Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20]3([CH2:26][NH:25][CH2:24]3)[O:19][CH2:18]4)=[N:12][CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.[CH3:31][S:32]([CH2:35][C:36](O)=[O:37])(=[O:34])=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:9][C:7]1[CH:6]=[C:5]([C:10]2([C:27]([F:29])([F:28])[F:30])[CH2:14][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20]3([CH2:24][N:25]([C:36](=[O:37])[CH2:35][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:26]3)[O:19][CH2:18]4)=[N:12][CH2:11]2)[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CN=C(c2ccc3c(c2)COC32CNC2)C1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To the stirred solution of 5′-(3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 13, 0.46 g, 0.963 mmol) in DMF (10 mL) was added TEA (0.67 mL, 4.81 mmol), methane sulfonyl acetic acid (0.266 g, 1.93 mmol) followed by addition of HOBt (0.13 g, 0.96 mmol) and EDC.HCl (0.276 g, 1.44 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete conversion of starting material, reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). Combined organic layer was washed with LiCl solution (2×40 mL) and brine (2×50 mL), dried over sodium sulfate and concentrated to get brown semi solid (0.597 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 0.8% methanol in DCM to get off white solid (403 mg). Compound was triturated thrice with chloroform n-hexane to get pure compound as off white solid (0.24 g, 44.4%), 1H NMR (400 MHz, DMSO-d6) δ: 3.14 (s, 3H), 3.73 (d, J=18.2 Hz, 1H), 3.87 (d, J=18.12 Hz, 1H), 4.23 (d, J=10.48 Hz, 4H), 4.42 (d, J=16.88 Hz, 1H), 4.57 (s, 2H), 4.82 (d, J=17.2 Hz, 1H), 5.13 (s, 2H), 7.57 (s, 2H), 7.65 (d, J=7.92 Hz, 1H), 7.70 (s, 1H), 7.86 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), LC-MS (m/z): 561.0 (M+H),
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:11]([Cl:10])[CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc(Cl)c(Cl)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-dichloroaniline gave 2-chloro-N4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine. LCMS: purity: 95%; MS (m/e): 294 (M+2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.[N+:21]([O-])([O-:23])=[O:22].[K+]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:21]([O-:23])=[O:22])=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
1-(2-tert-butylphenyl)pyrrolidine (350 mg, 1.72 mmol) was added portionwise to conc. H2SO4 (1 mL) to generate a yellow homogeneous solution. The solution was then cooled to 0° C. and KNO3 (191 mg, 1.9 mmol) was added portionwise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice-water and extracted with DCM, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to obtain 1-(2-tert-butyl-5-nitrophenyl)pyrrolidine (325 mg, 76%). LC/MS: m/z 248.9 (M+H)+ at 2.39 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[CH:14][CH2:15][N:16]([C:25](=[O:27])[CH3:26])[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].C(OCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14]1[C:18]2[C:17](=[CH:22][C:21]([F:23])=[CH:20][CH:19]=2)[N:16]([C:25](=[O:27])[CH3:26])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N(CC=CC1CCCN1C(=O)OC(C)(C)C)c1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)n1cc(CC2CCCN2C(=O)OC(C)(C)C)c2ccc(F)cc21
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of 18 (66 g, 0.15 mol) in anhydrous DMF (350 mL) was charged with (n-Bu)4NCl (41.5 g, 0.15 mol), K2CO3 (20.6 g, 0.15 mol), NaHCO2 (10.2 g, 0.15 mol), and Pd(OAc)2 (3.35 g, 0.015 mol) at ambient temperature. The heterogeneous mixture was immersed in a pre-heated (85° C.) oil bath. After 1 h, TLC analysis revealed some 18 remained therefore more catalyst (1 g) was added. After 1.5 h, another charge of catalyst (0.6 g) was added. After an additional 1.5 h of heating, 18 had been completely consumed by TLC analysis [TLC analysis, 2% MeOH/DCM, Rf(18)=0.7; Rf(19)=0.8]. The warm reaction mixture was transferred to an ice water bath to cool then diluted with diethyl ether and filtered through a pad of celite. The solids were washed with diethyl ether and the filtrate was washed several times with water to remove DMF then once with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 52.5 g of crude 19 which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ8.18 (m, 1H), 7.60 (m, 1H), 7.18 (m, 1H), 7.05 (dt, J=2.4, 8.7 Hz, 1H), 4.13 (m, 1H), 3.41 (m, 1H), 3.33 (m, 2H), 3.17 (app dd, J=14.1, 38.1 Hz, 1H), 2.61 (s, 3H), 1.83 (m, 3H), 1.69 (m, 1H), 1.49 (s, 9H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([CH2:21][O:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15].C(N(CC)CC)C.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:23]([O:22][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:27][CH:26]=2)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 88.4 %

Procedure:
To a solution of 4-(t-butoxycarbonyl)piperazine (1.50 g, 8.05 mmol) in methylene chloride (68 ml) were added chloroformic acid p-nitrobenzyl ester (1.90 g, 8.86 mmol) and triethylamine (1.24 ml, 8.86 mmol) in an ice bath. The mixture was stirred in the ice bath for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate=(1:3) as the eluant to afford 1-(t-butoxycarbonyl)-4-(p-nitrobenzyloxycarbonyl)piperazine (2.60 g, yield 89%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-])=O)[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Ni]>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH2:14])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2ccc(N)cc2[nH]1
Yield: 88.5 %

Procedure:
To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in MeOH (10 mL) was added Raney Nickel (0.2 g). The mixture was hydrogenated under 1 atm of hydrogen at room temperature for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was washed with petroleum ether to give 2-tert-butyl-1H-indol-6-amine (1.0 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.46 (s, 1H), 6.25 (dd, J=1.8, 8.1 Hz, 1H), 5.79 (d, J=1.8 Hz, 1H), 4.52 (s, 2H), 1.24 (s, 9H); MS (ESI) m/e (M+H+) 189.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C@H:4]1[CH2:7][C@H:6]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=[C:15]([I:18])[CH:16]=3)[C:11](=[O:23])[C:10]2=[O:24])[CH2:5]1)[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[Mg]I.C(=O)(O)[O-].[Na+]>O1CCCC1.CCOCC>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:11]1([OH:23])[C:12]2[C:17](=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[C:19]([F:21])([F:20])[F:22])[N:9]([CH2:8][C@H:6]2[CH2:5][C@H:4]([N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[CH2:7]2)[C:10]1=[O:24]
Reactant: Clc1ccc([Mg]I)c(Cl)c1
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(=O)c3c2cc(I)cc3C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 1-1 (3.13 g, 6.52 mmol) in tetrahydrofuran (65 mL) was added dropwise a solution of 2,4-dichlorophenylmagnesium iodide (9.78 mmol) in ether (19.6 mL) at −78° C. The mixture was stirred for 1 hour, and to the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then evaporated. The residue was purified by silica gel column chromatography (chloroform/methanol=1/0 to 20/1 to 10/1 to 5/1) to give the titled compound (2.95 g, 86%).
Reaction SMILES: [F:1][CH:2]([F:24])[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](Br)[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].O>CN(C=O)C>[F:1][CH:2]([F:24])[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]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Br
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1NC(C)(C)C
Yield: 40.4 %

Procedure:
A solution of 6.0 g (0.015 mol) of product from Example 106, 1.48 g (0.0147 mol) of triethylamine and 2.15 g (0.0244 mol) of t-butylamine in 30 ml of DMF was stirred at 50° C. for 12 hours. The reaction mixture was poured into H2O, and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was concentrated in vacuo to 2.8 g of a brown oil. The crude product was kugelrohr distilled at 67 Pa and collected at a pot temperature of 154°-155° C. affording 2.5 g (42%) of product as a beige solid; mp 30°-31° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[N+:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([OH:28])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([OH:28])=[C:20]([CH:6]([C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[O:3][CH3:2])[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:19]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: COc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1cc(Cl)c2ccccc2c1O)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-(2-methoxy-benzylidene)-piperidinium chloride and 4-chloro-1-naphthol.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[CH:14][C:15]([CH3:20])([CH3:19])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(O)C.[Pd]>[CH3:19][C:15]1([CH3:20])[CH2:14][CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=2)[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[O:16]1
Reactant: CC1(C)C=C(c2cccc(C(F)(F)F)c2)c2ccc(OCc3ccccc3)cc2O1
Agent: [Pd]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Reaction time: 18 h
Yield: 98 %

Procedure:
7-Benzyloxy-2,2-dimethyl-4-(3-trifluoromethylphenyl)-2H-chromene (10.0 g) was dissolved in ethanol (100 ml) and 10% Pd/C (1 g) added. This was hydrogenated at 60° and 5 atmospheres pressure for 18 hrs. Filtration through kiesleguhr and evaporation of the solvent under reduced pressure gave an oil which solidified on addition of carbon tetrachloride. Recrystallisation from carbon tetrachloride gave the title compound (7.7 g), m.p. 63°-68° C., (analysing as compound plus 1 mole of carbon tetrachloride).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([CH2:11]Br)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)([O-:26])=[O:25]>CN(C=O)C.ClCCl>[CH3:1][C:2]([C:5]1[CH:10]=[C:9]([CH2:11][N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=3)[CH2:34][CH2:35]2)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(CN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C(C)(C)C)c1O
Reaction time: 2 h
Yield: 54.3 %

Procedure:
In a 100 ml flask containing a solution of 2.99 g (10 mmoles) of 2,6-bis-(1,1-dimethylethyl)-4-bromomethylphenol in 30 ml of DMF, 1.38 g (10 mmoles) of potassium carbonate and 2.07 g (10 mmoles) of 1-(4-nitrophenyl)piperazine are added successively. After agitation for two hours at ambient temperature, the reaction medium is diluted with 150 ml of dichloromethane and washed successively with 3×40 ml of water followed by 40 ml of brine. The organic solution is dried over sodium sulphate, filtered and concentrated under reduced pressure. The brown residue obtained is purified on a silica gel column (eluant: petroleum ether (B.p. 40-70° C.)/ethyl acetate: 8/2). After concentration of the pure fractions, 2.31 g (54%) of a brown powder is obtained. Melting point: 177.5-178.5° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:8]([CH2:27][O:28]C(=O)C)([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:32]1[CH:47]=[CH:46][C:36]([NH:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:35][C:33]1=[O:34])(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@@H:9]1[C@@:8]([CH2:27][OH:28])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@@H:6]([N:32]2[CH:47]=[CH:46][C:36]([NH:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:35][C:33]2=[O:34])[C@@H:5]1[OH:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of nucleoside 54 (3.4 g, 5.3 mmol) in methanol (20 cm3) was added sodium methoxide (0.663 g, 11.66 mmol). The reaction mixture was stirred at room temperature for 10 min and then neutralised with 20% aqueous hydrochloric acid. The solvent was partly evaporated and the residue was extracted with dichloromethane (3×50 cm3). The combined organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×20 cm3) and was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98.5:1.5, v/v) as eluent to give compound 55 as a white solid material (1.6 g, 54%). δH (CDCl3) 9.95 (1H, br s, NH), 8.33 (1H, d, J 7.4, 6-H), 7.98 (2H, m, Bz), 7.60-7.12 (14H, m, Bn, Bz, 5-H), 6.17 (1H, d, J 1.6, 1′-H), 4.78 (1H, d, J 11.8, Bn), 4.48-4.27 (5H, m, Bn, 2′-H, 3′-H), 3.85 (1H, d, J 11.8, 5′-Ha), 3.66-3.61 (2H, m, 5′-Hb, 1″-Ha), 3.47 (1H, d, J 10.4, 1″-Hb). δC (CDCl3) 167.5, 162.31 (C-4, C═O), 155.36 (C-2), 145.34 (C-6), 137.49, 137.08, 133.09, 133.01, 128.94, 128.67, 128.48, 128.30, 128.01, 127.90, 127.80 (Bn, Bz), 96.53 (C-5), 93.97, 89.35 (C-1′, C-4′), 76.06, 75.28, 73.70, 72.76, 70.26, 62.44 (C-2′, C-3′, Bn, C-5′, C-1″). FAB-MS m/z 558 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([C:12]1[N:13]([CH2:22][C:23]#[N:24])[C:14]2[C:19]([CH:20]=1)=[C:18]([Br:21])[CH:17]=[CH:16][CH:15]=2)=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C>[Br:21][C:18]1[C:19]2[CH:20]=[C:12]3[CH2:10][NH:24][CH2:23][CH2:22][N:13]3[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc2c(Br)cccc2n1CC#N
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Brc1cccc2c1cc1n2CCNC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.1 %

Procedure:
Lithium aluminiumhydride (4.0 g, 106 mmol) was suspended in diethylether (600 mL) and 4-bromo-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (13.0 g, 42 mmol) was added in portions. The mixture was boiled for 15 h, cooled to room temperature and added to saturated potassium sodium tartrate solution. Thorough washing of the filter-cake with ethyl acetate followed the filtration over Celite® to remove solids. The phases of the filtrate were separated and the water phase was extracted with ethylacetate. The organic phases were pooled, washed with brine, dried with MgSO4 and the solvent was evaporated. Chromatography on silica gel (dichloromethane/methanol 95:5) yielded 9-bromo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (3.6 g, 34 %) as a colorless solid, MS: m/e=250.0 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31]>>[CH2:9]1[O:8][C:7]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:23]=[C:2]([C:27]3[CH:28]=[CH:29][C:30]([F:31])=[C:25]([Cl:24])[CH:26]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C1COC(c2cccs2)(c2cccs2)c2cc(Br)ccc2N1
Product: O=C1COC(c2cccs2)(c2cccs2)c2cc(-c3ccc(F)c(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5,5-dithien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.27 (s, 1H), 7.68 (m, 4H), 7.48 (t, J=8.8 Hz, 1H), 7.38 (m, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 7.04 (dd, J=5.0, 3.6 Hz, 2H), 6.93 (dd, J=3.6, 1.2 Hz, 2H), 4.22 (s, 2H); MS (ES) m/z 456 (M+H)+; Anal. Calc. For C23H15ClFNO2S2: C, 60.59, H, 3.32; N, 3.07. Found: C, 60.35, H, 3.28; N, 2.91.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:13][C:2]([F:12])([F:1])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:9][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccc(SC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1ccc(SC(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A mixture of 4-(trifluromethylthio)benzylamine (250 mg, 1.21 mmol), benzoyl chloride (178 mg, 1.27 mmol) and sodium bicarbonate (508 mg, 6.05 mmol) in DCM (15 mL) was stirred at rt until the reaction completed. The reaction was diluted with ethyl acetate, washed with brine and dried to give 372 mg (99%) of N-(4-trifluoromethylthiobenzyl)benzamide as a white solid. 1HNMR (360 MHz, DMSO-d6) δ 9.07 (m, 1H, NH), 7.88-7.90 (m, 2H), 7.66-7.68 (d, J=8.7 Hz, 2H), 7.45-7.56 (m, 5H), 4.53 (d, J=6.1 Hz, NCH2, 2H). MS-EI m/z 311 [M+].
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (118.9 mg, 0.34 mmol) and triphenylphosphine (133.5 mg, 0.51 mmol) in methylene chloride (848 μL) was cooled to 0° C. and then treated with N-bromosuccinimide (102.7 mg, 0.58 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. where it was stirred for 45 min. The reaction mixture was then treated with 2-aminopyridine (95.8 mg, 1.02 mmol). The resulting reaction mixture was stirred at 25° C. for 22 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 5/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide (37.1 mg, 26%) as a light yellow solid: mp 151-153° C.; EI-HRMS m/e calcd for C20H21F3N2O3S (M+) 426.1225, found 426.1220.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])(=[O:3])[CH3:2].[C:11]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCC1>CO>[C:11]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:2][C:1](=[O:3])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:10]2)[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: CC(=O)c1ccccc1O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC2(CCN(C(=O)c3ccccc3)CC2)Oc2ccccc21
Temperature: 25 °C
Yield: 68961.6 %

Procedure:
A solution of 2-acetylphenol (5 g, 0.037 mmol), 1-benzoyl-4-piperidone (7.5 g, 0.037 mmol), pyrrolidine (2.6 g, 0.037 mol) and CH3OH (50 ml) was heated at reflux for 8 hours. After cooling to room temperature overnight, the solid was filtered to yield 8.2 g of 1'-benzoyl-3,4-dihydro-spiro[(2H)-1-benzopyran-2,4'-piperidin]-4-one. The mother liquor was concentrated to dryness and the residue triturated with ether to yield an additional 1.7 g (83% total yield).