Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@H:21]([CH3:25])[C:22](O)=[O:23])[CH:15]=[CH:14]2.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C@H:21]([CH3:25])[C:22]([O:1][CH2:2][C:3]([CH2:7][OH:8])([CH3:4])[CH2:5][OH:6])=[O:23])[CH:15]=[CH:14]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(CO)(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2cc([C@H](C)C(=O)OCC(C)(CO)CO)ccc2c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 65.4 %

Procedure:
To a stirred solution of 1,1,1-tris(hydroxymethyl)ethane (13.1 g, 109 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 5.00 g, 21.7 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (4.80 g, 25 mmol), and N,N-dimethylaminopyridine (DMAP, 20 mg, catalytic amount) in acetonitrile (200 mL) was added triethylamine (4.2 mL, 30 mmol). The reaction mixture was stirred at ambient temperature for 25 hours, filtered, and the filtrate was concentrated to dryness. The residue was diluted with EtOAc, washed with 1N HCl (2×), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The resulting material was purified by crystallization (2×) from EtOAc/Hexanes (1:3 v:v) to give the title compound (4.72 g, 66% yield) as white flakes. Mp 105° C. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.66 (s, 1H), 7.39 (dd, J=8.5, 1.7 Hz, 1H), 7.17-7.10 (m, 2H), 4.25 (d, J=11.3 Hz, 1H), 4.09 (d, J=11.3 Hz, 1H), 3.90 (s, 3H), 3.88 (q, J=7.1 Hz, 1H), 3.46-3.25 (m, 4H), 2.65-2.55 (m, 2H), 1.60 (d, J=7.1 Hz, 3H), 0.67 (s, 3H). 13C NMR (75 MHz, CDCl3) δ175.8, 157.7, 135.3, 133.8, 129.2, 128.9, 127.3, 126.0, 119.2, 105.6, 67.7. 67.5, 66.8, 55.3, 45.6, 40.9, 18.1, 16.7. LRMS (API-TIS) m/z 350.2 ((M+NH4)+).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:4]1=2.CC1(C)C(C)(C)OB([C:28]2[CH:37]=[CH:36][C:31]3[NH:32][C:33](=[O:35])[NH:34][C:30]=3[CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.CO>[F:19][C:16]1[CH:17]=[CH:18][C:4]2[C:3](=[CH:2][C:28]3[CH:37]=[CH:36][C:31]4[NH:32][C:33](=[O:35])[NH:34][C:30]=4[CH:29]=3)[C:9]3[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:15]=1
Reactant: Fc1ccc2c(c1)COc1cc(F)ccc1C2=CBr
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
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: CO
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C=C3c4ccc(F)cc4COc4cc(F)ccc43)cc2[nH]1
Temperature: -26 °C
Yield: 27.1 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3,8-difluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 326 mg, 1.0 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (250 mg, 0.961 mmol), Na2CO3 (2M in water, 1.20 mL, 2.40 mmol), dioxane (7 mL), and Pd(PPh3)4 (58 mg, 0.051 mmol). Purify the crude product on silica gel (12 g) eluting with 50% to 70% THF/hexanes to afford two lots of yellow solid weighing 180 mg and 151 mg. Dissolve the 180 mg lot in boiling MeOH (20 mL), concentrate to 10 mL and cool to −26° C. to precipitate 165 mg (46%) of the title compound as a white solid. Repeat the recrystallization on the 151 mg lot to afford 98 mg (27%) of the title compound as a white solid. HPLC (ISO80-10) t=2.38 min, 97%; MS [ES] 375 (M−H), 377 (M+H); 1H-NMR (DMSO-d6) δ 10.57 (s, 1H), 10.46 (s, 1H), 7.57 (dd, 1H, J=8.4, 7.0 Hz), 7.49 (dd, 1H, J=9.2, 2.6 Hz), 7.08 (td, 1H, J=12.5, 4.3 Hz), 7.01 (d, 1H, J=5.7 Hz), 6.97 (s, 1H), 6.79 (td, 1H, J=12.0, 4.2 Hz), 6.73 (d, 1H, J=8.4 Hz), 6.67 (d, 1H, J=8.4 Hz), 6.61 (dd, 1H, J=10.6, 2.6 Hz), 6.52 (s, 1H), 5.78-4.78 (br d, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:19])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)C1(c2ccc(Cl)nc2)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1(c2ccc(Cl)nc2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
A mixture of 1-(6-chloropyridin-3-yl)cyclopropanecarboxylic acid (2.0 g, 0.010 mol) and sulfuric acid (0.42 mL, 0.0079 mol) in methanol (30 mL) was stirred at 80° C. for 6 h. The mixture was cooled to RT and concentrated. The residue was dissolved in saturated sodium bicarbonate and extracted with ethyl acetate. The organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure to give a crude product (2.0 g, 93%). Analytical LCMS: (M+H)+=212.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]2[CH2:13][C@H:12]([O:14][CH3:15])[CH2:11]2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C@H:10]2[CH2:11][C@H:12]([O:14][CH3:15])[CH2:13]2)[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CO[C@H]1C[C@H](Nc2cc(F)ccc2N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CO[C@H]1C[C@H](n2c([C@H](C)NC(=O)OC(C)(C)C)nc3ccc(F)cc32)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoro-N2(trans-3-methoxycyclobutyl)benzene-1,2-diamine (0.36 g, 1.7 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.35 g, 1.9 mmol) and HOAt (0.26 g, 1.9 mmol) in DCM (8 mL) was cooled to 0° C. under a nitrogen atmosphere. To this mixture was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.36 g, 1.9 mmol) portion wise and the mixture stirred at RT for 1 h. The reaction mixture was allowed to warm to RT then partitioned between DCM (30 mL) and a saturated aqueous solution of NaHCO3 (20 mL). The organic fraction was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the compound as a pink solid (0.188 g, 29%). The compound thus obtained was dissolved in AcOH (8 mL) and heated at 70° C. for 18 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue partitioned between DCM (40 mL) and a saturated aqueous solution of NaHCO3 (20 mL). The organic fraction was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting dark brown residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as yellow oil (0.125 g, 20%). LCMS (Method B): RT 2.84 min [M+H]+ 364.05
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30](OCC)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO>C1COCC1>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][CH2:30][OH:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)CCO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 58.1 %

Procedure:
A solution of ((S)-ethyl 3-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-oxopropanoate (96 mg, 0.20 mmol) and sodium borohydride (30 mg, 0.80 mmol) in THF (4 mL) was brought to reflux and MeOH (242 μL, 6.0 mmol) added drop-wise over a 1 h period. The reaction mixture was allowed to heat at reflux for an additional 16 h and then quenched with a few drops of a 1 N HCl solution. The reaction was partitioned between EtOAc (10 mL) and a saturated aqueous solution of NaHCO3 (10 mL). The organic extract was further washed with brine then dried over MgSO4, filtered, and evaporated to an oil that was purified by silica gel flash chromatography with EtOAc as eluant to afford the title compound as an oil (51 mg, 58%). LC/MS (Method A) 4.34 min, [M+1]+ 439.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[N:21]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1oc(-n2ncc3ccccc32)nc1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
A mixture of methyl 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionate (1.50 g), 1H-indazole (1.18 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (20 mL) was stirred at 120° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were collected by filtration, dried and dissolved in a mixed solvent of tetrahydrofuran (20 mL) and ethanol (20 mL). A 1N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was acidified with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were collected by filtration using isopropyl ether and dried to give 3-[4-(4-chlorophenyl)-2-(1H-indazol-1-yl)-5-oxazolyl]propionic acid (824 mg, yield 45%) as pale-yellow prism crystal. melting point: 204–205° C.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:16][C:12]1[CH:11]=[C:10]([S:7]([N:6]2[C:2]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:3][C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:5]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
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+]
Product: CN(Cc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2cccc(Cl)c2)c1)C(=O)OC(C)(C)C
Yield: 90.1 %

Procedure:
Using tert-butyl {{5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate (1 g), (4-fluorophenyl)boronic acid (628 mg), sodium carbonate (708 mg) and tetrakis(triphenylphosphine)palladium (388 mg), a procedure as in Reference Example 56 was performed to give the title compound as a pale-yellow oil (yield 930 mg, 87%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[C:19]2[N:20]([C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=2)[CH:21]=[C:22]([CH3:24])[CH:23]=1>CN(C=O)C>[F:10][C:9]1[C:4]([CH2:3][O:17][C:18]2[C:19]3[N:20]([C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:28])[N:27]=3)[CH:21]=[C:22]([CH3:24])[CH:23]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reactant: Fc1cccnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCc3ncccc3F)cc(C)cn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
15.78 g (86.7 mmol) of 2-(chloromethyl)-3-fluoropyridine hydrochloride (commercially available; additionally described in: U.S. Pat. No. 5,593,993 A1, 1997; WO2007/2181 A2, 2007) and 94.06 g (288.9 mmol) of caesium carbonate were added to 16.92 g (72.2 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 87A in 956 ml of DMF. The reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to RT and filtered, the filtercake was washed with ethyl acetate and the filtrate was concentrated. About 500 ml of water were added to the residue and the precipitated solid was filtered off and dried under high vacuum. This gave 24.1 g (93% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:42])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: O[C@H]1CCCC[C@@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 600 mg, 1.35 mmol) and (1S*,2R*)-2-phenylcyclohexanol (240 mg, 1.36 mmol) in DMSO (6.0 mL), sodium hydride (63%; 100 mg, 2.63 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (200 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=4:1) to yield the title compound (270 mg, 33%) as a colorless oil.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[CH:9]([C@@H:11]1[CH2:16][O:15][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:13][O:12]1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:14]2[CH2:13][O:12][C@H:11]([C@H:9]3[O:8][CH2:7][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6]3)[CH2:16][O:15]2)=[CH:18][CH:19]=1
Reactant: CCCC(CO)CO
Reactant: COc1ccc([C@H]2CO[C@H](C=O)CO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CO[C@H]([C@@H]2CO[C@@H](c3ccc(OC)cc3)CO2)OC1

Procedure:
A mixture of 1.2 g. 2-propylpropan-1,3-diol, 2.2 g. trans-5-formyl-2-p-methoxyphenyl-1,4-dioxane (obtainable by reaction of 1,1-ethylenedioxypropan-2,3-diol with p-methoxystyrene oxide and hydrolysis), 0.01 g. p-toluene sulphonic acid and 15 ml. toluene is boiled on a water separator for 3 hours, cooled, washed with water and evaporated. One obtains trans-2-p-methoxyphenyl-5-(trans-5-propyl-1,3-dioxan-2-yl)-1,4-dioxane.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:44][C:45]1[CH:46]=[C:47]([NH2:56])[C:48]2[CH:49]=[N:50][N:51]([CH2:54][CH3:55])[C:52]=2[CH:53]=1>CN(C=O)C>[Br:44][C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[N:50][N:51]2[CH2:54][CH3:55])=[C:47]([NH:56][C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[N:16]=2)=[O:19])[CH:46]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: CCn1ncc2c(N)cc(Br)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC(=O)c3cccc(C)n3)cc(Br)cc21
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
DIPEA (0.161 ml, 0.93 mmol) was added to 6-methyl-2-pyridinecarboxylic acid (available from Fluorochem, 51 mg, 0.37 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (174 mg, 0.46 mmol) in DMF (3 ml). The reaction was stirred for 30 mins under nitrogen then 6-bromo-1-ethyl-1H-indazol-4-amine (100 mg, 0.42 mmol) was added and the reaction was stirred overnight. The solvent was evaporated and water (5 ml) was added before extraction into DCM (2×20 ml). The compound was loaded onto an aminopropyl cartridge (20 g), eluted with 10% MeOH in DCM and evaporated to dryness. The residue was purified by silica chromatography, eluting with 0-50% ethyl acetate in DCM over 60 mins. Appropriate fractions were evaporated to give the title compound (107 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH2:21][CH3:22])C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([OH:17])([C:2]2[CH:1]=[CH:22][C:21]([O:20][CH3:18])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Product: COc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1
Reaction time: 15 h

Procedure:
mixture to a temperature of about 20° C., a solution of N-benzyloxycarbonyl-4-piperidone (48.2 g) in ethyl ether (450 cc) is poured in. Stirring is continued for 15 hours at this temperature. The reaction medium is then hydrolysed with a saturated solution of ammonium chloride to pH 6-7, the extracted with diethyl ether (3×500 cc). The organic phase is dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residual oil is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then a mixture of dichloromethane and methanol (90-10 vol) as eluant. N-Benzyloxycarbonyl-4-hydroxy-4-(4-methoxyphenyl)piperidine (21.2 g), m.p. 98° C. is thus obtained, which is used in the crude state in the subsequent syntheses.
Reaction SMILES: [SH:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]([CH3:16])([SH:15])[CH3:14].[H-].[Na+].[CH3:21]I>O1CCCC1>[CH3:21][S:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]([SH:15])([CH3:16])[CH3:14]
Reactant: CI
Reactant: CC(C)(S)CNc1ccccc1NCC(C)(C)S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC(C)(C)CNc1ccccc1NCC(C)(C)S
Reaction time: 1 h
Yield: 79.1 %

Procedure:
1,2-Bis (2-Mercapto-2-methylpropylamino)benzene (0.47 g, 1.69×10-3 mol), and 0.09 g (1.85×10-3 mol, 110 M %) sodium hydride were dissolved in 25 ml tetrahydrofuran. Methyl iodide (0.080 ml, 1.27×10-3 mol, 75 M %) was added, and the mixture was stirred under nitrogen for 1 hour. The excess hydride was destroyed by the slow addition of 10 ml 0.5 M HCl. The mixture was shaken with a mixture of 100 ml ether and 100 ml 0.5 N HCl. The aqueous layer was extracted with an additional 50 ml portion of ether, and the combined ether layers were washed with 100 ml saturated NaCl. The ether layer was then dried over anhydrous Na2SO4. Rotary evaporation yielded 0.30 g (94% yield) of 1-[2-methylthio-2-methylpropylamino]-2-(2-mercapto-2-methylpropylamino)benzene as a yellow oil. Isolation was performed by radial chromatograph on a 1 mm silica plate, using petroleum ether: ethyl acetate-80:20 as the eluting solvent to give yielding a mixture of the 1-[2-methylthio-2-methylpropyl- amino]-2-(2-mercapto-2-methylpropylamino)benzene, S,S'-dimethyl, and the dithiol starting material.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Cl[C:7]1[C:12]([NH2:13])=[C:11]([Cl:14])[N:10]=[CH:9][N:8]=1>C(N(CC)CC)C>[NH2:13][C:12]1[C:7]([CH2:1][NH2:2])=[N:8][CH:9]=[N:10][C:11]=1[Cl:14]
Reactant: CN
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NCc1ncnc(Cl)c1N
Temperature: 80 °C

Procedure:
To 1 mL of methylamine, cooled at −80° C. in a steel vial, ethanol (13 mL) and triethylamine (1.3 mL) were added. Commercially available 4,6-dichloro-pyrimidin-5-yl-amine (3.0 mmol) was added to the solution and the reaction mixture heated at 80° C. for 3 hours. The solvent was removed in vacuo, and the resulting compound, (5-amino-6-chloropyrimidin-4-yl)methylamine, was obtained after silica gel chromatography and/or crystallization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl.[NH2:36][OH:37].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19](=[N:36][OH:37])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1cc(C(=O)CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-fluoro-4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (5.8:1) as a colorless oil, MS (ESI+): m/z=469.1917 ([M+H]+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH:22]=O)[C@@H:20]2[CH2:24][C@H:17]1[CH2:18][CH2:19]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:20]2[CH2:24][C@H:17]1[CH2:18][CH2:19]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNCc1ccccc1
Reaction time: 0.33 h

Procedure:
Benzylamine (49.7 mmol) is added to a solution of (1R,35,45)-3-formyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (49.7 mmol) in DCM (200 mL). The mixture is treated with sodium triacetoxyborohydride (69.6 mmol), stirred for additional 20 min, poured into water (200 mL) and stirred vigorously for 10 min. The layers are separated and the aq. layer is extracted twice with DCM (2×100 mL). The combined organic layers are washed with sat. NaHCO3 solution (100 mL), water (100 mL) and brine (150 mL), dried over MgSO4 and treated with activated charcoal (5 g). The mixture is filtered through celite and the filtrate is concentrated in vacuo to give the desired benzylamine which is used without further purification. LC-MS (basic): tR=1.00 min; [M+H]+=317.3.