Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([N:9]([CH2:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]2[C:31]#[C:30][C:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:23]=4[CH:22]=2)=[CH:18][CH:17]=[C:16]([C:32]([OH:34])=[O:33])[CH:15]=3)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C)C=O>[CH2:44]([O:43][C:41]([CH2:40][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:32]([OH:34])=[O:33])[CH:15]=2)[C:20]([C:21]2[C:31]#[C:30][C:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:23]=3[CH:22]=2)=[C:12]1[CH2:11][N:9]([C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=1)[CH3:10])=[O:42])[CH3:45]
Reactant: COc1ccc(C(=O)N(C)Cc2[nH]c3cc(C(=O)O)ccc3c2-c2c#cc3c(c2)CCCCC3)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CN(C)C(=O)c2ccc(OC)cc2)c(-c2c#cc3c(c2)CCCCC3)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-{[(4-methoxy-benzoyl)-methyl-amino]-methyl}-3-(benzocyclohept-1-enyl)-1H-indole-6-carboxylic acid on Wang resin (100 mg; prepared according to the procedure outlined in Example 10) in dimethylformamide (1.5 mL) was added sodium hydride (60% in mineral oil; 20 mg) and the mixture was stirred at room temperature for 30 min. Ethyl bromoacetate (0.1 mL) was added and the mixture was stirred for 3 h. The mixture was filtered, washed with water (1×1.5 mL), tetrahydrofuran (2×1.5 mL), dichloromethane (2×1.5 mL), and dried. The product was cleaved from the resin by treatment with 1:1 trifluoroacetic acid/dichloromethane for 1 h; 1H NMR (DMSO-d6) δ 1.15 (t, 3 H), 2.10 (m, 2 H), 2.20 (m, 2 H), 2.70 (s, 3 H), 2.80 (m, 2 H), 3.80 (s, 3 H), 4.05 (q, 2 H), 4.80 (s, 2 H), 5.20 (br s, 2 H), 6.35 (t, 1 H), 6.80 (d, 1 H), 6.97 (d, 2 H), 7.08 (m, 2 H), 7.20 (m, 1 H), 7.38 (d, 2 H), 7.55 (d, 1 H), 7.80 (d, 1 H), 7.95 (s, 1 H), 11.40 (br s, 1 H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:16][C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=2)=[O:18])[C:9]([N:11]1[CH2:14][C:13](=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:29].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:38]O>CO>[CH2:1]([C@H:8]([NH:16][C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=2)=[O:18])[C:9]([N:11]1[CH2:12][C:13](=[N:38][OH:29])[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CN(C(=O)[C@H](Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CC(=NO)C1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
A solution of 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-oxo-azetidin-1-yl)-2-oxo-ethyl]-amide (product of Example 170, 50 mg, 0.13 mmol), sodium acetate trihydrate (43 mg, 0.32 mmol) and hydroxylamine hydrochloride (18 mg, 0.25 mmol) in methanol (2 mL) was heated at reflux for 8 h and concentrated. The residue was partitioned between dichloromethane and saturated aqueous NaHCO3. The organic layer was separated and dried giving a colorless solid which was triturated with ether-hexanes and dried (yield 36 mg, 69%): HPLC (50/50) 6.74 min (99%); TSPMS 411/413 (MH+, 10%), 180 (100%); 1H NMR (DMSO-d6) δ 11.75 (br, 1H), 11.10 (s, 0.5H), 11.08 (s, 0.5H), 8.99 (d, 1H, J=9 Hz), 7.73 (d, 1H, J=2 Hz), 7.4-7.1 (m, 8H), 5.0 (m, 1H), 4.84.5 (m, 4H), 3.1 (m, 2H).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=[O:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.[I:26][CH3:27]>CC(C)=O>[CH3:27][N+:13]1([CH2:14][CH:15]2[CH2:17][CH2:16]2)[C@@H:8]2[CH2:7][C:6]3=[CH:1][CH:2]=[C:3]([OH:25])[C:4]4[O:19][C@H:18]5[C:20]([CH2:22][CH2:23][C@:9]2([OH:24])[C@:10]5([C:5]=43)[CH2:11][CH2:12]1)=[O:21].[I-:26]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: CI
Solvent: CC(C)=O
Product: C[N+]1(CC2CC2)CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Product: [I-]
Temperature: 70 °C
Yield: 41 %

Procedure:
Naltrexone (1, 30 mg, 0.062 mmol) dissolved in 5 mL of dry acetone was added to iodomethane (0.04 mL, 0.62 mmol) in a reaction tube. The reaction tube was sealed and heated at 70° C. for four days. A white precipitate formed over the course of reaction. At the end of the reaction, the mixture was cooled and filtered and the precipitate was washed with cold acetone. The white precipitate was crystallized from methanol-ether to obtain the desired product 2 as a crystalline salt in 41% yield: mp 215-216° C. 1H NMR (DMSO-d6, 500 MHz) δ 9.52 (s, 1H) 6.67 (s, 2H), 6.35 (s, 1H), 4.90 (s, 1H), 4.02 (s, 1H), 3.91 (m, 2H), 3.62 (s, 3H), 3.52 (d, J=19.5 Hz, 1H), 3.05 (m, 1H), 2.92 (m, 2H), 2.76 (m, 2H), 2.10 (m, 1H), 1.97 (m, 1H), 1.59 (m, 2H), 1.22 (m, 1H), 0.77 (m, 1H), 0.70 (m, 1H), 0.61 (m, 1H), 0.37 (m, 1H). MS m/z 356 [(M−I—)+]. Anal. Calcd for C21H26INO4.0.75H2O: C, 50.77; H, 5.58; N, 2.82. Found C, 50.49; H, 5.70; N, 2.71.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[C:18]1[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[C:12]([C:18]2[N:19]([CH3:23])[N:20]=[CH:21][CH:22]=2)[CH:13]=1)=[O:29]
Reactant: CC1CCCCN1CCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCCN1CCOc1ccc(NC(=O)c2ccc(F)c(F)c2)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A mixture of 4-[2-(2-Methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.031 g, 0.1 mmol), 3,4-difluorobenzoyl chloride (0.015 mL, 0.12 mmol) and triethylamine (0.018 mL, 0.13 mmol)) in methylene chloride (1.5 mL) was stirred at room temperature overnight and concentrated to give a crude product that was subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to give a TFA-salt of Compound 459 as a white solid in 88.2% yield. LCMS m/z (%)=455.5 (M+H, 100).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:25]=[C:24]4[C:20]([N:21]=[CH:22][NH:23]4)=[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([C:32](O)=[O:33])[CH2:27]4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1C=CC2N(O)N=[N:41]C=2C=1.C(Cl)CCl.N>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:25]=[C:24]4[C:20]([N:21]=[CH:22][NH:23]4)=[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([NH2:41])=[O:33])[CH2:27]4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(=O)O)C4)c4nc[nH]c4n3)cc2)CC1
Agent: N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(N)=O)C4)c4nc[nH]c4n3)cc2)CC1
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
To a solution of 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-9H-purin-6-yl)piperidine-3-carboxylic acid (40 mg, 0.086 mmol) and HOBt (30 mg, 0.196 mmol) in DMF (2 mL), EDC (35 mg, 0.183 mmol) was added. After being stirred for 90 min, NH3 (0.5 M in dioxane, 1.00 mL, 0.500 mmol) was added. The mixture was stirred for 2 h. More EDC (52 mg, 0.271 mmol) was added. It was stirred for another 20 h. The mixture was then purified by HPLC to give the titled compound (30 mg). MS 464.3 (M+H); UV 204.8, 273.8 nm.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:23]3[CH2:24][CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC1CCCNC1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCC(C)C2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), 3-methyl piperidine (19 mg, 0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator afforded 34.2 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3-methylpiperidin-1-yl)ethanone as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.[I-]>[C:8]1([C:6]2[N:7]=[C:3]([CH2:2][O:20][C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH:24]=[O:25])[O:4][C:5]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccc(O)c1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
A mixture of 2-bromomethyl-4,5-diphenyloxazole (26.72 g, 85 mmol) obtained according to D. L. Aldous, et al., J. Org. Chem. 2, 228-334 (1937), 3-hydroxybenzaldehyde (9.34 g, 76 mmol), potassium carbonate (12.92 g, 93 mmol), potasssium iodide (0.5 g) and dimethylformamide (250 mL) was stirred at 110° C. After 45 minutes, the mixture was cooled, diluted with water and extracted with diethyl ether (3×). The combined extracts were washed with water (3×), dried over sodium sulfate and concentrated in vacuo to give an oil which was chromatographed on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (2:1) afforded 3-[(4,5-diphenyl-2-oxazolyl)methoxy]benzaldehyde (21.16 g, 70%). An analytical sample was recrystallized from a mixture of CH2Cl2 and hexanes and had mp 72°-75° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]([OH:11])=[O:10])[NH2:8])[CH:2]=1.N1C=CC=C(C=O)C=1.[CH3:20][O:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][O:27][C:28](N=[N+]=[N-])=[O:29])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]([NH:8][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:9]([OH:11])=[O:10])=[O:29])=[CH:33][CH:34]=1
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Reactant: NC(C(=O)O)c1cccnc1
Agent: O=Cc1cccnc1
Product: COc1ccc(COC(=O)NC(C(=O)O)c2cccnc2)cc1

Procedure:
DL-2-(3-Pyridyl)glycine (prepared from pyridine-3-aldehyde by the Strecker synthesis) is reacted with (p-methoxybenzyloxycarbonyl)azide according to the procedure set forth in Example 2(a) to yield DL-α-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-3-pyridineacetic acid; m.p. 155°-156° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(Cl)Cl.[CH2:29]([N:31]([CH2:34]C)CC)[CH3:30].CC.[N-]=C=[O:40]>>[CH2:29]([NH:31][C:34]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:15]2[N:14]=[CH:13][C:12]3=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:17]3[N:16]=2)[CH:20]=1)=[O:40])[CH3:30]
Reactant: COc1ccc(-c2ccc3cnc(Nc4cccc(N)c4)nn23)cn1
Reactant: CCN(CC)CC
Reactant: [N-]=C=O
Agent: CC
Solvent: ClCCl
Product: CCNC(=O)Nc1cccc(Nc2ncc3ccc(-c4ccc(OC)nc4)n3n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-benzene-1,3-diamine (0.075 g, 0.22 mmol) in Methylene chloride (1.3 mL, 21 mmol) and Triethylamine (62.9 uL, 0.451 mmol) was added Ethane, isocyanato-(21.4 uL, 0.271 mmol) at 0° C. The reaction was stirred at 0° C. for 1 h. About 5% conversion. Allowed to stir at rt o/n—about 50% conversion. Heated to 50° C. for 3 hours and added additional 3.0 eq isocyanate. Reaction went to completion. Filtered off title compound as a beige ppt (34 mg, 35%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.97 (s, 1H), 89.1 (j, J=2.3 Hz, 1 h), 8.55 (dd, J=8.7 Hz, 2.5 Hz, 1H), 8.29 (s, 1 h), 7.65 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.20 (d, J=4.6 Hz, 1H), 7.14 (dd, J=8.2 Hz, 8.2 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.95 (d, J=4.8 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.09 t, J=5.4 Hz, 1H) 3.92 (s, 3H), 3.09 (m, 2H), 1.04 (t, J=8.14 Hz, 3H). HPLC purity=90%, rt=2.029 min, LCMS=403.9 (M+H).
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:17])=[CH:12][CH:13]=2)[N:8]([CH3:18])[CH:7]=1)([OH:3])=[O:2].C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[C:1]([CH2:4][S:5]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:17])=[CH:12][CH:13]=2)[N:8]([CH3:18])[CH:7]=1)=[O:27])([OH:3])=[O:2]
Reactant: Cn1cc(SCC(=O)O)c(=O)c2ccc(F)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(S(=O)CC(=O)O)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
To a stirred solution (a part remained undissolved) of crude 3-difluoromethylthio-7-fluoro-1-methyl-4-quinolone (4) (3.43 g, 13.23 mmol) in DCM (200 ml) at 0° C. was added ˜80% MCPBA (2.50 g, 11.59 mmol) in a few portions over a period of approximately 1 min. The stirred mixture was allowed to warm to room temperature and was stirred for 30 min. An additional amount of MCPBA (640 mg) was added in 5 portions in approximately 1 h intervals, and the progress of the oxidation was monitored by 1H NMR 30 min after each addition. The mixture was washed with 5% aqueous Na2CO3 (70 ml), the aqueous layer was extracted with DCM (2×200 ml), the combined extracts were dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel with DCM and then with hexane-ethyl acetate (gradient 2:1,1:1,1:2) to give 980 mg (20.7%; two steps) of the product. The product was further purified by recrystallization from absolute ethanol to give 620 mg (13.1%) of 3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (5) as off-white crystals. 1H NMR, CDCl3; δ=3.94 s, 3H, N—CH3; 7.050, 6.870, 6.866, 6.686 (4 lines, X part of ABX), 1H, CHF2; 7.21 dd, 1H, J=10.2 & 2.4 Hz, H at C8, 7.27 ddd, 1H, J=8.9, 7.9 & 2.2 Hz, H at C6; 7.99 s, 1H, H at C2; 8.44 dd, 1H, J=9.0 & 6.3 Hz, H at C5.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][F:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>CO.C1COCC1>[Br:18][CH2:16][C:15]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][F:14])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:17]
Reactant: [Br-]
Reactant: CC(=O)c1cc(OCCF)cc(C(C)(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(OCCF)cc(C(=O)CBr)c1
Yield: 120.5 %

Procedure:
1-[3-tert-Butyl-5-(2-fluoroethoxy)phenyl]ethanone (O2.105; 600 mg) was dissolved in methanol/THF (15/15 ml). While stirring, phenyltrimethylammonium tribromide (950 mg) was added. After stirring at RT for 3 h, water (5 ml) was added and the mixture was dried. The residue was admixed with DCM (200 ml) and saturated sodium hydrogencarbonate solution (100 ml). The DCM phase was removed and the aqueous phase was extracted three times more with DCM. The combined DCM phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (50 g cartridge, n-heptane/EA gradient of 0-60% within 40 min). 560 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([Cl:13])[C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N:24]=[C:25]=[O:26]>C1COCC1>[Cl:13][C:10]1[C:9]([C:14]#[N:15])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[F:16])=[O:26])=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: N#Cc1c(Cl)nsc1-c1ccc(N)cc1
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(Cl)c3C#N)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.3 %

Procedure:
A solution of 5-(4-Aminophenyl)-3-chloroisothiazole-4-carbonitrile (4.565 g, 19.4 mmol) and 2-fluoro-5-methylphenyl isocyanate (5.85 g, 38.7 mmol) in 100 mL of dry THF was heated to reflux overnight. TLC indicated presence of considerable amount of starting material. Additional 2 g of 2-fluoro-5-methylphenyl isocyanate was added and the reaction was continued for another 24 h. The reaction was cooled to RT. THF was removed in vacuo and the resulting solid was stirred in 200 mL of Et2O for 1 h. Product was collected by filtration and washed with Et2O/hexanes to afford a light yellow solid (6.78 g, 90%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]2=[O:15].[CH3:22]I.Cl>CCCCCC.CS(C)=O>[OH:3][C:4]1[C:13]([O:14][CH3:22])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]2=[O:15]
Reactant: O=C1CC(c2ccccc2)Cc2c1ccc(O)c2O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1ccc2c(c1O)CC(c1ccccc1)CC2=O
Yield: 43 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.39 g, 9.8 mmol) was washed with hexane and the hexane was decanted. DMSO (15 mL) was added to the sodium hydride and the resultant suspension was stirred vigorously. To the suspension was added a solution of 2.5 g (9.8 mmol) of 5,6-dihydroxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone, from Step 1, in 10 mL of DMSO. The mixture was stirred at ambient temperature for 80 min and 0.61 mL (9.8 mmol) of methyl iodide was added in one portion. The reaction mixture was stirred at ambient temperature overnight and then made acidic with 5% aqueous hydrochloric acid solution. The mixture was stirred for 30 min and then filtered. The filter cake was dissolved in 20% ethyl acetate in hexane and chromatographed on a silica gel column eluted with 20% ethyl acetate in hexane and 50% ethyl acetate in hexane to give a brown solid. The solid was crystallized from ethyl acetate to give 1.13 g (43% yield) of the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7]Br.[C-:9]#[N:10].[K+]>C(O)C.O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:9]#[N:10]
Reactant: [C-]#N
Reactant: BrCc1sccc1Br
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1sccc1Br
Yield: 71.4 %

Procedure:
3-Bromo-2-(bromomethyl)thiophene (7.1 g) and potassium cyanide (2.7 g) were dissolved in ethanol (93 mL) and water (17 mL), and the mixture was stirred at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added water. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0−80/20) to give the title compound (4.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].[Li]C(C)(C)C.CN([CH:24]=[O:25])C>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:24]=[O:25])=[C:3]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cc(F)ccc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-(2-bromo-5-fluorophenyl)pivalamide(2.4 g, 8.75 mmol)) was dissolved in THF(30 mL) at room temperature, and the colorless solution was cooled to −78° C., followed by fast dropwise addition of t-BuLi (10.3 mL, 1.7M in heptane, 17.4 mmol) under N2 over 10 min. The resulting yellow solution was continued stirring at −78° C. for 1 hr, followed by dropwise addition of DMF(2.7 mL, 35.0 mmol) over 5 min. The light yellow solution was stirred for additional 30 min at −78° C. Thus the mixture was quenched with saturated NH4Cl (30 mL), extracted with Et2O (2×150 mL). The combined organic phase was washed with brine(30 mL), dried over MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 25˜50% EtOAc/hexanes (1400 mL) to afford an expected product, as a white solids(1.03 g, 53% yield); 1H NMR (400 MHz, CDCl3) δppm 1.30 (s, 9H), 6.80-6.86 (m, 1H), 7.63 (dd, J=8.56, 6.04 Hz, 1H), 8.53 (dd, J=12.21, 2.39 Hz, 1H), 9.83 (s, 1H), 11.54 (s, 1H); Mass spec. 224.16 (MH+), Calc. for C12H14FNO2 223.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[CH3:2].[Br:15][CH2:16][CH2:17][CH3:18]>C1COCC1>[Br-:15].[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]1[CH:14]=[CH:13][N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=1)[CH3:2]
Reactant: CCCBr
Reactant: CCOc1ccccc1-n1ccnc1
Solvent: C1CCOC1
Product: CCCn1cc[n+](-c2ccccc2OCC)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 5.3 mmol (1.00 g) 1-(2-ethoxyphenyl)imidazole and 6.4 mmol (0.780 g, 0.58 ml) 1-bromopropane are dissolved in 5 ml THF and heated for 21 h to 90° C.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([N:5]1[CH2:6][CH2:7][N:2]([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:3][CH2:4]1)(=[O:40])=[O:39]
Reactant: c1cnc2nc(Oc3ccc4c(CN5CCNCC5)coc4c3)sc2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
To a suspension of 2-(3-piperazin-1-ylmethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine hydrochloride (122 mg, 0.30 mmol) in DCM (3 mL) was added DIEA (158 μL, 0.91 mmol) and the reaction mixture was stirred (rt, 15 min). The resulting solution was treated with MsCl (26 μL, 0.33 mmol) and the resulting solution was stirred (rt, 2 h). The reaction mixture was partitioned with EtOAc and brine (20 mL each) and the organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a white solid (42 mg, 31%). MS (ESI): mass calcd. for C20H20N4O4S2, 444.54; m/z found, 445.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=7.9, 1.7, 1H), 7.74 (d, J=8.5, 1H), 7.62-7.56 (m, 2H), 7.30 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=8.0, 4.8, 1H), 3.69 (d, J=0.5, 2H), 3.32-3.21 (m, 4H), 2.79 (s, 3H), 2.67-2.54 (m, 4H).