Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[C:11]([C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:19]=[CH:18][CH:17]=3)=[N:10]2)[CH:6]=[CH:7][CH:8]=1.CSC1C=C(N2C=CC(=[O:41])C(C3C=CN(C4C=CC=CC=4)N=3)=N2)C=CC=1.C(=O)(O)[O-].[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[C:11]([C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:19]=[CH:18][CH:17]=3)=[N:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:41]
Reactant: CSc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Reactant: CSc1cccc(-n2ccc(=O)c(-c3ccn(-c4ccccc4)n3)n2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A mixture of 1-[3-(methylsulfanyl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one and 1-[3-(methylsulfanyl)phenyl]-3-(1-phenyl-1H-pyrazol-3-yl)pyridazin-4(1H)-one (0.180 g, 0.50 mmol), sodium bicarbonate (0.168 g, 2.0 mmol) in methylene chloride (8 mL) was treated with 3-chloroperoxybenzoic acid (0.140 g, 77%, 0.62 mmol) and the resulting mixture was stirred at ambient temperature for 2 h. After this time, the reaction was diluted with methylene chloride (20 mL), quenched with sodium thiosulfate (10%, 30 mL) and extracted with methylene chloride (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Flash chromatography (silica, methylene chloride to 1:10 methanol/methylene chloride), followed by preparative HPLC gave 1-[3-(methylsulfinyl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (84 mg, 45%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-:24])=[O:23])=[C:6]([S:8][C:9]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:10]=2[C:11](O)=[O:12])[CH:7]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[Cl:1][C:2]1[C:7]2[C:11](=[O:12])[C:10]3[C:9](=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][C:14]=3[O:20][CH3:21])[S:8][C:6]=2[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1
Reactant: COc1ccc(OC)c(C(=O)O)c1Sc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC)c2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3sc12
Temperature: 50 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A mixture of 19.7 g (0.053 mol) of the above benzoic acid, 600 ml of trifluoroacetic acid, and 300 ml of trifluoroacetic anhydride was stirred at 50° C. for four hours, treated with an additional 70 ml of trifluoroacetic anhydride, and stirred at 50° C. for 20 hours. The reaction mixture was poured into 9 l of H2O and the precipitate that accumulated was collected and dried to give 16.4 g of 1-chloro-5,8-dimethoxy-4-nitro-9H-thioxanthen-9-one, mp 222°-228° C.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C@H:24]([NH2:26])[CH3:25])=[CH:15]1.C(N(C(C)C)C(C)C)C>O1CCOCC1.CCOC(C)=O>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C@H:24]([NH:26][CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])[CH3:25])=[CH:15]1
Reactant: C[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](CF)CN[C@H](C)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (666 mg, 2.97 mmol) was added to a solution of (R)-1-(1H-indol-3-yl)propan-2-amine (470 mg, 2.7 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.700 ml, 4.05 mmol) in 1,4-dioxane (6.05 ml). The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (20 ml) and washed with water (20 ml). The aqueous was extracted with EtOAc (2×20 ml), then the combined organics were dried (MgSO4) and concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM. Pure fractions were evaporated to dryness to afford (S)—N—((R)-1-(1H-indol-3-yl)propan-2-yl)-3-fluoro-2-methylpropan-1-amine (590 mg, 88%) as a, brown oil. 1H NMR (400 MHz, CDCl3, 30° C.) δ 0.86 (3H, dd), 1.20 (3H, d), 1.94-2.11 (1H, min), 2.64-2.74 (2H, m), 2.85-2.98 (2H, m), 3.05-3.15 (1H, m), 4.13-4.39 (2H, m), 7.09 (1H, d), 7.12 (2H, ddd), 7.20 (1H, ddd), 7.33-7.41 (1H, m), 7.56-7.65 (1H, m), 8.10 (1H, s). m/z: ES+ [M+H]+ 249
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[C:14]1([C:11]2[S:10][C:9]([NH:8][CH2:7][C:6]([OH:20])=[O:5])=[N:13][N:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)CNc1nnc(-c2ccccc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNc1nnc(-c2ccccc2)s1

Procedure:
290 mg (0.99 mmol) of (5-phenyl-[1,3,4]thiadiazol-2-ylamino)-acetic acid tert-butyl ester in 5 ml of TFA and 5 ml of dichloromethane at room temperature for 16 h. The volatiles were removed under reduced pressure.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][C:5]=1[OH:14].[C:16]1([C:22](=[N:24][OH:25])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:14][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][O:25][N:24]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:15]
Reactant: CC(=NO)c1ccccc1
Reactant: COC(=O)c1ccc(OCCBr)cc1O
Product: CC(=NOCCOc1ccc(C(=O)O)c(O)c1)c1ccccc1

Procedure:
2-Hydroxy-4-[2-({[1-phenylethylidene]amino}oxy)ethoxy]benzoic acid was prepared as a white solid (0.712 g, 27%) from 4-(2-bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester and 1-phenyl-ethanone oxime using a procedure similar to that of step 1 of example 6. 1H NMR (400 MHz, DMSO-d6); δ 13.60 (bs, 1H), 11.50 (bs, 1H), 7.66 (m, 3H), 7.40 (m, 3H), 6.53 (dd, 1H), 6.52 (s, 1H), 4.44 (t, 2H), 4.32 (t, 2H), 2.18 (m, 2H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(OC)C=CC=CC=1.[ClH:37]>CCOC(C)=O.CCCCCC>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:37]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 0 °C

Procedure:
To an ice cold solution of 16.42 g of Boc-Phe-Met-OCH3 and 21.7 ml of anisole in 200 ml of EtOAc was introduced hydrogen chloride for 30 min. Evaporation of the solution gave a residue which was dissolved in 100 ml of EtOAc and diluted with 400 ml of hexane to give H-Phe-Met-OCH3.HCl which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:34][C@H:12]([CH2:13][O:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[OH-].[K+].[CH2:40](Cl)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O>C1C=CC=CC=1.O1CCOCC1.C(O)(=O)C>[CH2:40]([O:11][C@@H:10]1[C@@H:12]([CH2:13][O:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:34][C@@H:8]([N:7]2[CH:35]=[C:3]([CH2:1][CH3:2])[C:4](=[O:37])[NH:5][C:6]2=[O:36])[CH2:9]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O

Procedure:
A mixture of 6.5 g of 2'-deoxy-5-ethyl-5'-O-trityluridine, 19 g of powdered potassium hydroxide and 9.5 ml of benzyl chloride in a mixture of 60 ml of benzene and 21 ml of dioxane was stirred and heated under reflux for 4 hours. After cooling 65 ml of water and 20 ml of acetic acid were added and the phases were separated. The organic phase was washed twice with 90 ml of water each time, dried over anhydrous sodium sulfate and evaporated to give 4.5 g of 3'-O-benzyl-2'-deoxy-5-ethyl-5'-O-trityluridine in the form of a sticky solid.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[C:18](Cl)(=O)[C:19]1[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.Cl>C1COCC1>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: NC(=O)c1ccccc1N
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Temperature: 10 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a cooled (0-5° C.) mixture of anthranilamide (350 g, 2.57 mol) and triethylamine (286 g, 2.83 mol) in THF (2.5 L) was added dropwise o-anisoyl chloride (437 g, 2.57 mol) while maintaining the temperature between 0-20° C. The resulting suspension was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue was washed several times with water. The wet residue was suspended in 2 M aq. NaOH (13 L), and the mixture was heated to reflux. After 20 minutes a clear solution was obtained. After 1 h of reflux the clear solution was cooled in an ice water bath and then acidified to pH 6 with conc. aq. HCl. The suspension was filtered, and the residue was washed thoroughly with water. The white solid was dried by azeotropic distillation with toluene. 2-(2-Methoxyphenyl)quinazolin-4(3H)-one (567 g) was obtained in 82%. 1H-NMR (200 MHz, Me2SO-d6): δ 3.90 (s, 3H), 7.20 (m, 2H), 7.60 (t, 2H), 7.85 (m, 3H), 8.20 (d, 1H), 12.20 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[Cl:12].[CH2:14]([CH:16]([NH2:19])[CH2:17][CH3:18])[CH3:15]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([NH:19][CH:16]([CH2:17][CH3:18])[CH2:14][CH3:15])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[Cl:12]
Reactant: CCC(N)CC
Reactant: COC(=O)c1c(Cl)cc(C)nc1Cl
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Cl)c1C(=O)OC
Temperature: 110 °C
Yield: 42.5 %

Procedure:
A mixture of 2,4-dichloro-6-methyl-nicotinic acid methyl ester (2.228 g, 10.13 mmol) and 1-ethyl-propyl amine (1.762 g, 20.26 mmol) in DMSO (4 ml) was heated at 110° C. for 5 hours, then at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentratd to give 1.796 g of crude material. The crude material was purified through silica gel column chromatography using chloroform to 5% methanol in chloroform as eluent to give 1.167 g (43%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 7.14 (brs, 1H), 6.27 (s, 1H), 3.86 (s, 3H), 3.27 (m, 1H), 2.33 (s, 3H), 1.3–1.6 (m, 4H), 0.88 (t, 6H) ppm.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11](=O)[CH2:12][CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(O)C.C([O-])(=O)C.[Na+].[ClH:23].[NH2:24]O>O.C(OCC)(=O)C>[ClH:23].[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]([NH2:24])[CH2:12][CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CCC(=O)c1cccc(S(C)(=O)=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(N)c1cccc(S(C)(=O)=O)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To 1-(3-methane sulfonylphenyl)propan-1-one (188 g), ethanol (4.7 ml), sodium acetate (1.09 g), and hydroxylamine hydrochloride (0.68 g) were added and the mixture was stirred at 90° C. for 3 hours. Ethyl acetate and water were added to the reaction solution, the mixture was separated, then the organic layer was successively washed with saturated saline, dried over with anhydrous sodium sulfate, then concentrated. The obtained 1-(3-methane sulfonylphenyl)propan-1-one oxime was used instead of the starting material compound 1-(4-aminophenyl)propan-1-on oxime of Reference Example 109 for the similar procedure as with Reference Example 109 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccnc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cc(C)ccn2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (333 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 191 mg, 66%).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[O:37][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([C:36]1[O:37][C:33]([CH3:32])=[CH:34][CH:35]=1)(=[O:40])=[O:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cc1ccc(S(=O)(=O)Cl)o1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (50 mg, 0.120 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 5-methylfuran-2-sulfonyl chloride (24 mg, 0.130 mmol) and pyridine (11 uL, 0.130 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 58 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-5-methylfuran-2-sulfonamide (percentage yield: 85%), was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:23])([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:24].[OH:23][C:11]1([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#Cc2ccccc2F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC1(C#Cc2ccccc2F)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 1.4 g of 1-(tert-butoxycarbonyl)-4-hydroxy-4-[(2-fluorophenyl)ethynyl]piperidine in 20 ml of ethyl acetate, 10 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 1.28 g of 4-hydroxy-4-[(2-fluorophenyl)ethynyl]piperidine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:57]2[CH2:62][CH2:61]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][CH2:7][CH2:6][C:5]3[CH:34]=[CH:35][C:2]([CH:61]4[CH2:62][CH2:57]4)=[CH:3][CH:4]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Br)cc4)cc3)c(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C5CC5)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.4 %

Procedure:
To a stirred suspension of ethyl 7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (0.56 g, 1.0 mmol) in toluene (6 mL) at ambient temperature was added successively water (0.3 mL), potassium phosphate (0.64 g, 3.0 mmol), tricyclohexylphosphine (0.11 g, 0.40 mmol), and cyclopropylboronic acid (0.17 g, 2.0 mmol). The resulting mixture was stirred and a balloon of nitrogen with a three-way purge valve was attached, and the flask was evacuated and refilled five times with nitrogen. Palladium(II) acetate (0.045 g, 0.20 mmol) was added, and again the flask was evacuated and refilled five times with nitrogen. The mixture was stirred in an oil bath set to 100° C. under the nitrogen balloon for 3 hours. The mixture was cooled to ambient temperature and diluted with ethyl acetate (25 mL) and water (15 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 70/30 hexanes/ethyl acetate, to afford ethyl 6-chloro-7-(4-(4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a white solid (0.24 g, 46% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.COCCOCCN(CCO[CH2:29][CH2:30]OC)CCOCCOC>BrC1C=C(C)C=CC=1.[Cu]Cl>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:5]2[CH:6]=[C:29]([CH3:30])[CH:8]=[CH:9][CH:4]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(F)cc1
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Agent: Cl[Cu]
Agent: Cc1cccc(Br)c1
Agent: [H-]
Product: Cc1cccc(Oc2ccc(F)cc2)c1
Temperature: 45 °C

Procedure:
Sodium hydride (1 80 g) was suspended in 3-bromotoluene (51.3 g, Aldrich) and 4-fluorophenol (8.40 g, Aldrich) added over 1/4 hour with stirring. The mixture was then heated at 45° C. until effervescence stopped (1/2 hour). After cooling, copper(I) chloride (3.75 g) was added followed by TDA-1 (12 g) over 10 minutes with further cooling. The mixture was then heated at 180° C. under N2 for 24 hours. After cooling, the mixture was treated with 2 M aqu. HCl (100 ml) and extracted with ether. The extract was washed with 2 M aqu. HCl (2×100 ml), with 2 M aqu. NaOH and with water (2×100 ml), then treated with charcoal, filtered through Hyflo and stripped. The residue was distilled under reduced pressure to give the desired product, bp 130°-135° C./10 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)[CH2:10][N:11]1[CH:16]2[CH2:17][CH2:18][CH:12]1[CH2:13][N:14](C(OCC1C=CC=CC=1)=O)[CH2:15]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][N:11]2[CH:12]3[CH2:18][CH2:17][CH:16]2[CH2:15][NH:14][CH2:13]3)=[CH:37][CH:36]=1)#[N:39]
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(C#N)cc1)CN1C2CCC1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(C#N)cc1)CN1C2CCC1CNC2
Yield: 97.1 %

Procedure:
A solution of benzyl 8-[2-[(tert-butoxycarbonyl)amino]-4-(4-cyanophenoxy)butyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1 g, 1.8 mmol; from step (i) above) in 95% ethanol (200 mL) was hydrogenated over 5% Pd/C at 1 atm. for 1.5 h. The mixture was filtered through a pad of Celite® and the filtrate was evaporated to give 0.7 g (97%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.[NH2:11][C@H:12]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[CH:26][CH:25]=1)[CH2:13][C@:14]([CH2:19][O:20][CH2:21][CH3:22])([CH3:18])[C:15]([OH:17])=[O:16]>>[Cl:36][C:32]1[CH:31]=[C:30]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C@@H:12]([NH:11][C:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)=[O:10])[CH2:13][C@:14]([CH2:19][O:20][CH2:21][CH3:22])([CH3:18])[C:15]([OH:17])=[O:16])=[CH:29][CH:28]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: CCOC[C@](C)(C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Product: CCOC[C@](C)(C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(OC)no1)C(=O)O

Procedure:
3-Methoxyisoxazole-5-carboxylic acid and (2S,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-ethoxymethyl-2-methylpentanoic acid were reacted as described herein to yield the title compound (2 mg). MS m/z [M+H]+ calc'd for C26H29ClN2O6, 501.17. found 501.2.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:33](=[O:34])[CH2:32][O:31][C:30]3[CH:36]=[CH:37][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:25][CH:24]=3)[S:9][C:10]=2[N:11]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Cc1ccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Product: Cc1ccc(CCc2nc3c(N4CCN(C(=O)COc5ccc(Cl)cc5)CC4)nc(N)nc3s2)cc1
Yield: 51 %

Procedure:
This compound was prepared from 2-(4-methylphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 51%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12](=[S:14])[NH2:13])[CH:9]=[N:8]2)[CH:2]=1.Br[C:16]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[C:17]=1O.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[S:14][C:16]4[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[C:17]=4[N:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: NC(=S)c1cnn(-c2cccnc2)c1
Reactant: O=C1CCCC(Br)=C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2sc(-c3cnn(-c4cccnc4)c3)nc21
Temperature: 25 °C

Procedure:
1-(3-pyridyl)pyrazole-4-carbothioamide (2.50 mmol, 0.510 g) and 3-bromo-2-hydroxy-cyclohex-2-en-1-one (2.50 mmol, 0.477 g, described in Tet. Lett. 2011, 52, 3633) were suspended in 10 ml acetic acid and the reaction mixture heated to reflux for 20 h. The reaction was cooled down to room temperature, diluted with water, slowly neutralised by dropwise addition in a saturated NaHCO3 solution, and the aqueous phase was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude material was purified by Combiflash to give a solid which was crystallized in diethylether to yield the title compound as a light yellow solid.