Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[F:12].CCN(C(C)C)C(C)C.[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=2)[CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH:30][C:4]3[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([F:1])[C:3]=3[F:12])[CH:26]=2)[CH2:24][CH2:23]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 33.5 %

Procedure:
To a solution of 1,2,3-trifluoro-4-nitrobenzene (3.2 g, 18 mmol) and DIEA (4.2 ml, 24 mmol) in dry THF (20 ml) was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (2.0 g, 16 mmol) in THF (5 ml) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 21 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:EtOAc=5:2). Recrystallization from EtOAc (10 ml) and hexanes (˜100 ml) gave the title compound as red crystals (1.5 g, 33%). NMR (400 MHz) 11.90 (s, 1H), 8.78 (s, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.08 (q, J=8.7 Hz, 1H), 5.60 (s, 1H), 1.83 (m, 1H), 0.89 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 280; Found: [M+H]+ 281.
Reaction SMILES: C([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=[CH:26][N:27]=1)[C@@H:15]1[O:23][C:20](=[CH:21][F:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17])(=O)C1C=CC=CC=1>C(O)C>[F:22]/[CH:21]=[C:20]1/[C@@H:18]([OH:19])[C@@H:16]([OH:17])[C@H:15]([N:14]2[C:24]3[N:25]=[CH:26][N:27]=[C:10]([NH2:9])[C:11]=3[N:12]=[CH:13]2)[O:23]/1
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1OC(=CF)[C@@H](O)[C@H]1O)c1ccccc1
Solvent: CCO
Product: Nc1ncnc2c1ncn2[C@@H]1O/C(=C\F)[C@@H](O)[C@H]1O
Reaction time: 14 h
Yield: 33.5 %

Procedure:
Dissolve 83 mg of N6 -benzoyl-4',5'-didehydro-5'-deoxy-5'-fluoroadenosine (lower Rf isomer above) in absolute ethanol, evaporate and redissolve in 6 ml of ethanol. Bubble anhydrous ammonia through the ice cooled solution in a 20 mm×12 cm Carius tube. Seal the tube and remove the ice bath. After 14 hours at room temperature, open the tube and evaporate the solution to give 87 mg of crude product. Triturate in 1 ml of methanol and filter off the solid. Dry the product in vacuo to give 20 mg of the title compound (a white powder, softens at 100°-110° C. and melts at 225°-230° C.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1([CH2:37][OH:38])[CH2:36][O:35][CH2:34]1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3([CH2:37][OH:38])[CH2:36][O:35][CH2:34]3)=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)COC2)c1OCC1CC1
Temperature: 70 °C
Yield: 19.2 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.740 mmol) and (3-bromomethyl-oxetan-3-yl)-methanol (134 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 19.2%).
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1=[O:19])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl[Si](C)(C)C>C(OCC)(=O)C>[OH:37][C@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:2]([CH2:3][CH2:4][C:5]#[CH:6])[C:1]([N:8]1[C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][O:10][C:9]1=[O:19])=[O:7]
Reactant: C#CCCCC(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCC[C@@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](O)c1ccccc1
Reaction time: 72 h
Yield: 80.9 %

Procedure:
To a stirred solution of 56.8 g (221 mmol) of (4S)-3-hex-5-ynoyl-4-phenyl-1,3-oxazolidin-2-one from step A above in 265 mL of anhydrous ethyl acetate at ambient temperature under an atmosphere of nitrogen was added 6.31 g (66.2 mmol) of anhydrous magnesium chloride, 61.5 mL (442 mmol) of triethylamine, 26.9 mL (265 mmol) of benzaldehyde and 42.3 mL (331 mmol) of chlorotrimethylsilane and the resulting mixture was stirred for 72 h. The heterogeneous reaction mixture was filtered through a 300 mL plug of silica gel eluting with an additional 1 L of ethyl acetate. The filtrate was evaporated to dryness in vacuo and the residue suspended in 265 mL of methanol and 10 mL of trifluoroacetic acid. The resulting mixture was stirred at ambient temperature under nitrogen for 5 h during which time the reaction became homogeneous. All volatiles were then removed in vacuo and the residue was purified by silica gel chromatography eluting with a 5-15% ethyl acetate in hexanes gradient to afford the title compound as a white solid (65.0 g, 81.2%). 1H NMR (500 MHz, CDCl3): δ 7.30-7.28 (m, 8H), 7.09-7.07 (m, 2H), 5.42 (dd, J=8.7, 3.7 Hz, 1H), 4.76-4.72 (m, 1H), 4.72-4.67 (m, 1H), 4.65 (t, J=8.7 Hz, 1H), 4.18 (dd, J=8.7, 3.7 Hz, 1H), 3.05 (d, J=7.8 Hz, 1H), 2.24 (td, J=7.1, 2.5 Hz, 2H), 2.00-1.93 (m, 2H), 1.67-1.61 (m, 1H). LC-MS: m/z (ES) 346.1 (MH—H2O)+, 386.0 (MNa)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]([CH3:16])[C:14]#[N:15])[CH:10]=[CH:11][CH:12]=1)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[O:5]=[C:4]1[CH2:3][CH2:2][C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH3:16])[C:14]#[N:15])=[CH:10][CH:11]=2)[NH:6]1
Reactant: CC(C#N)c1cccc(NC(=O)CCCl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C#N)c1ccc2c(c1)NC(=O)CC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
To a solution of 2-[3-(3-chloropropionylamino)phenyl]propionitrile (0.654 g, 2.77 mmol) in CH2Cl2 (8 mL) at 0° C. AlCl3, (1.10 g, 8.31 mmol) was added portionwise. The reaction mixture was stirred 5 min, then was refluxed 8 h. After cooling at 0° C., the mixture was washed with 6N HCl solution (3×10 mL), water (3×10 mL) and brine (2×10 mL). After drying over Na2SO4 and solvent evaporation a crude residue was obtained that, after flash chromatography (eluent mixture n-hexane/EtOAc 85:15), afforded 2-(2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl]propionitrile as yellow oil (0.345 g, 1.72 mmol). Yield 62%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[C:12](O)=[C:11]([C:20](=O)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]2=[O:29])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[NH2:31][NH2:32].O>CN(C=O)C>[CH2:21]([C:20]1[C:11]2[C:10](=[O:29])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]=2[NH:32][N:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NN
Reactant: N#Cc1cccc(-n2c(=O)c(C(=O)Cc3ccccc3)c(O)c3cccnc32)c1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(-n2c(=O)c3c(Cc4ccccc4)n[nH]c3c3cccnc32)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a suspension of 1-(3-cyanophenyl)-4-hydroxy-3-(1-oxo-2-phenylethyl)-1,8-naphthyridin-2 (1H)-one (314 mg, 0.82 mmol, prepared in Synthetic Example 29) in DMF (4 ml) was added hydrazine monohydrate (80%, 132 μl, 4.12 mmol, 4.0 eq.), and the mixture was stirred at 100 to 110° C. for 2 hours. The reaction mixture was admixed with water, and filtered to give precipitates which were washed with water and dried to afford 3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (287 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.[CH:28]12[O:33][CH:29]1[CH2:30][CH2:31][CH2:32]2.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][C@H:29]2[OH:33])=[CH:25][CH:26]=1
Reactant: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C1CC2OC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O[C@@H]4CCC[C@H]4O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
A mixture of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.50 g), cyclopentene oxide (1.50 g) and potassium carbonate (0.45 g) in ethanol (1.5 mL) is stirred for 75 min at 100° C. in a microwave oven. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. After drying the combined organic phases over sodium sulfate, the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 9:1→1:1).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:8])C.Cl.[OH-].[Na+]>CO.O>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([N:9]2[CH:4]=[CH:5][NH:6][C:7]2=[O:8])=[CH:15][CH:14]=1
Reactant: CCOC(CNC(=O)Nc1ccc(C(F)(F)F)cc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]ccn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
1-(2,2-Diethoxyethyl)-3-(4-trifluoromethylphenyl)urea (9.2 g, 28.7 mmol) was dissolved in a mixture of 113 ml of methanol and 57 ml of water. To the reaction solution was added 67.5 ml of 0.48N hydrochloric acid and the mixture was stirred for 48 hours at room temperature. To the reaction solution was added 1N sodium hydroxide to adjust pH to 7, followed by being concentrated under reduced pressure. The residue was extracted with ethyl acetate (100 ml×4). The extracts were combined, washed with water and saturated aqueous solution of sodium chloride successively, dried over magnesium sulfate and distilled off. The crystals thus separated out were recystallized from ethyl acetate-isopropylether to give 4.87 g of 1-(4-trifluoromethylphenyl)-2(1H,3H)-imidazolone (74%) as colorless prisms.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@@H:34]([CH:44]([CH3:46])[CH3:45])[CH2:35][O:36]CC2C=CC=CC=2)[O:10][C:9]1([CH3:48])[CH3:47])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@@H:34]([CH:44]([CH3:46])[CH3:45])[CH2:35][OH:36])[O:10][C:9]1([CH3:47])[CH3:48])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](COCc3ccccc3)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](CO)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC

Procedure:
3.7 g of 3-tert-butoxycarbonyl-5(S)-(3-benzyloxy-2(S)-isopropyl-propyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine are hydrogenated in the presence of 1.0 g of 5% Pd/C in 50 ml of tetrahydrofuran for 15 minutes at room temperature and under normal pressure. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by means of FC (140 g of silica gel, ethyl acetate/hexane=1:2). The title compound is obtained: Rf (ethyl acetate/hexane=1:2)=0.28.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O.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.O1CCOCC1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[CH:3]=1
Reactant: N#Cc1ccc(NCCNc2nc(Cl)cc3ncnn23)nc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: C1COCCO1
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3ncnn23)nc1
Temperature: 150 °C

Procedure:
60 mg (0.19 mmol) of 6-({2-[(7-chloro[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino]ethyl}amino)nicotinonitrile (Example 54A), 35.6 mg (0.19 mmol) of (2,4-dichlorophenyl)boronic acid and 21.6 mg (0.019 mmol) of tetrakis(triphenylphosphine)palladium(0) are introduced into a mixture of 4 ml of dioxane and 1.3 ml of saturated aqueous sodium carbonate solution under argon. The mixture is degassed with argon and then heated in a microwave at 150° C. for 30 min. Cooling is followed by filtration through an Extrelut® cartridge. Purification by preparative HPLC results in 15.3 mg (19% of theory) of the product as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=2)[CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)#[CH:18]>>[F:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[N:10]=3)[CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(F)c1
Reactant: Brc1cnc2nc(N3CCOCC3)nn2c1
Product: Fc1cccc(C#Cc2cnc3nc(N4CCOCC4)nn3c2)c1

Procedure:
The title compound, a light brown solid, MS: m/e=324.3 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, step 1) and ethynyl-3-fluorobenzene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9]([NH:11][C:12]1[N:13]=[C:14](Br)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)#[CH:26].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.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>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH3:23])[C:9](=[O:10])[NH:11][C:12]1[N:13]=[C:14]([C:26]#[C:25][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccsc1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#Cc2ccsc2)n1

Procedure:
A mixture of tert-butyl-N-[1-[(1-bromoisoquinolin-3-yl)amino]-1-oxopropan-2-yl]-carbamate B4a (150 mg, 0.38 mmol), 3-ethynylthiophene (45 mg, 0.42 mmol), copper(I) iodide (7 mg, 0.04 mmol), Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) and DIPEA (200 μl, 2 mmol) is stirred under argon atmosphere in NMP (1 ml) for 1 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 102 mg (64%). HPLC-MS: M+H=422; tR=1.99 min (*Method—4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:15])C2C=CC=CC=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][N+:22]([O-:25])=[CH:21][CH:20]=1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:15][C:19]2[CH:24]=[CH:23][N+:22]([O-:25])=[CH:21][CH:20]=2)=[N:6][CH:7]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OC(c1ccccc1)c1ccc(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(OCc2ccc(F)cn2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) was dissolved in DMF (20 mL), and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (2.03 g, 15.7 mmol) was added, and the reaction mixture was heated for 1 h at 120° C. Upon cooling, the mixture was diluted with methylene chloride, washed with 5% lithium chloride solution (5×), dried, and concentrated. Purification by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) provided the title compound (1.76 g, 50%) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.12 (d, J=7.7 Hz, 2H), 7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).
Reaction SMILES: [I-].[Li+].[Cl:3][C:4]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[C:5]=1[C:6]([C:8]1[CH:9]=[C:10]([C:19]([O:22]C)=[CH:20][CH:21]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=1)=[O:7]>N1C(C)=CC(C)=CC=1C>[Cl:3][C:4]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[C:5]=1[C:6]([C:8]1[CH:9]=[C:10]([C:19]([OH:22])=[CH:20][CH:21]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2c(Cl)cc(Cl)cc2Cl)cc1Cc1ccc(=O)[nH]n1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(c1ccc(O)c(Cc2ccc(=O)[nH]n2)c1)c1c(Cl)cc(Cl)cc1Cl
Temperature: 165 °C
Yield: 81.5 %

Procedure:
Lithium iodide (4.0 g, 29.7 mmol) was added to a solution of 6-[3-(2,4,6-trichlorobenzoyl)-6-methoxybenzyl]-2H-pyridazin-3-one (2.5 g, 5.9 mmol) [prepared by proceeding as described in Example 3, but replacing 2-fluorophenylacetic acid with 2-methoxyphenylacetic acid] in 2,4,6-collidine (250 ml) and the reaction mixture was heated to 165° C. After 3 h the reaction mixture was cooled to room temperature, and the product was extracted into ethyl acetate. The organic extract was washed with aqueous HCl (5%), NaHCO3 and brine, and dried over MgSO4. The organic solvent was removed in vacuo to give 2.25 g of crude product, which upon recrystallization from chloroform/hexanes gave pure 6-[3-(2,4,6-trichlorobenzoyl)-6-hydroxybenzyl]-2H-pyridazin-3-one (1.97 g) as a solid, mp 257.8° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][CH:14]1[CH2:16][O:15]1>[OH-].[Na+].O>[OH:15][CH:14]([CH3:16])[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: CC1CO1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1c(C)cc(OCC(C)O)cc1C
Temperature: 140 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (500 mg, 3.1 mmol, 1.0 equiv) and 2-methyloxirane (0.22 mL, 3.1 mmol, 1.0 equiv) in 50% aqueous NaOH solution (5.0 mL) was stirred at 140° C. for 4.0 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 1-(4-(2-hydroxypropoxy)-2,6-dimethylphenyl)ethanone (445.9 mg. 2.1 mmol) as yellow oil in 66% yield: 1H NMR (CDCl3, 500 MHz) δ 6.57 (s, 2 H), 4.10-4.20 (s, 1 H), 3.90-3.93 (m, 2 H), 3.75-3.79 (m, 1 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 1.25-1.28 (m, 3 H); ESI-MS: m/z 223.4 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCl>[CH:24]1([C:30]([N:4]2[CH2:3][C:2](=[O:1])[N:7]3[CH2:8][CH2:9][O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:6]3[CH2:5]2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C1CNCC2c3ccccc3OCCN12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCCCC1)N1CC(=O)N2CCOc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Oxo-1,2,3,6,7,12b-hexahydropyrazino[1,2-d][1,4]benzoxazepine (0.9 g) and triethylamine (1 g) were dissolved in dichloromethane (20 ml), cooled in ice and cyclohexanoyl chloride (0.7 g, 1.1 equiv.) added. The mixture was stirred at room temperature for 3 h, then washed with dilute aqueous hydrochloric acid, followed by dilute aqueous ammonia solution. Evaporation of the dichloromethane gave an oil which was purified by column chromatography (SiO2 /chloroform) and crystallised from ether/40°-60° petroleum ether to give white crystals of the title compound m.p. 92°-3°;
Reaction SMILES: [Si](I)(C)(C)C.C(OC([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[N:31]([S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:30]3[CH:29]=[CH:28][N:27]=[C:26]([Cl:41])[C:25]=3[CH:24]=2)[C:18](=[O:42])[CH2:17]1)=O)C1C=CC=CC=1>CC#N>[C:35]1([S:32]([N:31]2[C:30]3[CH:29]=[CH:28][N:27]=[C:26]([Cl:41])[C:25]=3[CH:24]=[C:23]2[CH2:22][N:19]2[CH2:20][CH2:21][NH:16][CH2:17][C:18]2=[O:42])(=[O:33])=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1cc2c(Cl)nccc2n1S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: O=C1CNCCN1Cc1cc2c(Cl)nccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.6 %

Procedure:
TMSI (2.7 mL, 19.0 mmol) is added to a solution of 4-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (5.06 g, 9.38 mmol) in CH3CN (134 mL) at 0° C. The reaction mixture is warmed to RT and stirred for 5 hours. The reaction mixture is concentrated to dryness and the red residue is diluted with MeOH and concentrated to dryness (this is repeated twice). The mixture is diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The crude product is chromatographed eluting with 1-5% MeOH/CH2Cl2 to yield the title product (0.70 g, 1.74 mmol) and unreacted starting material (3.58 g, 6.64 mmol). 1H NMR (CDCl3, 300 MHz) δ8.20 (d, 1H), 7.93 (d, 1H), 7.85 (d, 2H), 7.60 (d, 1H), 7.51 (m, 2H), 6.50 (s, 1H), 5.01 (s, 2H), 3.45 (m, 2H), 3.18 (m, 2H). Ion spray [M+H]+=405, 407, Cl pattern.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=NC=[CH:10][C:5]=2[S:4][CH:3]=1.S1C2=[CH:16][N:17]=CC=C2C=C1>>[Br:1][C:2]1[C:6]2[C:5](=[CH:10][N:17]=[CH:16][CH:7]=2)[S:4][CH:3]=1
Reactant: Brc1csc2ccncc12
Reactant: c1cc2ccsc2cn1
Product: Brc1csc2cnccc12

Procedure:
The title compounds is prepared essentially as described in synthesis of 3-bromothieno[3,2-c]pyridine using thieno[2,3-c]pyridine. mass spectrum (m/e): 215 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[CH3:8][S:9][C:10](SC)=[CH:11][C:12]#[N:13].[H-].[Na+]>CN(C=O)C>[CH3:8][S:9][C:10]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:11][C:12]#[N:13]
Reactant: CSC(=CC#N)SC
Reactant: Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(=CC#N)Nc1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of pyridin-4-ylamine (1.0 g, 11.0 mmol) and 3,3-Bis-methylsulfanyl-acrylonitrile (2.05 g, 12.6 mmol) in DMF at room temperature, was added powdered 4 A molecular sieves. The mixture was stirred for 1 hr. Subsequently the mixture was cooled to 0° C., 60% NaH dispersion in oil (0.92 g, 23.0 mmol) was added portionwise over 1 hr. and it was stirred at 0° C. for an additional 2 hrs. The cold bath was removed and the mixture was stirred at room temperature for 20 hrs. DMF was removed in vacuo and the crude was purified by column chromatography (gradient of EtOAc to 25% MeOH/EtOAc) to afford the desired product as an off-white solid (1.9 g, 89%).