Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.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>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)c1ccc(Br)cn1
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: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc(F)cc2)cn1
Temperature: 77.5 °C
Yield: 69.8 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)ethanone (1.0 g, 4.99 mmol) in toluene (100 mL) and ethanol (50 mL) was added 4-fluoro phenyl-boronic acid (1.4 g, 9.99 mmol), 2M sodium carbonate (3.7 g, 34.99 mmol, 12 mL water), Pd(PPh3)4 (0.228 g, 0.25 mmol) under argon. The resulting mixture was heated at 75-80° C. for 6 h. The contents were cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with bicarbonate solution (2×100 mL) and brine solution (2×100 mL). The organic layer was dried over sodium sulphate and distilled off to obtain the crude product. The product was purified by flash chromatography (100-200μ; 35% ethyl acetate in hexane) to afford 1-(5-(4-fluorophenyl)pyridin-2-yl)ethanone (0.75 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.25 (dd, 1H), 8.00 (d, 1H), 7.86 (m, 2H), 7.36 (t, 2H), 2.65 (s, 3H); LC-MS m/z calculated for [M+H]+ 216.23 found, 216.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:33])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]5[O:30][CH2:29][CH2:28][NH:27][CH2:26]5)=[C:19]([O:31][CH3:32])[CH:18]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[C:34]([O-])([O-])=O.[K+].[K+].[Na+].[I-].CI>CC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:33])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]5[O:30][CH2:29][CH2:28][N:27]([CH3:34])[CH2:26]5)=[C:19]([O:31][CH3:32])[CH:18]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OCC1CNCCO1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OCC1CN(C)CCO1
Product: Cl
Reaction time: 8 h

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-[3-methoxy-4-(morpholin-2-ylmethoxy)-phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (460 mg, 0.928 mmol) in dry acetone (3 mL) under nitrogen. Add K2CO3 (321 mg, 1.11 mmol) and NaI (14 mg, 0.092 mmol). Evacuate under vacuum and charge the reaction mixture with nitrogen. Mix well and then add MeI (70 mL, 1.11 mmol). Stir the reaction mixture overnight. Add saturated NH4Cl solution (5 mL) and extract with EtOAc (3×10 mL). Wash the combined organic layers with water (10 mL), dry with Na2SO4, filter, and concentrate. Purify the resulting residue with silica gel chromatography, using 0-10% MeOH/CHCl3 to give the title compound. Dissolve the compound in minimal CH2Cl2 and add HCl/Et2O to make the HCl salt as a yellow-orange solid (74 mg, 15%). MS (ES+) 500.0 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[NH2:22][N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:22][N:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: Nn1cccc1
Solvent: Cc1ccccc1
Product: CC(=Nc1c(C)cc(C)cc1C)c1cccc(C(C)=Nn2cccc2)n1
Reaction time: 40 h

Procedure:
Monoimine (1, 3.0 g, 10.7 mmol) and 1-aminopyrrole (1.0 g, 12.18 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 40 hours the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield 1.85 g (50%) of mixed diimine 15.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH4+]=[S:12].C(N(CC)CC)C>N1C=CC=CC=1.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4](=[S:12])[NH2:5]
Reactant: N#Cc1cc(F)ccc1F
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1cc(F)ccc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
A stirred solution of 2,5-difluorobenzonitrile (25 g, 180 mmol) in pyridine (90 mL) was treated with 20 wt % ammonium sulfide in water (67.4 mL, 198 mmol) and triethylamine (27.4 mL, 198 mmol). The reaction mixture was stirred at 50° C. for 5 hr until the reaction was complete. After cooling to room temperature, the mixture was diluted with cold water and extracted with EtOAc. The organic layer was separated, then washed with H2O (×3), brine (×3), then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product. Purification on silica gel column (20% EtOAc in hexanes) to afford 2,5-difluorobenzothioamide as yellow solid (31.0 g, 99%). 1H NMR (CDCl3, 300 MHz): δ 7.12 (m, 2H), 7.90 (br, 2H), 8.08 (m, 1H). LC/MS (uplc): MH+174.0, 0.64 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.C[Si]([C:15]#[N:16])(C)C.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>[C:15]([CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]1[C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])#[N:16]
Reactant: CC(C)C(=O)Cl
Reactant: C[Si](C)(C)C#N
Reactant: c1ccc2cnncc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C(=O)N1N=Cc2ccccc2C1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A stirred solution of phthalazine (3.25 g) and trimethylsilylcyanide (4.96 g) in dichloromethane (40 ml), containing a catalytic amount of anhydrous aluminium chloride (10 mg), was treated dropwise with isobutyryl chloride (5.3 g), keeping the temperature of the mixture below 32° C. The mixture was then stirred at the ambient temperature for 18 hours and then it was washed successively with water (50 ml), aqueous hydrochloric acid (1N; 2×30 ml), water (50 ml), aqueous sodium hydroxide solution (1N; 2×30 ml) and water (50 ml) and then it was dried over magnesium sulphate. The solution was evaporated and the resulting residue was triturated with a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (3:1 v/v; 30 ml). The solid which separated was collected and dried, to give 1-cyano-2-isobutyryl-1,2-dihydrophthalazine (5.56 g) in the form of a colourless solid, m.p. 144°-146° C. [Elemental analysis: C, 68.9; H, 5.61; N, 18.4%; calculated: C, 68.7; H, 5.77; N, 18.5%; NMR (in CDCl3): 1.16 (3H, d, J=7 Hz), 1.27 (3H, d, J=7 Hz), 3.55 (1H, septet, J=7 Hz), 6.66 (1H, s), 7.36-7.44 (2H, m), 7.50-7.58 (2H, m), 7.73 (1H, s); Mass spectrum (electron impact) m/z=227].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH:10]([CH:12]=O)=O>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=CC=O
Solvent: CO
Product: Cc1ccc2nccnc2c1
Reaction time: 16 h
Yield: 25 %

Procedure:
A solution of 4-methyl-1,2-phenylenediamine (5.0 g, 41 mmol) in methanol (250 mL) was treated with a solution of 40% aqueous glyoxal and stirred for 16 h. The solvent was evaporated and the residue was distilled under vacuum (2 mm Hg, 85-88° C.) to leave a colorless oil (1.5 g, 25%). LC/MS (Method A): r.t.=1.02 min., purity=99.5%.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:31])[C:19]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)[CH:18]1[C:28](Cl)=[O:29].[C-:32]#[N:33].[K+]>O>[CH3:16][C:17]1([CH3:31])[C:19]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)[CH:18]1[C:28]([O:12][CH:11]([C:32]#[N:33])[C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:29]
Reactant: [C-]#N
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)Cl)C12C=Cc1ccccc12
Agent: [K+]
Solvent: O
Product: CC1(C)C(C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C12C=Cc1ccccc12

Procedure:
A mixture of 0.05 gram-mole of m-phenoxybenzaldehyde and 0.05 gram-mole of 3,3-dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylic acid chloride is added slowly, portionwise, to a solution of 0.075 gram-mole of potassium cyanide in 100 ml of water at 5° C. the mixture is stirred for 1.5 hours at 5° and then extracted with three 50--ml portions of ether. The extracts are washed with 10% hydrochloric acid solution, saturated sodium bicarbonate solution, and water and then dried over sodium sulfate. Removal of the ether under vacuum leaves α-cyano-m-phenoxybenzyl 3,3-dimethylspiro[cyclopropane-1,1'-indene]-2-carboxylate as a yellow-brown oil which is a useful insecticide as taught in U.S. Pat. No. 3,966,959 (1976).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl.O>CO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 36 h
Yield: 89.6 %

Procedure:
To a solution of methyl 5-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexyl)amino]-2-fluoro-benzoate (454 mg, 0.91 mmol) in MeOH (40 mL) was added an aqueous solution of NaOH (2.7 mL, 1N). The reaction mixture was stirred at 50° C. for 36 hrs. Then an aqueous solution of HCl (5 mL, 1N) was added and the reaction mixture was poured into water (100 mL) and extracted with Et2O (200 mL+2×100 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give 396 mg (90%) of the title compound as a beige powder. HPLC, Rt: 5.8 min (purity: 99.1%). LC/MS, M+(ESI): 486.1, M−(ESI): 484.0. 1H NMR (CDCl3) δ: 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.29 (dd, J=5.6, 3.3 Hz, 1H), 7.17 (m, 4H), 6.97 (dd, J=10.2, 9.0 Hz, 1H), 6.78 (ddd, J=9.0, 3.4, 3.3 Hz, 1H), 4.52 (s, 2H), 3.39 (t, J=7.6 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.61 (m, 4H), 1.42-1.25 (m, 8H), 0.94 (t, J=7.3 Hz, 3H), 0.90 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([C:30](=[S:32])[NH2:31])[CH:16]=2>CN(C=O)C.O>[F:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([C:30]1[S:32][CH:2]=[C:3]([CH3:4])[N:31]=1)[CH:16]=2
Reactant: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(C(N)=S)ccc3n2Cc2cccc(F)c2)C1
Reactant: CC(=O)CCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(-c2ccc3c(c2)c2c(n3Cc3cccc(F)c3)CC[C@@H](NC(=O)C(C)C)C2)n1
Yield: 85.1 %

Procedure:
Combine chloroacetone (0.197 g, 2.13 mmol) and (R)-N-(9-(3-fluorobenzyl)-6-thiocarbamoyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Preparation 22) (0.300 g, 0.708 mmol) and heat at 80° C. in DMF under nitrogen for 2.5 h. Upon cooling, dilute the mixture with water and collect the precipitate by filtration. Slurry the precipitate in hot EtOAc to give 0.278 g of a yellow solid. MS (ES): m/z 462 (M+1); HPLC: Rt=3.33 min (100%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.Cl.[CH2:18]([NH2:20])[CH3:19].C(N(CC)CC)C>C(O)(C)C>[CH2:18]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1)[CH3:19]
Reactant: CCN
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCNc1nc(-c2ccccc2)ncc1[N+](=O)[O-]
Yield: 93.3 %

Procedure:
A mixture of 4-chloro-5-nitro-2-phenylpyrimidine (3 g), ethylamine hydrochloride (1.6 g), triethylamine (3.9 g) and isopropanol (60 ml) is refluxed for three hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added chloroform and water. The chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from isopropanol to give the desired compound (2.9 g).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21](O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:25]1([NH:24][C:21]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:18])([F:19])[F:20])=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 4-phenyl-8-trifluoromethyl-quinoline-3-carboxylic acid (0.24 g, 0.757 mmole) in 15 mL DMF was added aniline (0.137 mL, 1.51 mmole), EDCI-HCl (0.218 g, 1.13 mmole), and DMAP (0.184 g, 1.51 mmole). After stirring at room temperature overnight, the solution was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded onto silica gel and chromatographed with hexanes:ethyl acetate (9:1) to afford 0.211 g (71%) of the title compound as a white solid: mp 207-208° C.; Calculated mass for C23H15N2F3O is 392.38, found by ESI MS, 393 (M+H)+, found by HRMS (ESI), 393.12056 (M+H)+; 1H NMR (DMSO-d6) δ 10.40 (bs, 1H), 9.25 (bs, 1H), 8.31 (d, 1H, J=6.9 Hz), 7.90 (d, 1H, J=8.3 Hz), 7.77 (t, 1H, J=7.5 Hz), 7.47 (m, 7H), 7.28 (t, 2H, J=7.5 Hz), 7.06 (t, 1H, J=7.06 Hz). Anal. Calcd for C23H15N2F3O: C, 70.40; H, 3.85; N, 7.14. Found: C, 70.00; H, 3.61; N, 6.96.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:17])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[F:20][CH2:21][C:22]([CH2:26][F:27])([OH:25])[C:23]#[CH:24]>CS(C)=O.C(N(CC)CC)C.O>[F:19][C:3]1[C:2]([C:24]#[C:23][C:22]([CH2:26][F:27])([OH:25])[CH2:21][F:20])=[CH:18][C:6]2[C:7]3[N:8]=[C:9]([C:15]([NH2:17])=[O:16])[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(O)(CF)CF
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: NC(=O)c1nc2c(s1)CCOc1cc(F)c(C#CC(O)(CF)CF)cc1-2

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G. Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (200 mg, 0.58 mmol, 1.00 equiv), 1-fluoro-2-(fluoromethyl)but-3-yn-2-ol (280 mg, 1.75 mmol, 3.00 equiv) and Pd(PPh3)Cl2 (82 mg, 0.20 equiv) in DMSO (0.7 mL) and triethylamine (0.7 mL). The final reaction mixture was irradiated with microwave radiation for 1 h at 70° C. The resulting solution was diluted with 15 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM:MeOH (10:1). This resulted in 72.9 mg (32%) of 8-Fluoro-9-(4-fluoro-3-fluoromethyl-3-hydroxy-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid. LC-MS: (ES, m/z): 383[M+H]+; 1H-NMR: (400 MHz, CD3OD, ppm) δ 8.735 (d, 1H), 6.875 (d, 1H), 4.559 (d, 4H), 4.400 (t, 2H), 3.450 (t, 2H).
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].ClCCl.[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[OH:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([C:6]([O:8][CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:7])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(C(=O)OC(c2ccccc2)c2ccccc2)cc(OC)c1O
Reaction time: 1 h

Procedure:
Combine 4-hydroxy-3,5-dimethoxybenzoic acid (2.0 g, 12.6 mmol) and dichloromethane (200 mL). Add diphenyl diazomethane (2.67 g). After 1 hour, add an additional portion of diphenyl diazomethane (1.2 g). After 1 hour, add 4-hydroxy-3,5-dimethoxybenzoic acid (0.5 g). Concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting sequentially with 20% ethyl acetate/hexane and 50% ethyl acetate/hexane to obtain the diphenylmethyl 4-hydroxy-3,5-dimethoxybenzoate: Rf=0.56 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(CO)cc3C)cc12
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C=O)cc3C)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)methanol (from the previous step) in DMSO was added 2-iodoxybenzoic acid (IBX, 2.5 eq). The reaction was stirred at room temperature for 3 hours before being diluted with water. Extraction with EtOAc followed by concentration gave a crude residue which was purified by chromatography (silica gel, 50-100% EtOAc in hexanes) to afford 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzaldehyde.
Reaction SMILES: C(Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N-]=[N+]=[N-].[Na+].[N-:17]=[N+]=[N-].C1(C)C=CC=CC=1.C[C:28](C)=[O:29]>O>[CH2:2]([N:17]=[C:28]=[O:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(C)=O
Reactant: CCCCCCCCCC(=O)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCN=C=O
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
A solution of decanoyl chloride (20 g, 104.8 mmoles) in acetone (30 ml) was dropped into a solution of sodium azide (9.53 g, 146.6 mmoles) in water (30 ml), cooled in an ice bath. The temperature of the azide solution was kept between 10 and 15° C. after one hour, the solution was transferred in a separatory funnel and the lower phase (the aquoeus one) was eliminated. The higher phase was transferred into a flask containing 100 ml of toluene, previously warmed at 65° C. After 1.5 hours, the solution was evaporated to dryness, giving 13.37 g crude product, which after vacuum distillation gave 8.3 g pure product in the form of colorless liquid.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16](=[O:29])[NH:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:13][N:12]=2)=[C:7]([Cl:36])[CH:6]=1.[Li+].[OH-].Cl.C(Cl)Cl>C1COCC1.O>[Cl:36][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:37])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[C:15]([C:16](=[O:29])[NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:14]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:13][N:12]=1
Reactant: COC(=O)Cc1ccc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=C(O)Cc1ccc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (3-Chloro-4-{4-[2-(2,4-dichloro-phenoxy)-ethylcarbamoyl]-5-phenyl-isoxazol-3-yl}-phenyl)-acetic acid methyl ester 36 (0.85 mmol) is dissolved in THF (5 mL). A solution of 1 M LiOH in H2O (2 mL) is added and the mixture is stirred overnight at room temperature. The mixture is acidified with 1 M HCl (3 mL), DCM (50 mL) is added and the organic layer washed with H2O (3×30 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound G1 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.93 (dd, J=1.8 Hz, J=7.8 Hz, 2H), 7.52-7.23 (m, 7H), 7.17 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.15 (t, J=5.3 Hz, NH), 3.92 (t, J=4.8 Hz, 2H), 3.72 (q, J=5.3 Hz, 2H), 3.50 (s, 2H). MS calculated for C26H20Cl3N2O5 (M+H+) 545.0, found 545.3.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.BrC1C=C2C(C=C([CH:27]([NH:29][CH:30]3[CH2:32]C3)C)N2)=CC=1.[Li][CH2:34]CCC.S1CCC(=O)CC1>>[CH3:34][N:29]([CH2:30][CH2:32][N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:2]3([OH:1])[CH2:7][CH2:6][S:5][CH2:4][CH2:3]3)[CH:16]=2)[CH:12]=[CH:13]1)[CH3:27]
Reactant: CC(NC1CC1)c1cc2ccc(Br)cc2[nH]1
Reactant: OC1(c2ccc3cc[nH]c3c2)CCSCC1
Reactant: [Li]CCCC
Agent: O=C1CCSCC1
Product: CN(C)CCn1ccc2ccc(C3(O)CCSCC3)cc21

Procedure:
1-(N-Cyclopropylamino)ethyl)-6-(4-hydroxy-tetrahydrothiopyran-4-yl)-1H-indole: (34.2 mg, 8%); from 6-bromo-1-(N-Cyclopropylamino)ethyl indole (400.0 mg, 1.32 mmol), nBuLi (2.5M, 1.32 mL, 3.30 mmol) and tetrahydrothiopyran-4-one (760.0 mg, 6.59 mmol).
Reaction SMILES: II.Cl[CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CN(C)[CH:12]=[CH:13][C:14](=[O:16])[CH3:15]>O1CCCC1>[O:7]1[CH2:8][CH2:9][CH:4]([CH:12]=[CH:13][C:14](=[O:16])[CH3:15])[CH2:5][CH2:6]1
Reactant: ClC1CCOCC1
Reactant: CC(=O)C=CN(C)C
Agent: II
Solvent: C1CCOC1
Product: CC(=O)C=CC1CCOCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
10.8 g (400 mmol) of Mg turnings are introduced into 30 ml of tetrahydrofuran containing a catalytic amount of iodine, and 5 ml of 4-chlorotetrahydropyran are added. The mixture is warmed to 50° C., and 45.2 g (375 mmol) of 4-chlorotetrahydropyran, dissolved in 120 ml of tetrahydrofuran, are added dropwise at such a rate that the internal temperature does not exceed 70° C. The mixture is stirred for a further 1 hour and subsequently cooled to room temperature. 42.4 g (375 mmol) of 1-(dimethylamino)but-1-en-3-one are added dropwise to the stirred mixture at such a rate that the reaction temperature does not exceed 30° C. The mixture is subsequently stirred for a further 2 hours and hydrolyzed, and the pH of the solution is adjusted to exactly 7. The phases are separated, and the aqueous phase is extracted several times with 200 ml of ethyl acetate or methyl tert.-butyl ether, dried and subjected to fractional distillation, to give 42.0 g (75%) of 1-(4-tetrahydropyranyl)but-1-en-3-one of boiling point 93° to 95° C./5 mmHg.