Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-])=O.[H][H]>CCO.[Pd]>[NH2:14][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:6]=1[NH:5][CH2:4][CH2:3][CH2:2][OH:1])[C:10]#[N:11]
Reactant: [H][H]
Reactant: N#Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(NCCCO)c(N)c1

Procedure:
A mixture of 1.12 g (5.06 mmol) of 4-[(3-hydroxypropyl)amino]-3-nitrobenzonitrile (Intermediate 11) and 26.94 mg of 10% Pd on charcoal in 39 ml of EtOH is shaken in an hydrogen atmosphere (14 psi) for 20 hr at rt. After filtration and evaporation 1.012 g of the pure title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][NH2:14].O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([NH:14][CH3:13])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)Cc1ccccc1Br
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To a solution of (2-bromophenyl)methanesulfonyl chloride (2 g, 7 mmol) in THF (15 mL) was added CH3NH2/H2O (25%, 2 g, 20 mmol) at 0° Celsius. The resulting mixture was warmed up to rt, stirred for 16 hours, concentrated to dryness and purified by HPLC to give the title compound (0.8 g, 41%). MS (ESI): mass calcd. for C8H8BrO2S, 262.96; m/z found, 264.0 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 7.65-7.54 (m, 2H), 7.35 (m, 1H), 7.22 (dd, J=7.6, 1.7, 1H), 4.53 (s, 2H), 4.10 (s, 1H), 2.72 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:26][CH:27]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CN
Reactant: Clc1ccc(Br)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 429 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[S:13][C:14](C(O)=O)=[CH:15][C:4]=2[NH:3]1>C(O)(=O)C>[S:13]1[C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[NH:3][C:4]=2[CH:15]=[CH:14]1
Reactant: O=C(O)c1cc2c(s1)Oc1ccccc1C(=O)N2
Solvent: CC(=O)O
Product: O=C1Nc2ccsc2Oc2ccccc21
Temperature: 25 °C
Yield: 79 %

Procedure:
To a stirring solution of compound 120 (0.801 g, 3.07 mmol) in acetic acid (30 mL) was added mercuric oxide (red) (0.664 g, 3.07 mmol) and the reaction mixture was stirred at reflux for 8 hours. The mixture was then cooled to room temperature and poured into ice-cold water (75 mL). The resulting solid was filtered and triturated in ethanol to afford title compound 121 (0.527 g, 79%) as a beige solid. LRMS (ESI): (calc) 217.02. (found) 217.9 (MH)+. 1H NMR (DMSO-d6) δ (ppm): 10.45 (s, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.33 (t, J=7.4 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.99 (d, J=6.1 Hz, 1H), 6.63 (d, J=6.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[CH:30]=[CH:29][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+].CN(C=O)C>O>[CH3:14][C:11]1([CH2:13][N:26]2[CH2:25][CH2:24][CH:23]([C:21](=[O:22])[C:20]3[CH:29]=[CH:30][C:17]([C:16]([F:31])([F:32])[F:15])=[CH:18][CH:19]=3)[CH2:28][CH2:27]2)[O:12][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CN2CCC(C(=O)c3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
A mixture of 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (80 mg, 0.37 mmol), 4-(4-trifluoromethylbenzoyl)piperidine (95 mg, 0.37 mmol), sodium acetate (150 mg, 1.83 mmol) and DMF (2 ml) was stirred at 80° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, washed with a saturated saline solution, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to afford 2-methyl-6-nitro-2-[4-(4-trifluoromethylbenzoyl)piperidin-1-yl]methyl-2,3-dihydroimidazo[2,1-b]oxazole (46 mg, yield 29%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1
Reactant: Oc1ccc(F)cc1F
Reactant: Cc1nc(Cl)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Oc2ccc(F)cc2F)ccc1C#N
Temperature: 80 °C

Procedure:
A mixture of 6-chloro-2-methylnicotinonitrile (Example 1, step 1; 500 mg, 3.27 mmol), 2,4-difluorophenol (0.47 mL, 4.91 mmol) and cesium carbonate (1.60 g, 4.91 mmol) in DMF (5 mL) was heated in an oil bath at 80° C. for 5 h. The reaction mixture was treated with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with 1 N NaOH (15 mL) followed by brine, dried over MgSO4 and concentrated. Purification on an ISCO (40 g column, 5-50% EtOAc in hexanes) provided 6-(2,4-difluorophenoxy)-2-methylnicotinonitrile as a white crystalline solid. MS (ESI, pos.ion) m/z: M+1=247.0
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1(C2C=C(C=CC=2)N)[CH:34]=[CH:33][CH:32]=[CH:31]1>>[N:30]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)[CH:21]=[CH:20][CH:19]=2)[CH:34]=[CH:33][CH:32]=[CH:31]1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1cccc(-n2cccc2)c1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2cccc2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(1H-pyrrol-1-yl)aniline in step 1. MS: 392.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:8]1[C:7]([Cl:12])=[C:3]([C:2]([Cl:1])=[C:10]([Cl:11])[CH:9]=1)[C:4]([OH:6])=[O:5])([O-:15])=[O:14]
Reactant: O=C(O)c1c(Cl)ccc(Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(Cl)c(Cl)cc([N+](=O)[O-])c1Cl
Temperature: 43 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
2,3,6-Trichlorobenzoic acid (20.84 g, 92.4 mmol, prepared by the method of M. T. Goebel, U.S. Pat. No. 3,391,185, E.I. DuPont, Jul. 2, 1968) was stirred at 40°-45° C. in 89.1 mL of concentrated sulfuric acid. A solution containing 23.2 g of concentrated sulfuric acid and 23.2 g of fuming nitric acid was added at a rate so to maintain the temperature between 40°-45° C. An additional 20 mL of concentrated sulfuric acid was added. The reaction mixture was stirred at 43° C. for 1.5 hours and then poured over ice water. The resulting crystals were filtered and recrystallized from toluene-hexane to give 23.40 g (94%) of product; mp 149°-151° C.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[CH3:20][Si:21]([CH3:37])([CH3:36])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[CH:30]=[N:29][C:28](C(O)(C#C)C)=[N:27]1>>[F:19][C:18]1[C:2]([C:3]#[C:4][C:5]([OH:6])([C:30]2[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:20])([CH3:36])[CH3:37])[N:27]=[CH:28][N:29]=2)[CH3:17])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)c1ncn(COCC[Si](C)(C)C)n1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)c1ncnn1COCC[Si](C)(C)C

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with and 2-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,2,4-triazol-3-yl)but-3-yn-2-ol to give 8-fluoro-9-(3-hydroxy-3-(1((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)but-1-yn-1-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide. A solution of crude give 8-fluoro-9-(3-hydroxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)but-1-yn-1-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide (150 mg, 0.28 mmol, 1.00 equiv) and hydrofluoric acid (2 mL) in CH3CN (4 mL) was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 10 with saturated NaHCO3 (10 mL). The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (1#pre-HPLC-006(waters)): Column, sunfire prep C18 19*150 mm 5 um; mobile phase, Water with 0.5% CF3COOH and CH3CN (10% CH3CN up to 45% in 12 min, up to 100% in 3 min, down to 10% in 2 min); Detector, UV 220/254 nm. 10 mg of product was obtained. This was treated by strong anion exchange resin (cleanert SAX-SPE). This resulted in 7.2 mg (6%) of the titled compound as an off-white solid.
Reaction SMILES: O.[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[C:4]=1[C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:11][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=2)[CH:6]=[C:5]([OH:10])[C:4]=1[C:11](=[O:13])[CH3:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1c(O)cc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(O)cc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2′,4′,6′-trihydroxyacetophenone monohydrate (5 g) and potassium carbonate (7.42 g) in N,N-dimethylformamide (100 mL) was added benzyl bromide (6.39 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1-5/1) to give 2′,4′-dibenzyloxy-6′-hydroxyacetophenone (5.71 g). This material was suspended in ethanol (45 mL)-water (15 mL). To the suspension was added potassium hydroxide (11.0 g), and the mixture was stirred at room temperature for 10 minutes. Benzaldehyde (2.51 mL) was added to the mixture, and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was acidified by addition of concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 2′,4′-dibenzyloxy-6′-hydroxychalcone (4.85 g). This material was dissolved in N,N-dimethylformamide (40 mL)-acetone (12 mL). To the solution were added potassium carbonate (2.3 g) and methyl bromoacetate (1.1 mL), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (30 mL). To the solution was added 10% palladium-carbon powder (0.5 g), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-2/1) to give the title compound (2.26 g).
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[N:21]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1>C(O)(C(F)(F)F)=O.O>[Br:1][C:2]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)cn2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)cn2)n1

Procedure:
tert-Butyl (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetate (2.50 g, 4.68 mmol) was dissolved in a mixture of TFA (11.3 mL) and water (1.3 mL). After a period of 18 h at room temperature the reaction mixture was evaporated followed by two co-evaporations with toluene. The yellow oil was dissolved in ethyl acetate (12.5 mL) and hexane (37.5 mL) was then added slowly. The resulting solid was filtered to provide (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetic acid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[NH:11][N:10]=[N:9][C:8]=1[C:12](=[O:14])[NH2:13].C(O)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([NH:6][C:7]1[NH:11][N:10]=[N:9][C:8]=1[C:12](=[O:14])[NH2:13])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1nn[nH]c1N
Agent: O=S(=O)(O)O
Solvent: CCO
Product: NC(=O)c1nn[nH]c1NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
Concentrated sulphuric acid (1.5 ml.) was added dropwise, under anhydrous conditions, to an ice-cooled, stirred suspension of 5-amino-4-carbamoyl-1H-1,2,3-triazole (1.27 g.) in benzoyl chloride (15 ml.), and the reaction mixture then stirred at room temperature overnight. The mixture was poured into ice-water, whereupon a gummy precipitate was formed. The aqueous solution was decanted off, and the gum triturated thoroughly with diethyl ether. The remaining solid was then filtered off, and washed well with diethyl ether, to give crude 5-benzamido-4-carbamoyl-1H-1,2,3-triazole (2.26 g.), m.p. 280° C. (with decomposition). An aliquot was heated in boiling ethanol, and the solid filtered off, while still hot, to give pure 5-benzamido-4-carbamoyl-1H-1,2,3-triazole, m.p. 306° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Br-].[CH2:22]([Zn+])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.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>[CH2:22]([C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(-c3ccnc(Cc4ccccc4)n3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
N-(6-(2-Chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (59.0 mg, 194 μmol) was suspended in THF (1.8 mL) to which tetrakis(triphenylphosphine)palladium (25.6 mg, 22 μmol) and benzylzinc bromide, 0.5 m solution in THF (0.55 mL, 275 μmol) were added under argon, and the reaction solution was stirred at RT. After about 2 hours, the reaction was heated to 80° C., and stirring was continued under argon. After about 100 minutes, additional Pd(PPh3)4 (21 mg) and benzylzinc bromide (0.57 mL) were added, and the reaction was stirred. After another hour or so, additional benzylzinc bromide (0.73 mL) was added, and stirring was continued at 80° C. The reaction was stirred overnight and quenched with saturated ammonium chloride (1.5 mL) and 0.5 M EDTA (2.5 mL), extracted with 10:1 DCM/MeOH, and the organic phases were dried over sodium sulfate, filtered through Celite®(diatomaceous earth), and concentrated. The crude concentrate was purified on a silica gel column (20:1 to >5:1 DCM/MeOH), and the product-containing fractions were collected, concentrated, and washed with Et2O and MeOH and filtered. The solid was collected and purified on HPLC (10% to >95% MeCN/water with 0.1% TFA over 40 minutes), to provide N-(6-(2-benzylpyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (8 mg, 11% yield). MS (ESI pos. ion) m/z: 361. Calculated exact mass for C20H16N4OS: 360. 1H NMR (400 MHz, DMSO-d6): 12.50 (s, 1H), 8.85 (s, 1H), 8.78 (d, J=5.5 Hz, 1H), 8.29 (d, J=8.0 Hz, 1H), 7.95 (d, J=5.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.38 (m, 2H), 7.31 (m, 2H), 7.21 (m, 1H), 4.28 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.C1OCCOCCOCCOCCOC1.[Cl:28][C:29]1[CH:38]=[C:37](Cl)[C:36]2[C:31](=[C:32]([Cl:42])[C:33]([O:40][CH3:41])=[CH:34][CH:35]=2)[N:30]=1>CN(C=O)C.O>[Cl:28][C:29]1[CH:38]=[C:37]([O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[C:36]2[C:31](=[C:32]([Cl:42])[C:33]([O:40][CH3:41])=[CH:34][CH:35]=2)[N:30]=1
Reactant: COc1ccc(CO)cc1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
NaH (60% in oil) (670 mg, 1.2 eq.) was added portionwise to a stirred solution of p-methoxybenzylalcohol (2.31 g, 1.2 eq.) and 15-crown-5 (3.32 mL, 1.2 eq.) in anhydrous DMF (10 mL). The mixture was stirred at room temperature for 30 min. Compound 220d (3.66 g, 1 eq.) in anhydrous DMF (25 mL) was then added and the reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was then poured into water (300 mL), extracted with EtOAC, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (petroleum ether/DCM, 50/50) to give compound 221d as a yellow solid in 38% yield. 1H NMR (CDCl3, 376 MHz) δ (ppm) 3.86 (s, 3H), 4.05 (s, 3H), 5.20 (s, 2H), 6.77 (s, 1H), 6.98 (d, J=8.53 Hz, 2H), 7.23 (d, J=9.41, 1H), 7.42 (d, J=8.53 Hz, 2H), 8.08 (d, J=9.41 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Reactant: NCc1ccccc1
Product: COc1cc2c(cc1OC)CC(NCc1ccccc1)CC2

Procedure:
The title compound is prepared analogously to Example L by reacting 6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-one with benzylamine. Mp: 237°-238° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[C:19]([CH2:21][C:22]4[C:23](=[O:34])[C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[C:26](=[O:29])[C:27]=4[CH3:28])[CH:18]=[CH:17][C:16]=3[O:35]C(=O)C)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>CO.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[C:19]([CH2:21][C:22]4[C:23](=[O:34])[C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[C:26](=[O:29])[C:27]=4[CH3:28])[CH:18]=[CH:17][C:16]=3[OH:35])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3N3CCOCC3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3N3CCOCC3)c2)=C(C)C1=O
Yield: 99 %

Procedure:
N-(2-Morpholinopyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.110 g, 0.205 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.100 g, 0.203 mmol, 99%).
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27].CCOC(C)=O>CN1C(=O)CCC1>[NH2:27][CH2:26][CH2:25][NH:28][C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(Cl)c23)c(C)c1
Reactant: NCCN
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(NCCN)c23)c(C)c1

Procedure:
Heat a solution of 4-chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizine (0.3 g, 0.89 mmol), and ethylene diamine (0.6 mL, 8.93 mmol) in dry NMP (3 mL) at 100 ° C. for 14 h. Pour the cooled mixture onto water (30 mL) and extracte twice with EtOAc (30 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (20% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.CO.[C:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])(=[O:10])[CH3:9].[C:20]([O-])(O)=O.[Na+]>O>[CH3:20][O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([C:8](=[O:10])[CH3:9])[CH:12]=1
Reactant: O=C([O-])O
Reactant: CC(=O)c1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(C(C)=O)c1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
Sulfuric acid (23.4 μl, 0.430 mmol) was added into the MeOH (15 ml) solution of 3-acetylbenzoic acid (720 mg, 4.30 mmol). The mixture was stirred at 70° C. for 20 h. After that time, the mixture was cooled and was treated with saturated NaHCO3 till pH>9, followed by adding water to dissolve the solid which was formed, extracted with EtOAc (2×50 ml). The extracts were washed with water (50 ml), brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo, giving the title compound as brown oil. 1H NMR (400 MHz, CDCl3): δ=2.66 (s, 3H), 3.96 (s, 3H), 7.54-7.59 (m, 1H), 8.14-8.19 (m, 1H), 8.22-8.26 (m, 1H), 8.59-8.61 (m, 1H). MS (ES+): m/z 179.17 [MH+]. HPLC: tR=2.82 min (polar—5 min, ZQ3).