Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#N)=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].C[OH:30]>C(O)=O.O.[Ni].[Al]>[CH:1]([O:4][C:5](=[O:28])[NH:6][C@@H:7]1[CH2:27][C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:12]3[CH:13]=[CH:14][C:15]([CH:18]=[O:30])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccccn3)c3ccc(C#N)cc23)C1
Reactant: CO
Agent: [Ni]
Agent: [Al]
Solvent: O
Solvent: O=CO
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccccn3)c3ccc(C=O)cc23)C1
Temperature: 25 °C
Yield: 91 %

Procedure:
Dissolve (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (200 mg, 0.53 mmol) in 88% formic acid (10 ml) and water (1 mL). Add aluminum-nickel catalyst (50/50 wt %) and heat at 90° C. for 24 h. Add water (1 mL) and heat for an additional 24 h. After cooling to room temperature, add methanol and filter off the catalyst through Celite®. Dilute with ethyl acetate and basify to pH=10 using 10% potassium carbonate. Separate the phases and wash the organic phase with 10% potassium carbonate. Dry the organic portion over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound as an orange oil (181 mg, 91%). Use the crude product without further manipulation. MS (m/z): 378.2 (M+1).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N:20]=[C:19]([NH:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[N:18]=1)[CH2:27][CH2:26][CH2:25]3.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N+:20]([O-:4])=[C:19]([NH:30][CH2:31][CH2:32][N:33]([CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH3:39])[N:18]=1)[CH2:27][CH2:26][CH2:25]3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCN(CCC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
H2O2 (70%, 0.39 mL, ca. 7.7 mmol) was added dropwise to a stirred solution of TFAA (1.1 mL, 7.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 28 (253 mg, 0.8 mmol) and TFA (0.30 mL, 3.8 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 5° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 29 (134 mg, 50%) as a red solid: mp (MeOH/EtOAc) 142-145° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.46 (br s, 1H, NH), 3.54-3.60 (m, 2H, CH2N), 3.03-3.11 (m, 4H, H-6, H-8), 2.74 (dd, J=6.1, 5.9 Hz, 2H, CH2N), 2.43-2.47 (m, 4H, 2×CH2N), 2.16-2.24 (m, 2H, H-7), 1.45-1.54 (m, 4H, 2×CH2), 0.91 (t, J=7.4 Hz, 6H, 2×CH3); 13C NMR δ 155.5, 149.5, 145.7, 138.0, 129.6, 115.7, 111.6, 56.0 (2), 52.5, 39.1, 33.4, 32.4, 25.6, 20.4 (2), 11.8 (2). Anal. calcd for C18H27N5O2: C, 62.6; H, 7.9; N, 20.3. Found: C, 62.3; H, 8.0; N, 20.2%.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:38]=[CH:37][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:29])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH:65]2[CH2:67][O:66]2)=[CH:59][CH:58]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:31]([NH:30][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:37]=[CH:38][C:7]([CH2:6][CH2:5][NH:4][CH2:67][C@H:65]([OH:66])[CH2:64][O:63][C:60]4[CH:61]=[CH:62][C:57]([OH:56])=[CH:58][CH:59]=4)=[CH:8][CH:9]=3)[CH2:17][CH2:16]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1)=[O:29])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Solvent: O=CO
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 33.3 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]-N′-hexylurea formate (0.327 g 0.597 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.242 g, 0.598 mmol) according to Procedure G to give the title compound (0.180 g, 0.199 mmol).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[C:18]([C:31](OCC)=[O:32])=[CH:17]2.O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH:12][C:31]([C:18]2[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)=[O:32])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(Cl)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccc(Cl)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 0 °C

Procedure:
23.8 ml (47.57 mmol) of a 2M solution of trimethylaluminum in toluene are added to a solution, stirred at 20° C. under an argon atmosphere, of 4.48 g (34.89 mmol) of 6-chloro-3-aminopyridine in 317 ml of toluene. The solution is then brought to 120° C. and 10 g (31.71 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate are added in several steps (WO 2006/024776). The reaction mixture is refluxed for 4 hours and is then cooled to 0° C. 15 ml of water are added to the reaction medium, which is then extracted with twice 200 ml of ethyl acetate. The organic phases are combined and washed twice with 50 ml of water and once with 50 ml of a saturated sodium chloride solution, and then dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is triturated in 100 ml of ethyl ether, the product is filtered, and 10 g of expected product are recovered in the form of a powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:19]=1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([Cl:47])[C:33]=1[OH:48]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[CH:19]=2)=[CH:3][C:2]([C:36]2[CH:35]=[C:34]([Cl:47])[C:33]([OH:48])=[C:32]([Cl:31])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Yield: 15.2 %

Procedure:
Following general procedure A-1, {6-bromo-4-[3-(2-(pyrrolidin-1-yl)ethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (56 mg, 0.120 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.180 mmol) to afford the desired product (10 mg, 15%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.46 (s, 1H), 8.22 (dd, J=8.8, 1.9 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H), 7.90-7.85 (m, 1H), 7.66-7.59 (m, 1H), 7.58-7.53 (m, 1H), 7.47 (s, 1H), 7.42-7.36 (m, 1H), 7.19 (s, 2H), 3.72-3.63 (m, 2H), 3.45-3.37 (m, 2H), 3.18-3.04 (m, 4H), 2.92-2.84 (m, 1H), 2.20-2.08 (m, 2H), 2.08-1.97 (m, 2H), 1.31-1.13 (m, 4H); ESI MS m/z 546 [C31H29Cl2N3O2+H]+; HPLC 97.3% (AUC), tR=11.04 min.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.O>CS(C)=O>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:11][C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]1[O:4][CH3:3]
Reactant: Fc1ccccc1CCl
Reactant: CO[C@H]1CCCC[C@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CO[C@H]1CCCC[C@H]1OCc1ccccc1F
Temperature: 45 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
772 g (19.3 mol) of sodium hydroxide powder were added in portions to 1,672 g (12.8 mol) of cis-2-methoxycyclohexanol and 1,853 g (12.8 mol) of 2-fluorobenzyl chloride in 10 l of dimethylsulphoxide, whilst cooling with water. The mixture was stirred at 35° C. for 2 hours and at 45° C. overnight. Thereafter, it was cooled to 18° C., 10 l of petroleum ether were added and the mixture was discharged onto 10 ml of ice-water. The organic phase was separated off, extracted by shaking with water, dried over sodium sulphate and filtered and the filtrate was concentrated. The oily residue was distilled. 2,685 g (87.5% of theory) of cis-1-(2-fluorobenzyloxy)-2-methoxy-cyclohexane of boiling point 150° C./2 mm Hg were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH:13]([N:16](C(C)C)CC)(C)[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][CH:14]=[CH:13][N:16]=2)=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1-c1ncco1
Temperature: 135 °C

Procedure:
4-Bromo-2-ethyl-benzoic acid (6.8 g, 30 mmol), diisopropylethylamine (7.8 mL, 44.7 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 14 g, 37 mmol), and aminoacetaldehyde dimethyl ether (4 mL, 37 mmol) in 2:1 dichlormethane/dimethylformamide (120 mL) 5 h at room temperature. The solution was washed with several portions of water, then 1 N HCl(aq) and saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a crude light yellow oil. The residue was redissolved in Eaton's reagent (P2O5 in methanesulfonic acid, 100 mL), and the solution was heated at 135° C. under argon for 6 h. The solution was cooled to room temperature and carefully poured onto ice. The mixture was extracted with dichloromethane, and the organic layer was backwashed with saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a crude oil. The residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to pure brown liquid (3.16 g, 44%) 1H NMR (300 MHz, CDCl3): δ ppm 1.24 (t, J=7.54 Hz, 3H) 3.09 (q, J=7.54 Hz, 2H) 7.27 (s, 1H) 7.42 (dd, J=8.38, 1.98 Hz, 1H) 7.48 (d, J=2.07 Hz, 1H) 7.74 (s, 1H) 7.81 (d, J=8.48 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[CH:14]1([CH2:20][CH2:21][C@H:22]2[CH2:24][O:23]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH2:7]([O:6][CH2:5][C@H:2]([NH:1][CH2:24][C@@H:22]([OH:23])[CH2:21][CH2:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@H](CO)COCc1ccccc1
Reactant: C1CCC(CC[C@H]2CO2)CC1
Solvent: CCO
Product: OC[C@H](COCc1ccccc1)NC[C@@H](O)CCC1CCCCC1
Temperature: 80 °C
Yield: 57.2 %

Procedure:
Dissolve (R)-(+)-2-amino-3-benzyloxy-1-propanol (317 mg, 1.75 mmol) and 2-(S)-(2-cyclohexylethyl)-oxirane (270 mg, 1.75 mmol) in absolute ethanol (8 mL) and heat at 80° C. in a sealed glass pressure vessel overnight. Concentrate and purify (silica gel chromatography, eluting with 8:92 to 10:90 methanol:dichloromethane) to give the desired compound (336 mg, 57%).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([F:27])[C:22]=1[O:23][CH2:24][C:25]#[CH:26])[C:11]([N:13]1[CH:19]2[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:5]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[NH:13][C:11](=[O:12])[C:10]1[CH:20]=[C:21]([F:27])[C:22]([O:23][CH2:24][C:25]#[CH:26])=[C:8]([F:7])[CH:9]=1)#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: C#CCOc1c(F)cc(C(=O)N2C3CCCCC32)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCOc1c(F)cc(C(=O)NC2CCCCC2C#N)cc1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
At room temperature, 99 mg of trimethylsilyl cyanide was added dropwise to a mixture of 12 ml of tetrahydrofuran and 291 mg of 7-[3,5-difluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane and, further, tetrabutylammonium fluoride (0.05 ml of 1M tetrahydrofuran solution) was added. The resulting mixture was heated with stirring at 40° C. for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.24 g of N-(2-cyanocyclohexyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 80 of the present invention) represented by the formula:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[SH:21].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C1COCC1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[S:21][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc(C)c(S)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(Sc2ccc(C#N)cc2[N+](=O)[O-])c1
Yield: 94.8 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitrile (5.4 g, 29.67 mmol) in THF (100 mL) was added 2,5-dimethylthiophenol (4.921 g, 35.60 mmol) and K2CO3 (20.45 g, 148.0 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes). After refluxing for 16 hrs, the reaction was complete. The solid was filtered and washed with copious amounts of EtOAc. The filtrate was washed sequentially with saturated NaHCO3, water, saturated NaCl solution, dried over MgSO4, filtered, and evaporated in vacuo. The resulting solid was then sonicated in hexanes and filtered to yield compound 24 as a yellow/white solid (8.00 g, 97.8% HPLC purity, 95% yield). 1H NMR (500 MHz, DMSO-d6): δ8.77 (d, J=2 Hz, 1H), 7.94 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 2.32 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].ClS(C1C=CC=CC=1C(O)=O)(=O)=[O:16].O>C1(C)C(C)=CC=CC=1>[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:16])(=[O:4])=[O:3]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cl
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Yield: 95.6 %

Procedure:
300 g of 3-(chlorosulfonyl)benzoic acid containing 38.8% water (corresponding to 183.6 g (0.83 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 150 g of water and heated at 100° C. for 1 hour. Then 600 g of xylene are added dropwise over 1 hour and a total of 260 ml of water are azeotropically distilled off with xylene. The reaction mixture is cooled and the precipitate is filtered off with suction. After drying at 100° C./100 torr (13.16 kPa) 164.7 g of 3-sulfobenzoic acid are obtained, the purity determined by titration being 97.7%; this corresponds to a yield of 95.6%.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[C:26]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:25]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
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: CCO
Product: C[C@H](Oc1ccc(-c2cc(C(F)(F)F)cc(S(N)(=O)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 75.2 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.20 g, Example 33), 3-bromo-5-trifluoromethylbenzosulphonamide (0.40 g, Example 74), 2M aqueous sodium carbonate (0.76 ml) and tetrakis(triphenylphosphine)palladium (0) (0.019 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.24 g). m.p. 57-59° C.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][CH:9]([CH3:30])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CN(C)C=O.[Pd]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH:17]([CH3:18])[C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:32][CH:31]=2)[CH3:30])=[O:29])=[CH:21][CH:22]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(N)cc1)C(=O)OCCOC(=O)C(C)Oc1ccc(N)cc1
Reaction time: 4 h
Yield: 72.1 %

Procedure:
2-(4-Nitrophenoxy)-propionic acid 2-[2-(4-nitrophenoxy)propionyloxy]-ethyl ester 31 (50 g, 89.3 mmol) was dissolved in dry dimethylformamide (400 ml) in a pressure vessel. Palladium on carbon (5%, 12.5 g) was added, and the mixture stirred under an atmosphere of hydrogen (4 kg) for 4 hours. Catalyst was removed by filtration and ice water (3 L) was added to the filtrate. Crude 32 was extracted into ethyl acetate, dried over Na2SO4, and distilled and purified by column chromatography on silica gel using chloroform as eluant to give pure 32 (25 g, 58%) as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: Fc1ccccc1N1CCNCC1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 98 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 98%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.11-3.18 (m, 4H), 3.77-3.86 (m, 4H), 4.12 (s, 3H), 6.95-7.61 (m, 7H), 7.73 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([CH3:12])[CH2:10]O)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[Br:13][CH2:10][C@@H:9]([CH3:12])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: C[C@H](CO)Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@H](CBr)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of (2S)-3-(4-chlorophenyl)-2-methylpropan-1-ol (300 mg) in DCM (20 mL) were added N-bromosuccinimide (347 mg) and triphenylphosphine (511 mg) under ice-cooling. The reaction liquid was stirred at room temperature for 2 hours, and then the reaction liquid was poured into water, followed by extraction with chloroform. The organic layer was washed with brine and dried over MgSO4, and then vehicle was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:EtOAc=100:0 to 90:10) to obtain 1-[(2S)-3-bromo-2-methylpropyl]-4-chlorobenzene (373 mg) as a colorless liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH:10]([OH:22])[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH:2]=1>[Pd].C(O)C>[OH:22][CH:10]([CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: OC(CC#Cc1cccnc1)CCCCOC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: OC(CCCCOC1CCCCO1)CCCc1cccnc1
Reaction time: 8 h

Procedure:
A mixture of 7.36 g (24 mmol) 1-(3-pyridyl)-4-hydroxy-8-(2-tetrahydropyranyloxy)-1-octyne, 100 ml ethanol and 0.74 g 10% palladium on charcoal is hydrogenated in a Parr apparatus at 3 atmospheres (=3.04 bar) pressure and room temperature for 8 h. The catalyst is filtered off and washed with ethanol. The combined filtrate is evaporated to give 5-hydroxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)-octane; NMR (CDCl3): delta 4.4 (brs,1H), 2.67 (t,2H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[H-].[Na+].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:13][CH:15]1[CH2:16][O:17]1
Reactant: COc1ccc(I)c(O)c1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(I)c(OCC2CO2)c1
Temperature: 5 °C
Yield: 93 %

Procedure:
A 5.0 g (0.02 mole) sample of 2-iodo-5-methoxyphenol was added in portions to a suspension of 1.01 g (0.021 mole) of 50% sodium hydride (from which the oil had been removed by washing with hexane) in 40 ml of dry DMF. The resulting solution was cooled to 5° C. and 9.14 g (0.099 mole) of epichlorohydrin was added. The mixture was heated at 60° C. for 15 minutes. The mixture was cooled and filtered through diatomaceous earth. The solvent was evaporated in vacuo from the filtrate. The residue was taken up in ether, the ether washed with water and brine, dried (MgSO4) and the solvent evaporated in vacuo to give 5.72 g (93% yield) of [(2-iodo-5-methoxyphenoxy)methyl]oxirane as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[C:21]([CH2:20][Cl:19])=[N:1]2
Reactant: O=C(Cl)CCl
Reactant: Cc1ccccc1NC(=O)c1c(N)cccc1Cl
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Yield: 37 %

Procedure:
Prepared according to Procedure B with 1j (750 mg, 2.88 mmol) and chloroacetyl chloride (0.69 mL, 8.63 mmol) in acetic acid (15 mL). Purified by chromatography in CH2Cl2, followed by recrystallization from isopropanol to afford 340 mg of a white solid (37%). 1H NMR (CDCl3) δ: 7.69 (d, J=2.1 Hz, 1H); 7.68 (q, J=7.4 Hz, 1H); 7.54 (dd, J=2.2, 7.0 Hz, 1H); 7.35-7.47 (m, 3H); 7.21-7.25 (m, 1H); 4.27 (d, J=12 Hz, 1H); 4.11 (d, J=12 Hz, 1H); 2.18 (s, 3H). MS (ES): m/z 319.0 (M+).