (sieves 3 Å) benzene (50 mL) was added and the resulting solution was concentrated in vacuo (finally on the pump). The glassy residue was dissolved in dry (sieves 3 Å) benzene (150 mL) under nitrogen and the solution was cooled on an ice-bath (+4° C.). MeMgBr in Et2O (3.0M; 32.0 mL, 96 mmol) was added to the stirred solution above at a rate that kept the internal temperature below +5° C. (the reaction is exothermic). After the addition was complete (30 min) the solution was stirred at +4° C. for 0.5 h. The cooling bath was taken away and 15 min later the solution was poured on saturated NaHCO3 and ice (300 mL total). The mixture was washed repeatedly with ether (3×150 mL). The organic phases were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica [eluent: EtOAc (2 and 10%) in CHCl3 ] gave 2.9 g. of the tert-butyl hydroxylamine derivative. The latter was dissolved in CS2 (100 mL) under nitrogen and the solution was stirred at room temperature for 4.5 h. The solvent was evaporated in vacuo to give an orange oil. Acetone (approx. 50 mL) was added and the solution was stirred for a short time (15 min) at room temperature (to precipitate elemental sulfur), then filtered and concentrated to give an oil. Flash chromatography on silica [eluent: EtOAc (10 to 25%) in hexane] gave 2.34 g (31% total yield) of the title compound as a yellow oil. [α]21D =-82.8° (C=1; CHCl3). GC-MS (70 eV) M=253 (53%).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(Cl)Cl.[CH3:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>O>[CH3:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)=[O:35])=[CH:32][CH:31]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)N2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2.34 ml of triethylamine were added to 50 ml of chloroform. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of chloroform solution containing 2.3 g of 4-methylbenzoyl chloride. After completion of addition, the reaction mixture was stirred for 30 minutes. After completion of reaction, 100 ml of chloroform and then a large amount of water was added to separate chloroform and the chloroform layer was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from chloroformether to give 1.8 g of 5-[4-(4-methylbenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 239.5°-240° C., colorless powders.
Reaction SMILES: C(O[N:5]=[C:6]([C:8]1[C:13]([OH:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[OH:16])[CH3:7])(=O)C.Cl>N1C=CC=CC=1>[CH3:7][C:6]1[C:8]2=[C:13]([OH:14])[CH:12]=[C:11]([CH3:15])[CH:10]=[C:9]2[O:16][N:5]=1
Reactant: CC(=O)ON=C(C)c1c(O)cc(C)cc1O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c2c(C)noc2c1
Yield: 47.2 %

Procedure:
To 1-(2,6-dihydroxy-4-methylphenyl)ethanone O-acetyloxime (Intermediate 18, 1.0 g) pyridine (10 ml) was added and the reaction mixture was stirred at reflux under N2 for 2 hours. After the addition of HCl (10.0 ml of a 5M aqueous solution), the mixture was extracted 3 times with Et2O and the gathered organic phases were washed with HCl (1M). The separated organic phase was then dried over sodium sulphate, filtered and evaporated to afford 345 mg of the title compound.