Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[C:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7].C(=O)([O-])[O-].[K+].[K+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:25][C@H:26]1[O:28][CH2:27]1)(=O)=O>CN(C)C=O>[O:28]1[CH2:27][C@H:26]1[CH2:25][O:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[C:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=C1OCCC1=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To α-(2′-hydroxybenzylidene)-γ-butyrolactone (60 g) were added dimethylformamide (600 ml) and potassium carbonate (87 g) and (S)-glycidyl nosylate (82 g) was added. The reaction mixture was stirred for 2 days at room temperature. The reaction mixture was concentrated under reduced pressure and water was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate to give the title compound (55 g), melting point 68–70° C.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>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.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(O)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (54.5 mg, 0.65 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (30 mg) and Cul (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 56 mg, 64%).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=1[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)C.[OH-].[Na+:34]>C1COCC1.CO>[CH3:15][CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([O-:32])=[O:3])=[C:8]([CH2:16][N:17]2[CH2:18][CH2:19][N:20]([S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH2:21][CH2:22]2)[CH:9]=1)[CH3:14].[Na+:34]
Reactant: CCOC(=O)COc1ccc(C(C)C)cc1CN1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccc(OCC(=O)[O-])c(CN2CCN(S(=O)(=O)c3ccccc3)CC2)c1

Procedure:
A solution of the product from step (e) (113 mg) in NaOH (0.25 ml, 1M), THF (1.5 ml) and MeOH (1 ml) was stirred for 4 h. The solvent was removed in vacuo and the residue triturated with ether to give the title compound (97 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2C(OC)=O)=[CH:4][CH:3]=1>Br>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C@H:7]2[CH2:12][C@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1Cc1ccc(Cl)cc1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3ccc(Cl)cc3)C2)o[nH]1
Yield: 52.1 %

Procedure:
Methyl 2-(4-chlorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (347 mg, 0.99 mmol) was stirred in HBr (33% in AcOH) overnight (19 hours). Evaporation of solvents and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) yielded 5-(trans-2-(4-chlorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (151 mg, 52%). 1H NMR (400 MHz, tfa) δ 2.25-2.60 (m, 4H), 3.06-3.20 (m, 2H), 3.35-3.52 (m, 1H), 3.55-3.75 (s, 2H), 3.77-3.96 (m, 1H), 6.59 (s, 1H), 7.15-7.22 (m, 2H), 7.22-7.41 (m, 2H). HRMS Calcd for [C15H17ClN2O2+H]+: 293.1057. Found: 293.1031.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:13].[CH3:14][NH:15][CH:16]([OH:18])[CH3:17]>C(O)CCC>[NH2:13][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[C:10]=1[N:11]=[CH:12][N:4]2[CH2:3][CH2:2][N:15]([CH:16]([OH:18])[CH3:17])[CH3:14]
Reactant: Nc1ncnc2c1ncn2CCCl
Reactant: CNC(C)O
Solvent: CCCCO
Product: CC(O)N(C)CCn1cnc2c(N)ncnc21
Yield: 95.9 %

Procedure:
0.6 g (3 mmol) 9-(chloroethyl)-6-amino-9H-purine (Chemistry of Heterocyclic Compounds, 1996, 32, 333–337) was dissolved in 10 ml n-butanol and treated with 0.684 g (9 mmol) of N-methylaminoethanol at 110° C. for 18 h. The solvent was evaporated under reduced pressure and the crude mixture purified by flash chromatography on silica gel with a gradient of 0 to 25% methanol in dichloromethane to yield 0.68 g (94%) of a light orange solid. MS (ISP): 237.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CN1CCc2ccccc21
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: Cn1ccc2ccccc21
Temperature: 25 °C
Yield: 57 %

Procedure:
The N-methyl indoline product in Example 47 (70 mg, 0.22 mmol) was dissolved in toluene (9 mL) in a 50-mL flask under N2 fitted with a condenser. MnO2 (199 mg, 2.3 mmol) was added, and the mixture was heated to reflux for 1.5 h. The mixture was cooled to rt, Celite, and the pad was washed several times with liberal amounts of MeOH. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (gradient 25-35% EtOAc/hexane) to provide the N-methyl indole product (39 mg, 57%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ6.93-7.11 (m, 5H), 6.72 (d, J=8.5 Hz, 1H), 6.42 (d, J=3.1 Hz, 1H), 4.29 (t, J=5.8 Hz, 1H), 3.84-3.96 (m, 2H), 3.77 (s, 3H), 2.99 (dd, J=11.3, 5.0 Hz, 1H), 2.67 (dd, J=11.3, 6.7 Hz, 1H), 2.49 (s, 3H); ESI MS m/z=313 [C19H18F2N2+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1.O1CCOCC1CN1CCC2C=C(OC)C(N)=CC=2CC1.Cl[C:42]1[N:47]=[C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)[C:45]([Cl:62])=[CH:44][N:43]=1>>[Cl:62][C:45]1[C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[N:47][C:42]([NH:19][C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([CH2:7][CH:2]4[CH2:3][O:4][CH2:5][CH2:6][O:1]4)[CH2:9][CH2:10][C:11]=3[CH:18]=2)=[N:43][CH:44]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Reactant: Nc1ccc2c(c1)CCN(CC1COCCO1)CC2
Agent: COc1cc2c(cc1N)CCN(CC1COCCO1)CC2
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)CCN(CC3COCCO3)CC4)ncc2Cl)c(-n2cccn2)c1

Procedure:
3-1,4-Dioxinan-2-ylmethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine, prepared in a similar manner as 3-1,4-Dioxinan-2-ylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine of Example 636b, was reacted with (2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, in a similar manner as Example 601b to yield desired product 5-Chloro-N*2*-(3-[1,4]dioxan-2-ylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-N*4*-(4-methoxy-2-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine as a lyophylate (38%); 1H NMR (400 MHz, DMSO-d6) δ 9.73 (bs, 1H), 9.36 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.96 (bd, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 7.30-7.25 (m, 2H), 7.02-7.00 (m, 2H), 6.54 (s, 1H), 4.06 (m, 1H), 3.88 (s, 3H), 3.85-3.55 (m, 6H), 3.4-3.0 (m, 6H), 2.95 (m, 1H), 2.75 (m, 1H), MS (m/e) 562.15 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([O:20]C)[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4].C(OCC)(=O)C>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([OH:20])[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(OC)cnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(O)cnc21
Temperature: 25 °C
Yield: 113 %

Procedure:
850 mg 1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-5-methoxy-1H-pyrrolo[2,3- b]pyridine was dissolved in 50 ml dichloromethane. At −78° C. 1.90 ml of a 1 molar solution of borontribromide in dichloromethane was added. The reaction mixture was allowed to warm up to room temperature. Then the reaction mixture was heated under reflux for additional two hours. 150 ml ethyl acetate were added and the mixture washed with 50 ml of a one molar solution of hydrochloric acid. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by RP-HPLC to provide 930 mg 1-[4-Butyl-2-(4-trifluoromethylphenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-ol as a lyophilisate.
Reaction SMILES: [Si:1]([N:8]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:10]([CH2:18][C:19]([CH2:21]O)=[CH2:20])[C:9]1=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Li+].[Cl-].CS([Cl:38])(=O)=O.N#N>CN(C=O)C.O>[Si:1]([N:8]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:10]([CH2:18][C:19]([CH2:21][Cl:38])=[CH2:20])[C:9]1=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C=C(CO)C[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1c1ccccc1
Agent: N#N
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1cccc(C)n1
Product: C=C(CCl)C[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1c1ccccc1
Reaction time: 0.33 h
Yield: 107 %

Procedure:
To a stirred and ice-cooled slurry of (3S*,4R*)-1-tert-Butyldimethylsilyl-3-(2-hydroxymethyl-2-propenyl)-4-phenyl-2-azetidinone (13.66 g, 41.0 mmol), 2,6-lutidine (15.3 ml, d0.920, 123 mmol), and LiCl (anhydros, 4.37 g, 103 mmol) in DMF (103 ml) was added MeSO2Cl (MsCl, 7.93 ml, d1.480, 103 mmol) dropwise under an atmosphere of N2. After the reaction mixture was stirred with ice-cooling for 5 hours and 50 minutes, H2O (40 ml) was added. The stirring was continued at room temperature for additional 20 minutes to destroy the excess MsCl. The resultant dark red mixture was poured into H2O (70 ml). The mixture was extracted with Et2O (70 ml×5). The combined Et2O extracts were washed with H2O (×3), sat. NaHCO3 aq. solution (×1), and sat. NaCl aq. solution (×1), dried (MgSO4), treated with activated charcoal, and concentrated in vacuo to give practically pure title compound (15.36 g, quantitative) as a pale yellow oil. IRmax (film): 1735(v.s), 1650(w), 1175(s), 825(s), 750(s), 700(s) cm-1 ; 1H-NMR δ: 7.43-7.25(m, 5H), 5.14(br.s, 1H), 4.87(br.s, 1H), 4.22(d, J=2.6 Hz, 1H), 3.99(s, 2H), 3.25(ddd, J=10.1, 5.1, 2.6 Hz, 1H), 2.78(dd, J=16.1, 5.1 Hz, 1H), 2.60(dd, J=16.1, 10.1 Hz, 1H), 0.92(s, 9H), 0.22(s, 3H), -0.20(s, 3H) ppm. This was employed in the next step without further purification.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24]OS(C3C(C)=CC=CC=3)(=O)=O)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:36].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][F:36])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: Cc1ccccc1S(=O)(=O)OCCCCc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(SCc2ccc(CCCCF)cc2)c(Cl)c1=O
Reaction time: 0.5 h

Procedure:
To a round bottom flask is added 2-tert-butyl-4-chloro-5-(4-(4-toluenesulfonyloxybutyl)benzyl)thio-3(2H)-pyridazinone (0.05 g, 0.093 mmol) and to it is added tetrabutylammonium fluoride (1.0 M solution in THF, 0.93 μl, 0.93 mmol) followed by 0.2 ml of THF. The reaction is heated to 60 C and stirred at that temperature for 30 minutes. The mixture is then cooled and concentrated and the crude subjected to flash chromatography to obtain the above mention compound.
Reaction SMILES: [Cl:1]Cl.[CH3:3][CH:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:12][C:7]=2[O:6][C:5]1=[O:19]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:10]1[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:12][C:7]2[O:6][C:5](=[O:19])[CH:4]([CH3:3])[C:8]=2[CH:9]=1
Reactant: ClCl
Reactant: CC1C(=O)Oc2cc(N3CCOCC3)ccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1C(=O)Oc2cc(N3CCOCC3)c(Cl)cc21

Procedure:
A cold solution of chlorine in chloroform is added dropwise at from 0° to 5° C., while stirring, to a mixture of 14.7 g (0.063 mole) of 3-methyl-6-morpholinobenzofuran-2(3H)-one in 100 ml of chloroform until no more educt is visible in the thin layer chromatograph. The reaction mixture is diluted with methylene chloride and washed in succession with 10% strength sodium thiosulphate solution, dilute sodium bicarbonate solution and water. The crude product remaining after drying and concentrating by evaporation the organic phase is chromatographed over silica gel with petroleum ether/ether. Recrystallisation of the pure fractions from ether/petroleum ether yields 5-chloro-3-methyl-6-morpholinobenzofuran-2(3H)-one having a melting point of 103°-105° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COC1(c2cccc(Cl)c2F)CCNC1
Yield: 63 %

Procedure:
To a solution of (+)-1-benzyl-3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (1.04 g, 3.25 mmol) in 1,2-dichloroethane (10 ml), was added 1-chloroethyl chloroformate (1.42 ml, 13.08 mmol) and the mixture was heated to reflux for 2 h after which the solvent was evaporated. The mixture was dissolved in methanol (20 ml) and heated to reflux for 1 h, the solvent was evaporated and purified by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) give the title compound 0.47 g (63%). [a]D=+6.5° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 183-185° C. MS m/z (rel. intensity, 70 eV) 229 (M+, 1), 199 (86), 187 (bp), 157 (49), 133 (42).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9][C:10]([O:12]CC)=[O:11])#N.BrC1[CH:17]=[CH:18][C:19]2[S:23][CH:22]=[CH:21][C:20]=2[CH:24]=1.[OH-].[Na+]>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.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Na+].O.C(O)C.C1(C)C=CC=CC=1>[S:23]1[C:19]2[CH:18]=[CH:17][C:7]([CH2:9][C:10]([OH:12])=[O:11])=[CH:24][C:20]=2[CH:21]=[CH:22]1
Reactant: CCOC(=O)CC#N
Reactant: Brc1ccc2sccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
To toluene (25 mL) suspension of 0.16 g of dichlorobis(triphenylphosphine)palladium(II) were added 0.12 g of triphenylphosphine, 0.01 g of sodium borohydride, 5.79 g of potassium tert-butoxide and 2.92 g of ethyl cyanoacetate, which was then stirred at room temperature for 10 minutes. Thereto were added 5.00 g of 5-bromobenzothiophene and 25 mL of toluene, which was then refluxed for 4 hours. Thereto was added 0.14 g of tetrakis(triphenylphosphine)palladium(0), which was then refluxed for 2 hours. Next, to the reaction solution were added 25 mL of ethanol, 2.82 g of sodium hydroxide and 5 mL of water, which was then refluxed for 6 hours. Thereto was added 2.82 g of sodium hydroxide, which was then refluxed for 5 hours. To the reaction mixture were added 15 mL of water and 0.5 g of activated carbon, and insoluble matter was filtered off. The aqueous layer was separated, and to the solution was added 35 mL of ethanol. The pH was adjusted to 2 with 15 mL of hydrochloric acid. Thereto was added 15 mL of water, which was then stirred at 40° C. Thereto was added 30 mL of water, which was stirred. After that, it was cooled. The precipitate was collected by filtration to provide 3.38 g of 2-(1-benzothiophen-5-yl)acetic acid as pale yellow solid form.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.[I-].[K+].C1(=O)[O:30][CH2:29][CH2:28]O1>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:28][CH2:29][OH:30])=[CH:12][CH:11]=2)([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:12][CH2:13][OH:16])=[CH:21][CH:22]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1ccc(OCCO)cc1)(c1ccc(OCCO)cc1)c1ccc(OCCO)cc1
Temperature: 145 °C
Reaction time: 6 h

Procedure:
A 500 ml round bottom flask is equipped with a mechanical stirrer, thermometer and condenser. Add 50 grams 1,1,1-tris(4-hydroxyphenyl)ethane, 100 grams DMF, 0.5 g. potassium iodide and 47.4 grams of ethylene carbonate. Heat to 145° C. and hold for 6 hours. Add 200 g. ethyl acetate and wash the organic portion four times with 150 g. saturated brine. Strip the solvent from the mix on a rotary evaporator. The yield of tan solid is 78 grams. Recrystallize this crude product by dissolving in 300 g. boiling ethyl acetate and allowing to cool slowly. Collect 70.3 grams of a tan solid; the mp=78-81° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16]O.C(N(CC)CC)C>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][O:8][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)=[O:9]
Reactant: COCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOS(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Toluene-4-sulfonyl chloride (25.4 g, 133.2 mmol) is slowly added to a solution of 3-methoxy-1-propanol (8.49 mL, 88.8 mmol) and triethylamine (14.8 mL, 106.5 mmol) in CH2Cl2 (80 mL) at 0° C. The reaction mixture is then allowed to warm to RT and stirred for another 16 h. The solvent is evaporated, water is added and the mixture is extracted with CH2Cl2. Drying (Na2SO4) of the combined organic extracts, filtering and evaporation of the solvent affords the crude product which is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 5:1) to give the desired product. MS (LC-MS): 262.1 [M+18]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.12 min.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH:13]=[CH2:14].O.[OH-].[Li+].[CH2:18]1COCC1>O>[CH:13]1([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=2[F:1])[C:6]([OH:8])=[O:7])[CH2:14][CH2:18]1
Reactant: C1CCOC1
Reactant: C=Cc1cc(C(=O)OCC)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(F)c(C2CC2)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of compound 3 ethyl 4-fluoro-3-vinylbenzoate (Preparation 54, 87 g, 0.42 mol, 1 eq) in THF (470 mL) and water (400 mL) was added lithium hydroxide monohydrate (35.1 g, 0.84 mol, 2.0 eq). The resulting mixture was stirred at 40° C. overnight. THF was removed in vacuum, then 6N hydrogen chloride solution was added dropwise until pH=2. The mixture was extracted with ethyl acetate (3×600 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo to give title compound as a white solid (60.8 g, 0.34 mol, 81%).
Reaction SMILES: [N:1]([C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][CH2:11][CH2:12][OH:13])[C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N+]=[N-]>[C].[Pd].C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][CH2:11][CH2:12][OH:13])[C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: Cc1ccc(-c2c(N=[N+]=[N-])ncnc2OCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-c2c(N)ncnc2OCCO)cc1
Yield: 89.7 %

Procedure:
A mixture of 2-{6-azido-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (19.6 g), 10% palladium-carbon (50% moist) (4.0 g) and ethanol (240 ml) is subjected to catalytic hydrogenation at room temperature under hydrogen atmosphere (1 atm) for one hour. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate/n-hexane to give 2-{6-amino-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (15.9 g).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[SH2:10].[OH-].[Na+].[OH-].[Na+].CO>CO>[SH:10][CH2:1][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:9]
Reactant: c1ccc(C2CO2)cc1
Reactant: S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC(CS)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
1-mercapto-2-phenyl-2-ethanol was prepared from 1000 grams of styrene oxide, 567 grams of H2S and 10 mL of a 20 weight % NaOH solution in methanol. These reactants were pumped into a 1 gallon autoclave reactor and heated from 28° C. to 59° C. during a 1-hour period while the pressure rose from about 350 psig to about 500 psig. At the end of the 1-hour period an additional 20 mL of the NaOH in methanol solution was charged to the autoclave and the reaction mixture was reheated to about 60° C. (at 490 psig) during a 2 hour period. Thereafter, 50 mL of the NaOH/methanol solution was charged to the autoclave and the entire reaction mixture was heated to about 100° C. (at 490 psig) during a period of 50 minutes. Then 50 mL of methanol was added to the autoclave and heating at about 100° C. (400 psig) continued for about 1 hour. 1353 grams of the product, 1-mercapto-2-phenyl-2-ethanol, were recovered.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[CH2:26]([SH:30])[CH2:27][CH2:28][CH3:29].[OH-].[K+].CN1CCCC1=O.Cl>>[CH2:26]([S:30][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCS
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCCSc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Temperature: 150 °C
Reaction time: 4.5 h

Procedure:
5-Chloro-2-(2-hydroxy-3,5-di-tert-butylphenyl)-2H-benzotriazole (21.2 g, 0.06 mol), n-butyl mercaptan (7.2 g, 0.08 mol), potassium hydroxide (6.7.1 g, 0.12 mol) and N-methylpyrrolidone (50 g, 0.5 mol) are charged to a reactor and heated to 150° C. The reaction mass is held at 150° C. for 4.5 hours at which time it then cooled to ambient temperature. A mixture of 15 g of concentrated hydrochloric acid aand 70 g of ice are then added to the reactor. The solids are filtered off and washed with water. Thirty gram of crude, wet, yellow crystals are obtained as the tide compound. This product can be used “as is” in procedure of Example 33.