Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:25]=1[CH2:26][N:27]1[C@@H:32]([CH2:33][CH3:34])[CH2:31][NH:30][C:29](=O)[C:28]1=[O:36]>C1COCC1>[Cl:23][C:24]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:25]=1[CH2:26][N:27]1[C@@H:32]([CH2:33][CH3:34])[CH2:31][NH:30][C:29](=[S:10])[C:28]1=[O:36]
Reactant: CC[C@H]1CNC(=O)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC[C@H]1CNC(=S)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 55 °C
Yield: 181.3 %

Procedure:
To a heterogeneous mixture of Lawesson's reagent (346 mg, 0.83 mmol) in THF (16 mL) was added (6S)-1-(2-chloro-3-(trifluoromethyl)benzyl)-6-ethylpiperazine-2,3-dione (555 mg, 1.7 mmol) at once. The mixture was heated at 55° C. for 20 minutes and then concentrated to remove the solvent. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a yellow oil (528 mg, 91%). MS (ESI): mass calcd. for C14H14ClF3N2OS, 350.1; m/z found, 335.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.69 (dd, J=15.9, 7.8 Hz, 2H), 7.38 (t, J=7.8 Hz, 1H), 5.24 (d, J=15.3 Hz, 1H), 4.50 (d, J=15.3 Hz, 1H), 3.67 (dd, J=13.7, 3.9 Hz, 1H), 3.45 (dd, J=12.8, 5.4 Hz, 2H), 1.91-1.75 (m, 2H), 1.00 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>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>[CH3:15][O:14][C:12]([C:3]1[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1)=[O:13]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)c(C(=O)OC)c1

Procedure:
Electrospray MS (positive ion): (M+Na) 338; from dimethyl 4-bromoisophthalate (1.26 g), 3-nitrophenylboronic acid (795 mg) and tetrakis(triphenylphosphine)palladium(0) (167 mg).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][C@@H:18]2[O:23][C:22]3[C:24]([CH:29]=[CH:30][CH3:31])=[C:25]([NH2:28])[CH:26]=[CH:27][C:21]=3[O:20][CH2:19]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][CH:18]2[O:23][C:22]3[C:24]([CH:29]=[CH:30][CH3:31])=[C:25]([NH:28][C:2]([O:4][CH3:5])=[O:3])[CH:26]=[CH:27][C:21]=3[O:20][CH2:19]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CC=Cc1c(N)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC=Cc1c(NC(=O)OC)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
Methyl chloroformate (2.93 mL, 37.9 mmole) was added to a solution of {(2R)-7-amino-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methyl-benzenesulfonate (2.35 g, 6.30 mmole) in ethyl acetate (125 mL), followed by the addition of N,N-diisopropylethylamine (5.50 mL, 31.6 mmole) dropwise over a period of 20 minutes. The solution was stirred under nitrogen at room temperature over a period of 10 hours. This solution was then washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. Filtration, evaporation in vacuum and column chromatography on silica gel with 0.2% methanol/methylene chloride gave the (R)-enantiomer of the title compound as a white foam (1.90 g, 70%). 1H (CDCl3) doublet, 7.8 δ (2 H); doublet, 7.3 δ (3 H); doublet, 6.7 δ (1 H); broad singlet, 6.6 δ (1 H); multiplet, 6.1 δ (2 H); multiplet, 4.4 δ (1 H); multiplet 4.2 δ (3 H); multiplet, 4.0 δ (1 H); singlet, 3.7 δ (3 H); singlet, 2.4 δ (3 H); doublet, 1.9 δ (3 H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 4-trifluoromethylbenzamide (79 mM) and Lawesson's reagent (39 mM) in toluene (200 mL) was heated at reflux for 4 hours under N2. The reaction mixture was cooled and the resulting precipitate was isolated by filtration to give 4-trifluoromethylthiobenzamide as a solid: mp 125° C. (The following general procedure was used to synthesize the various substituted thiobenzamides (Tetrahedron 35,2433, (1979)):
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)[CH:22]=[C:21]([CH3:29])[N:20]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][C:25]([C:23]3[CH:24]=[C:19]([CH3:18])[N:20]=[C:21]([CH3:29])[CH:22]=3)([OH:26])[CH3:27])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cc(C2(C)CO2)cc(C)n1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc(C)n1
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF and sodium hydride (120 mg, 3 mmol) was added. The reaction mixture was stirred for 10 min and 2,6-dimethyl-4-(2-methyloxiran-2-yl)pyridine (210.6 mg, 1.3 mmol) was added dropwise to the reaction mixture with constant stirring. The reaction mixture was stirred at RT overnight. The reaction mixture was poured on crushed ice and the precipitate obtained was filtered under vacuum; washed with water and hexane to obtain 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,6-dimethylpyridin-4-yl)propan-2-ol (323 mg) which was dissolved in DCM (3 mL) and cooled to 0° C. Thionylchloride (3 mL) was added dropwise and the reaction mixture was allowed to cool to RT. The reaction mixture was then stirred at RT for 2 h. Thionylchloride was evaporated under vacuum by azeotropic distillation with DCM. 1N NaOH solution was added to basify (pH—12-13) the reaction mixture and the compound extracted with EtOAc (2×30 mL). The organic layer was concentrated under vacuum to get the crude desired product. The crude compound was further purified through reverse phase HPLC. Yield: 17 mg. 1H NMR (CD3OD, Di-HCl salt) δ (ppm): 7.95 (s, 2H), 7.66 (s, 1H), 7.58 (s, 1H), 7.25 (m, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.22 (m, 2H), 3.10 (s, 6H), 2.10 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([CH:22]=[O:23])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CN(C)C=O
Reactant: CN1CCCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCCCc2cc(C=O)ccc21
Temperature: 70 °C
Reaction time: 5 h

Procedure:
The starting material was prepared as follows: A. 45 ml of dimethylformamide were treated under an argon atmosphere with 16.2 ml of phosphorus oxychloride. After the reaction had faded away, 7.30 g of 2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine were added and the reaction mixture was stirred at 70° C. for 5 hours. Thereafter, the mixture was poured on to ice, made alkaline with sodium hydroxide solution, extracted with ether, washed with water, dried and evaporated. Chromatorgraphy on silica gel (petroleum ether/ethyl acetate (87:13)) yielded 4.38 g of 2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine-7-carboxaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[O:14]>C1(C)C=CC=CC=1>[OH:14][CH:13]([CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11])[C:12]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)CC(=O)c1ccc(OC)cc1
Yield: 82 %

Procedure:
15.02 g (0.10 mol) of 4′-methoxyacetophenone and a 45% toluene solution (25 ml) of ethyl glyoxalate were stirred overnight at 100° C. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 20.62 g (yield: 82%) of ethyl 2-hydroxy-4-(4-methoxyphenyl)-4-oxo-butyrate as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)=[O:9]
Reactant: O=C(O)c1cc(F)ccc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)ccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)benzoic acid (Anales de la Asociacion Quimica Argentina 1985, 73, 509) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 7.99 (4H, m), 7.30 (2H, d, J=7.6 Hz), 7.14–7.03 (3H, m), 6.96–6.92 (2H, m), 6.80 (1H, dd, J=9.2, 4.4 Hz), 4.70 (2H, d, J=5.9 Hz), 3.91 (3H, s); MS (ESI) m/z 398 (M+H)+, 396 (M−H)−.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[CH:11]=1>O>[CH3:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH:6]=[CH:16][C:12]1[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(=O)C=Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
100 ml of 10% strength sodium hydroxide solution were added to a solution of 35 g (0.35 mol) of 3,3-dimethylbutan-2-one and 38 g (0.355 mol) of 3-pyridinealdehyde in 2,000 ml of water and the solution was stirred overnight at room temperature. The crystalline precipitate was filtered off, dried and recrystallized from n-hexane. 34.1 g (51.5% of theory) of 4,4-dimethyl-1-pyridin-3-yl-1-penten-3-one of melting point 68°-70° C. were obtained. ##STR117##
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:31][CH2:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NCC1CCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCC3CCC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclobutylmethanamine as an off-white solid (67%). MS 414 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][O:8][C:4]1[N:3]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(OCc2cccs2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: c1cc(OCc2cccs2)nc(N2CCNCC2)c1
Temperature: 125 °C
Yield: 47 %

Procedure:
A mixture of the product from step 1 above (1.35 g, 5.98 mmol), piperazine (1.55 g, 17.9 mmol) and K2CO3 (0.91 g, 6.58 mmol) in acetonitrile (5 mL) was heated at 125 125° C. for 6.5 h in a sealed pyrex flask. The reaction mixture was diluted with dichlorometane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel (16×4 cm) chromatography using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated and the oily residue was redissolved in CHCl3/ether (1:1). Filtration and concentration in vacuo furnished 0.78 g (47%) of the title compound as a beige oil.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH2:8]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH3:9].[OH-].[Na+].N>>[CH2:8]([O:10][CH2:11][CH2:12][N:13]([CH3:5])[C:14](=[O:16])[CH3:15])[CH3:9]
Reactant: COS(=O)(=O)OC
Reactant: CCOCCNC(C)=O
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: CCOCCN(C)C(C)=O
Yield: 89.9 %

Procedure:
37.8 g (0.3 mole) of dimethyl sulfate and 26.2 g (0.2 mole) of N-α-ethoxyethyl-acetamide are simultaneously added dropwise to 100 ml of 50% strength sodium hydroxide solution at 10°-15° C., while stirring intensively. The mixture is subsequently stirred for 3 hours, residual dimethyl sulfate is decomposed by adding concentrated ammonia, the phases are separated in a separating funnel, the aqueous layer is extracted several times with toluene and, after stripping off the solvent, the residue is distilled in vacuo. 26.1 g (90% of theory) of N-α-ethoxyethyl-N-methylacetamide of boiling point24 90°-94° C. are obtained.
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])[CH:13]=2)[CH:8]=[CH:7]1.O.CN([CH:30]=[O:31])C>>[CH:30]([C:8]1[C:9]2[C:14](=[CH:13][C:12]([CH2:15][C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)[NH:6][CH:7]=1)=[O:31]
Reactant: COC(=O)c1cccc(Cc2ccc3cc[nH]c3c2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cc(Cc3cccc(C(=O)O)c3)ccc12
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
(I-8): 3 ml anhydrous DMF was cooled in ice-water bath, then 50 μl POCl3 was added, the solution was stirred about 15 minutes, then 32 mg of methyl 3-(1H-indol-6-ylmethyl)benzoate in 2 ml DMF was added. The mixture was heated to 40° C. for 3 hours. After cooling to room temperature, the mixture was treated by cold water, following the general procedure above, the target compound was purified as a brown solid. Mass calculated for C17H13NO3: 279; LCMS: 280.6 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.87 (1H, s), 8.24 (1H, d, J=3.0 Hz), 7.99 (1H, s), 7.80 (1H, d, J=7.3 Hz), 7.76 (1H, d, J=7.9 Hz), 7.52 (1H, d, J=7.9 Hz), 7.41 (1H, t, J=7.9 Hz), 7.34 (1H, s), 7.12 (1H, d, J=7.3 Hz), 4.12 (2H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]2=[C:7]3[C:12](=[C:13]([NH2:15])[N:14]=[C:5]2[CH:4]=1)[N:11]=[CH:10][CH:9]=[CH:8]3)=[CH2:2]>CCO.C(Cl)Cl.[Pd]>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]2=[C:7]3[C:12](=[C:13]([NH2:15])[N:14]=[C:5]2[CH:4]=1)[N:11]=[CH:10][CH:9]=[CH:8]3)[CH3:2]
Reactant: C=Cc1ccc2c(c1)nc(N)c1ncccc12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCc1ccc2c(c1)nc(N)c1ncccc12
Reaction time: 8 h

Procedure:
A mixture of 8-vinylbenzo[f][1,7]naphthyridin-5-amine (1.0 eq) (from Example 91) and Pd/C (wet, 10% wt) in EtOH was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The Pd/C was filtered off through celite, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-60% EtOAc/Hexanes to give 8-ethylbenzo[f][1,7]naphthyridin-5-amine as a white foam: 1H NMR (acetone-d6): δ 8.98 (dd, 1H), 8.88 (dd, 1H), 8.35 (d, 1H), 7.82 (dd, 1H), 7.46 (d, 1H), 7.22 (dd, 1H), 6.63 (br s, 2H), 2.78 (q, 2H), 1.30 (t, 3H). LRMS [M+H]=224.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>C(#N)C>[CH2:24]([O:12][C:10]1[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[CH:23]=[CH2:22]
Reactant: COC(=O)c1cc(C(C)C)c(O)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(O)c(C(=O)OC)cc1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.9 %

Procedure:
A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (10 ml) was treated with allyl bromide (0.35 ml, 4.0 mmol) and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The organic material was extracted with dichloromethane (2×20 ml), the combined organic extracts were evaporated in vacuo and the residue subjected to column chromatography on silica. Elution with 2-10% ethyl acetate in petroleum ether afforded methyl 4-allyloxy-2-hydroxy-5-isopropylbenzoate (330 mg, 60%) as a colourless solid. 1H NMR (DMSO-d6) 10.68 (1H, s), 7.55 (1H, s), 6.54 (1H, s), 6.06 (1H, m), 5.42 (1H, dm), 5.29 (1H, dm), 4.65 (2H, m), 3.88 (3H, s), 3.16 (1H, m), 1.16 (6H, d).
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:18]=1.C(O)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:17]([O:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:18]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1c(O)ncc2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(OCC)ncc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To the title compound of Step A (583 mg, 2.68 mmol) in THF (13 mL) was added triphenylphosphine (1.06 g, 4.03 mmol), ethanol (0.24 mL, 4.03 mmol) and DIAD (0.79 mL, 4.03 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was evaporated. The crude was purified via silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound of Step B (498 mg, 76%). MS (ESI) mass calcd. for C14H15NO3, 245.1. m/z found 246.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) δ 8.97 (s, 1H), 7.91-7.82 (m, 2H), 7.65-7.60 (m, 1H), 7.42-7.36 (m, 1H), 4.59-4.48 (m, 4H), 1.48-1.39 (m, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([O:24][CH3:25])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([O:24][CH3:25])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(C)(C)C)ccc1S(=O)(=O)Nc1ccsc1C(=O)O
Temperature: 77.5 °C
Yield: 78.3 %

Procedure:
To a solution of 32 (0.25 g; 0.65 mmol) in tetrahydrofuran (15 mL) and methanol (5 mL) was added aqueous sodium hydroxide (10 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL, 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a white solid (188 mg).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.CCOCC>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-:21])[CH:3]=1
Reactant: Clc1ccc2c(Br)cncc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: [O-][n+]1cc(Br)c2ccc(Cl)cc2c1
Temperature: 25 °C

Procedure:
4-bromo-7-chloroisoquinoline (3-6)(1 g, 4.12 mmol, 1.0 equiv.) was dissolved in anhydrous CH2Cl2 (8.2 mL) and treated with mCPBA (1.622 g, 9.40 mmol, 2.3 equiv.). The reaction mixture was stirred at room temperature, forming 3-7 as a white precipitate. Following dilution with Et2O, the solid was collected and used without further purification in the next step. LRMS m/z (M+H) 260.1 found, 259.9 required.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS([C:13]1[N:18]=[C:17]([C:19]2[C:20]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Cl:39])[CH:33]=3)=[N:21][N:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=23)[CH:16]=[CH:15][N:14]=1)(=O)=O>O>[Cl:39][C:34]1[CH:33]=[C:32]([C:20]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:18]=3)=[C:23]3[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][N:22]3[N:21]=2)[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)c(Cl)c3)nn3cc(C(F)(F)F)ccc23)n1
Reactant: NCCN1CCCC1
Solvent: O
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(NCCN3CCCC3)n2)cc1Cl

Procedure:
2-Pyrrolidin-1-ylethylamine (0.04 mL) and 4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl methyl sulfone (0.02 g) were mixed at room temperature and heated with an airgun until a homogenous melt was obtained (2 min). Upon cooling, water was added. The precipitated solid was filtered and dried to give the title compound as a beige solid (0.012 g); 1H NMR (d6-DMSO) δ 9.50(1H, s), 8.48(1H, bs), 8.18(1H, d), 7.83(1H, d), 7.68(1H, dd), 7.62(1H, m), 7.56(1H, dd), 7.12(1H, bs), 6.42(1H, bs), 2.44(2H, bs), 1.67(4H, bs); m/z 505 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1.S(Cl)([Cl:17])=O>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:17])=[O:14])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(OCCBr)cc1
Product: O=C(Cl)Cc1ccc(OCCBr)cc1
Yield: 86 %

Procedure:
4-Hydroxyphenylacetic acid (100 g, 0.6 mol) and cesium carbonate (250 g) were suspended in 300 mL of anhydrous acetonitrile followed by addition of 1,2-dibromoethane (300 mL). The suspension was brought to reflux for 24 hours in a 2L 3 neck round bottom flask fitted with a mechanical stirrer and reflux condenser then cooled to room temperature. The mixture was diluted to a volume of 2L by addition of ethyl ether and the suspension was filtered. Concentration of the filtrate in vacuo afforded a colorless oil which was purified by vacuum distillation (0.2 mm Hg, 140-145° C.) to give methyl 4-(2-bromoethoxy)-phenylacetate (93.14 g, 60% yield) as a colorless oil. The methyl 4-(2-bromoethoxy)-phenylacetate was taken into methanol (250 mL) and the resulting solution was cooled to 0° C. Sodium hydroxide (29 g) in a minimum of water was added to the methanol solution in portions and the mixture was stirred at 0° C. for an additional 30 minutes. The solution was warmed to room temperature then concentrated to a white solid. The residue was taken into water and the solution washed once with ethyl ether. The aqueous solution was then acidified to pH 1 by addition of concentrated aqueous hydrochloric acid to give a thick suspension. Filtration and drying afforded 4-(2-bromoethoxy)-phenylacetic acid (86 g, 97% yield) as a colorless solid. The 4-(2-bromoethoxy)-phenylacetic acid (50 g) was taken into thionyl chloride (70 mL) and brought to reflux under an atmosphere of nitrogen for 2 hours. Fractional vacuum distillation (0.2 mm Hg, 139-140° C.) afforded 4-(2-bromoethoxy)phenylacetyl chloride (46.0 g, 86% yield) as a colorless oil that quickly crystallized on cooling. 1H NMR (CDCl3) 6.95, 6.76, 6.60 (m, 11 H, Ar—H), 4.68 (m, 1H), 4.24 (m, 2 H), 3.80 (m, 1H), 3.41-3.63 (m, 3H), 3.07 (m, 1H), 2.87 (m, 2H), 2.61 (m, 1H); ES-MS (m/z) 458 [M+H]+.