Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.[H][H].Cl>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2]1
Reactant: NC(=O)c1cccc2nc(-c3cccc(-c4cccnc4)c3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cccc(C4CCCNC4)c3)oc12
Yield: 9.8 %

Procedure:
A solution of 2-(3-(Pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (110 mg, 0.35 mmol) and platinum (IV) oxide monohydrate (55 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (dichlormethane/methanol=9:1) to give the solid. The solid was acidified by hydrochloride acid and wash with ethyl acetate. The solvent was removed in vacuum. 11 mg of 2-(3-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 10%. 1H-NMR (400 MHz, CD3OD) δ 1.93-1.97 (m, 2H), 2.12-2.14 (m, 2H), 3.07-3.27 (m, 3H), 3.51 (t, 2H), 7.53 (t, 1H); 7.60-7.63 (m, 2H), 7.91 (d, J=6.4 Hz, 1H); 7.94 (d, J=6.4 Hz, 1H); 8.26-8.29 (d, J=3.2 Hz, 1H). LC-MS (ESI) m/z: 321 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]2([CH3:19])[NH:13][C:12](=S)[C@:11]([F:16])([CH3:15])[CH2:10][C:9]2([F:18])[F:17])[CH:7]=1.CO.[NH3:23]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]2([CH3:19])[N:13]=[C:12]([NH2:23])[C@:11]([F:16])([CH3:15])[CH2:10][C:9]2([F:18])[F:17])[CH:7]=1
Reactant: N
Reactant: C[C@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)NC1=S
Solvent: CO
Product: C[C@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)N=C1N
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione (750 mg, 2.44 mmol) was dissolved in 7M ammonia in methanol (36 ml, 252 mmol). The reaction mixture was stirred in a sealed vial at 60° C. overnight. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to afford (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethyl-3,4,5,6-tetrahydropyridin-2-amine (708 mg, 2.448 mmol, 100% yield) as a pale yellow solid that was used in the next reaction without further purification.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:18])[CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][OH:17].B(F)(F)F.[CH3:23]COCC>C(OC)(OC)OC>[O:1]1[CH:23]=[N:18][C:3]([CH2:4][CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][OH:17])=[N:2]1
Reactant: N=C(CCCn1c(CO)nc2ccccc21)NO
Reactant: CCOCC
Agent: FB(F)F
Solvent: COC(OC)OC
Product: OCc1nc2ccccc2n1CCCc1ncon1
Temperature: 100 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
1H NMR (DMSO) δ 1.97-2.06 (m, 4H), 4.27 (t, 2H, J=7.4 Hz), 4.72 (s, 2H), 5.44 (br s, 2H), 5.64 (br s, 1H), 7.18 (t, 1H, J=7.5 Hz), 7.23 (t, 1H, J=7.5 Hz), 7.57 (d, 1H, J=7.5 Hz), 7.59 (d, 1H, J=7.5 Hz), 8.83 (s, 1H); MS m/e 249 (MH+); [1-(3-[1,2,4]Oxadiazol-3-yl-propyl)-1H-benzoiidazol-2-yl]-methanol A suspension of N-hydroxy-4-(2-hydroxymethyl-benzoimidazol-1-yl)-butyramidine, 203, (500 mg, 2.01 mmol) in trimethyl orthoformate (5 mL) in the presence of BF3.OEt2 (50 μL) in a sealed tube was placed in a microwave oven (Smith Creator, Personal Chemistry) and heated at 100° C. for 15 min while stirring, resulting in the dissolution of all the material. The reaction was repeated 5 times. The 6 batches were combined and concentrated in vacuo. The residue was treted with 1M HCl (15 mL) and THF (15 mL) and left overnight. Concentration followed by trituration from dichloromethane and recrystallization from isopropyl alcohol and methanol afforded [1-(3-[1,2,4]oxadiazol-3-yl-propyl)-1H-benzoimidazol-2-yl]-methanol (2.28 g, 73%) as a white solid:
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3cnccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)sc2cnccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylthieno[2,3-c]pyridin-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (151 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (80.2 mg, 56%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:6]=[C:5]2[CH:19]=[O:20].[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:6]=[C:5]4[CH:19]=[O:20])[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:22][CH2:23]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(CO)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C=O)c2c1
Yield: 64.8 %

Procedure:
6-Bromo-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 26d 16.8 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (20.61 g), Pd-118 (1.619 g) and potassium carbonate (17.16 g) in DMF (140 mL) was heated to 70° C. for 4 h under nitrogen. The mixture was cooled, diluted with water (250 mL), and extracted with ethyl acetate (300 mL). The separated organic layer was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography, elution with 50 to 100% ethyl acetate in DCM) to give a solid, which was triturated with isohexane 1:1 diethyl ether (200 mL) for 1 h. The suspension was filtered and dried to give the subtitle compound (14.5 g) as a solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[C:22]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[O:33][C:34]=2[CH3:35])=[CH:24][CH:23]=1>O1CCCC1.CN(C)C=O.CN(C1C=CN=CC=1)C>[C:1]([NH:39][S:36]([C:32]1[O:33][C:34]([CH3:35])=[C:30]([CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:23][CH:24]=2)[CH:31]=1)(=[O:38])=[O:37])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1oc(S(N)(=O)=O)cc1COc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1oc(S(=O)(=O)NC(=O)c2ccccc2)cc1COc1ccc(-c2ccccc2)cc1

Procedure:
To a stirred solution of benzoic acid (61 mg) in a mixture of tetrahydrofuran (10 mL) and N,N-dimethylformamide (5 mL) was added 4-(N,N-dimethylamino)pyridine (3.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (118 mg) and 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid amide (45) (206 mg). After 16 hours at room temperature the reaction mixture was concentrated in-vacuo, then partitioned between 0.1 M hydrochloric acid (30 mL) and ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by HPLC to give compound 46 as light beige solid (17 mg). LC/MS System C: Rt=5.69 mins, m/z (ES−)=446 (M− for C25H21NO5S).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][C:10]([OH:12])=O)(=[O:3])[CH3:2].[NH2:16][CH2:17][CH:18]([OH:30])[CH2:19][N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][C:10]([NH:16][CH2:17][CH:18]([OH:30])[CH2:19][N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(OCC(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To a stirred mixture of 2-(3-acetamidophenoxy)acetic acid (85 mg, 0.41 mmol) in DCM (5 mL) was added TEA (0.5 mL), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (83.8 mg, 0.41 mmol) and HATU (171 mg, 0.451 mmol). The mixture was stirred at 25° C. for 3 hours. The reaction mixture was quenched by addition of water (20 mL) and extracted with DCM (3×20 mL) and the combined extracts washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the title product (55 mg, Yield 35%). 1H NMR (400 MHz, MeOD) δ=7.36 (s, 1H), 7.27-7.17 (m, 1H), 7.19-7.01 (m, 6H), 6.68-6.66 (m, 1H), 4.53 (s, 2H), 4.03-4.00 (m, 1H), 3.71-3.62 (m, 2H), 3.50-3.35 (m, 2H), 2.95-2.85 (m, 2H), 2.83-2.74 (m, 2H), 2.56 (d, J=6.3 Hz, 2H), 2.12 (s, 3H). LCMS (m/z): 398.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:26][CH:25]([S:22]([NH:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][C:35](=[O:37])[CH3:36])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)(=[O:24])=[O:23])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CCN)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(-c2ccc([C@@H]3CCC[C@H]3NS(=O)(=O)C(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(+,−) Trans propane-2-sulfonic acid {2-[4′-(2-amino-ethyl)-biphenyl-4-yl]-cyclopentyl}-amide (prepared in example 9) was dissolved in 20 mL of dry methylene chloride and triethylamine added (0.275 mL, 1.98 mmol). To this stirred mixture was added acetyl chloride (0.084 mL, 1.19 mmol). The reaction was stirred at room temperature for 3 days. The reaction was concentrated in vacuo and chromatographed on a Chromatotron® eluting with 98:2 methylene chloride:methanol which afforded 150 mg (64% 2 steps) of the title compound. The NMR was consistent with the assigned structure.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:7]2[N:14]([CH3:15])[CH:13]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[C:8]2=[N:9][C:10]=1[CH3:11])=[O:4].[OH-].[Na+].Cl>CO.O>[CH2:27]([CH:26]([NH:25][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:10]([CH3:11])[N:9]=[C:8]2[C:12]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])=[CH:13][N:14]([CH3:15])[C:7]=12)[CH2:29][CH3:30])[CH3:28]
Reactant: CCC(CC)Nc1c(C(=O)OC)c(C)nc2c(-c3c(C)cc(C)cc3C)cn(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)Nc1c(C(=O)O)c(C)nc2c(-c3c(C)cc(C)cc3C)cn(C)c12

Procedure:
A mixture of 7-(1-ethyl-propylamino)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid methyl ester and NaOH in a 1:1 mixture of MeOH/water was heated at reflux over night. The resulting mixture was acidified with 2N HCl to a pH of 4-5, and extracted with chloroform. The organic layer was dried and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:27][CH2:26][CH2:25][C:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1.[C:28]([Cu])#[N:29].C(N)CN>CN1C(=O)CCC1>[Cl:23][C:18]1[CH:17]=[C:16]([N:11]2[C:10](=[O:24])[C@:9]3([CH2:25][CH2:26][CH2:27][C@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([C:28]#[N:29])=[CH:3][CH:4]=3)[N:13]([CH3:14])[C:12]2=[O:15])[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)C12CCCC2c1ccc(Br)cc1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(C#N)cc1
Temperature: 180 °C

Procedure:
A mixture of 6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (1 g, 2.1 mmol) (Example 1) and CuCN (0.45 g, 5 mmol) in NMP was heated to 180° C. for 6 h. After cooling, the reaction mixture was poured on a mixture of ice and ethylene diamine and extracted twice with DCM. The brown residue was chromatographed over silica gel to yield 4-[(5R*,6S*)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3-diazaspiro[4.4]non-6-yl]benzonitrile as a beige solid. 1H NMR (CDCl3): 7.62 (2H, d, J=8.1 Hz), 7.25-7.3 (3H, m), 6.67 (2H, br s), 3.45 (1H, dd, J1=12.8 Hz, J2=6.4 Hz), 3.16 (3H, s), 2.4-2.7 (1H, m), 1.8-2.4 (5H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[C:5]([C:7]1[S:20][C:10]2[C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6].CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([NH:1][CH2:2][CH2:3][N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[C:5]([C:7]1[S:20][C:10]2[C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: NCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Yield: 17.4 %

Procedure:
To a solution of N-(2-aminoethyl)-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 131 (0.300 g, 0.6 mmol) in methylene chloride (1.5 ml) was added DIEA (0.262 ml, 1.5 mmol). The reaction mixture was cooled with an ice water bath and acetyl chloride (0.0944 g, 1.2 mmol) was added drop-wise via syringe. The reaction mixture was stirred at cool temperature for 30 minutes and equilibrated to room temperature. The reaction mixture was washed with water, then saline and concentrated to a solid. The crude solid was taken into DMF and purified by RP-HPLC to give 46 mg of 258 (yield 18% of theoretical). MS: (ESI+) 441.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].[CH3:22][C:23]1([CH3:26])[CH2:25][O:24]1>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:22][C:23]([OH:24])([CH3:26])[CH3:25])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
A solution of 5-fluoro-2-(1H-indazol-5-yloxy)-benzonitrile (0.100 g, 0.395 mmol) in DMF (4 mL) was treated with NaH (0.022 g, 60%, 056 mmol) and stirred for 5 minutes. 2,2-Dimethyloxirane (0.035 g, 0.48 mmol) was added and the solution was stirred at room temperature for 1 hour. The reaction mixture was then heated to 80° C. for 1.5 hours. The solution was cooled to room temperature, diluted with ether (50 mL), washed with water (3×5 mL), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed eluting with ethyl acetate/hexanes (1:1) to afford 0.070 g of product (47% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][CH3:7])[CH2:4][SH:5].CO[C:12](OC)(OC)[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1>C(N(CC)CC)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]23[S:5][CH2:4][C:3]([CH2:6][CH3:7])([CH2:8][O:9]2)[CH2:2][O:1]3)=[CH:14][CH:15]=1
Reactant: COC(OC)(OC)c1ccc(Br)cc1
Reactant: CCC(CO)(CO)CS
Solvent: CCN(CC)CC
Product: CCC12COC(c3ccc(Br)cc3)(OC1)SC2
Reaction time: 0.75 h

Procedure:
(iv)a) 2,2-Di-(hydroxymethyl)-butanethiol (0.5 g.), trimethyl 4-bromo-orthobenzoate 2 (1.0 g.) and triethylamine (0.1 ml.) were heated at 130°, under a current of nitrogen, for 45 minutes. The volatile components were removed in vacuo (2.00 mm.), at 140°. The residue was purified by chromatography on alumina (alumina Woelm TSC) eluting with 1:6 dichloromethane: hexane, saturated with ammonia. 1-(4-Bromophenyl)-4-ethyl-2,6-dioxa-7-thiabicyclo[2,2,2]octane was obtained as colourless crystals (80 mg.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][OH:19].CCO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([C:12](=[NH:13])[NH:18][OH:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(C(=N)NO)c1
Temperature: 60 °C

Procedure:
A 5 L round bottom flask equipped with an overhead stirrer, and 500 mL addition funnel was charged with 3-(t-butyloxycarbonylamino)benzonitrile (264.4 g, 1.21 mol), hydroxylamine hydrochloride (294.6 g, 4.24 mol) and 95% EtOH (1 L). The resulting suspension was treated with a solution of potassium carbonate (711.8 g, 5.15 mol) in water (1 L) and the suspension heated to 60° C. The reaction was followed by TLC and HPLC for starting material consumption to completion. The reaction mixture was then cooled to ambient temperature the organic layer was separated and concentrated to approximately 500 mL, then diluted with water (1 L). The resulting precipitate was collected by vacuum filtration and dried to yield the title compound as an off white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:30])[N:13]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)[C:14](=[O:21])[C:15]=2[C:16]([O:18]CC)=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)C.Cl>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH3:30])[N:13]([C:22]3[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)[C:14](=[O:21])[C:15]=2[C:16]([OH:18])=[O:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)O)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 38 %

Procedure:
A mixture of 34.5 g of 3-(4-t-butylphenyl)-1-(4-cyanophenyl)-4-ethoxycarbonyl-2-methyl-2H-pyrazol-5-one, 23.6 g of potassium carbonate, 621 ml of ethanol and 69 ml of water was refluxed under heating for 9 hours. The reaction solution was cooled to room temperature and adjusted to pH 1-2 with dilute hydrochloric acid. The resulting crystals were collected by filtration and dried under reduced pressure. The resulting crude crystals were recrystallized in methanol-ethyl acetate to give 12.2 g of the title compound as colorless crystals. The mother liquor was concentrated, and the resulting residue was crystallized in chloroform-diethyl ether to give 8.3 g of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5](N)=[C:4]([Cl:10])[CH:3]=1.Br.N([O-])=O.[Na+].[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>CC(C)=O.O>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5](/[CH:18]=[CH:17]/[C:16]([O:20][CH3:21])=[O:19])=[C:4]([Cl:10])[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)/C=C/c1c(Cl)cc(Br)cc1Cl
Temperature: 0 °C

Procedure:
4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL), and a 48% hydrogen bromide aqueous solution (120 mL) was added, followed by stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 mL) was added dropwise thereto, the mixture was stirred for 30 minutes, and methyl acrylate (200 mL), and water (200 mL) were added, followed by stirring for 1 hour. At room temperature, cuprous oxide (2 g) was added, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved in dichloromethane, an ozone gas was introduced at −70° C., and ozone oxidization was performed. To the reaction solution was added dimethyl sulfide (40 mL), and this was extracted with ethyl acetate to obtain 4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8].[CH3:16][S-:17].[Na+].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]2[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]=1[CH2:2][S:17][CH3:16]
Reactant: C[S-]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1c(C)oc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (200 mg) and sodium thiomethoxide (68 mg) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was poured into cold water and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 2-methyl-3-methylthiomethyl-7-nitrobenzo[b]furan (144 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)#[CH:23]>CCCCCCC>[CH:24]1([C:22]#[C:23][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(C(F)(F)F)c2)cc1
Reactant: C#CC1CCCCC1
Solvent: CCCCCCC
Product: FC(F)(F)c1cccc(C#CC2CCCCC2)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 3-trifluoromethyl-phenyl ester and ethynyl-cyclohexane following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (82 mg, 65%); δH (CDCl3): 7.67 (s, 1H), 7.61-7.7.49 (m, 2H), 7.46-7.37 (m, 1H), 2.70-2.52 (m, 1H), 2.04-1.30 (m, 10H); LCMS m/z: 252.