Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:30])([F:29])[CH:23]([F:28])[C:24]([F:27])([F:26])[F:25])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13]([CH2:14][C:15]([F:18])([F:17])[F:16])=[O:39])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:30])([F:29])[CH:23]([F:28])[C:24]([F:25])([F:26])[F:27])[CH:3]=1
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)cc2Cl)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)cc2Cl)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 103.3 %

Procedure:
0.15 g of 5-chloro 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 90mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 1 hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.16 g of 5-chloro 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][CH2:18]3)=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][CH2:18]3)=[CH:14][C:12]=2[N:13]=1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: CN(C)CCN
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 87.3 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.45 mL, 4.1 mmol) was added to a stirred solution of chloride 21 (305 mg, 1.4 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 22 (334 mg, 88%) as a yellow solid: mp (MeOH/EtOAc) 122-124° C.; 1H NMR δ 8.06 (s, 1H, H-9), 7.38 (s, 1H, H-5), 5.80 (br s, 1H, NH), 3.50-3.55 (m, 2H, CH2N), 2.96-3.03 (m, 4H, H-6, H-8), 2.55 (t, J=6.0 Hz, 2H, CH2N), 2.27 [s, 6H, N(CH3)2], 2.09-2.18 (m, 2H, H-7); 13C NMR δ 158.8, 154.5, 148.8, 143.2, 129.8, 120.5, 114.6, 57.6, 45.1 (2), 38.8, 33.1, 32.3, 25.7. Anal. calcd for C14H19N5O. ¼ H2O: C, 60.5; H, 7.1; N, 25.2. Found: C, 60.6; H, 6.8; N, 25.2%.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25]>CS(C)=O.O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: O=c1[nH]cccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 80 °C

Procedure:
44.5 g (280 mmol) of 3-bromopyridin-2(1H)-one are dissolved in 750 ml of anhydrous dimethyl sulfoxide and admixed at room temperature with 33.4 g (298 mmol) of potassium tert-butoxide in portions. The suspension is stirred at this temperature for 1 h, before 38.5 g (280 mmol) of 1-fluoro-2-methyl-4-nitrobenzene are added and the reaction solution is heated to 80° C. for 20 h. It is allowed to cool and diluted cautiously with water. The precipitated crystalline solid is filtered off, washed with a little water and dried under reduced pressure. This affords 62 g (80% of theory) of the desired product.
Reaction SMILES: [Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](O)=[O:12])=[N:9][CH:10]=1.[NH3:16]>C(O)C.Cl>[Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:16])=[O:12])=[N:9][CH:10]=1
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Reactant: N
Agent: Cl
Solvent: CCO
Product: NC(=O)c1ccc(CCC(Br)CBr)cn1
Reaction time: 72 h

Procedure:
10 g of 5-(3,4-dibromobutyl)picolinic acid was dissolved in 200 ml of ethanol saturated with dry hydrochloride gas and resulting solution was refluxed for six hours. Reaction mixture was evaporated in reduced pressure and resulting pale yellow oil was dissolved in 300 ml of ethanol saturated with dry ammonia gas. The solution was kept to stand at room temperature for three days, and then evaporated in reduced pressure. Resulting solid was crystallized from benzene to give 6.5 g of the pure product as platelets.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[CH:9]N(C)C)=[N:6][CH:7]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C([O-])(O)=O.[Na+]>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][N:8]=2)[CH:7]=1
Reactant: CN(C)C=Nc1ccc(Br)cn1
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)c1cnc2ccc(Br)cn12
Temperature: 90 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
Reaction mixture containing N′-(5-bromopyridin-2-yl)-N,N-dimethylformimidamide (6.5 g, 28.5 mmol), methyl 2-bromoacetate (5.6 g, 3.5 mL, 37.0 mmol) and NaHCO3 (4.1 g, 48.8 mmol) in i-PrOH (60 mL) was heated at 90° C. under nitrogen. The heating was stopped after 12 h and cooled the dense heterogeneous reaction mixture to room temperature. The reaction mixture was concentrated and diluted with water. The resultant slurry was collected by suction filtration and obtained methyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (6.9 g) as a tan white solid upon drying. 1H NMR (300 MHz, DMSO-d6): δ 9.31 (d, J=1.8 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J=9.5 Hz, 1H), 7.71 (dd, J=9.5, 1.6 Hz, 1H), 3.88 (s, 4H). Ester hydrolysis was done by stirring a solution of methyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (2.5 g), LiOH.H2O (1.2 g) in THF/MeOH/H2O (1/1/1, 75 mL) at room temperature. Reaction mixture was concentrated upon complete hydrolysis of ester to corresponding acid, diluted with water/ice and acidified with 2N. aq HCl until pH 6. The resulting solid was filtered, suction dried followed by drying under P2O5 under vacuum to obtain 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (2.2 g) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 9.36 (s, 1H), 8.24 (s, 1H), 7.77 (d, J=9.5 Hz, 1H), 7.67 (d, J=9.5, 1.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[O:10][CH3:11].CCN(C(C)C)C(C)C.[CH2:21]([O:23][CH:24]([O:29][CH2:30][CH3:31])[C:25](=[NH:28])OC)[CH3:22]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:25](=[NH:28])[CH:24]([O:29][CH2:30][CH3:31])[O:23][CH2:21][CH3:22])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: CCOC(OCC)C(=N)OC
Reactant: COc1cc(CN)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(Cl)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of (4-chloro-3-methoxyphenyl)methanamine (392 mg, 2.284 mmol) (as the hydrochloride salt), Hunig's Base (0.5 mL, 2.86 mmol), and MeOH (2 mL) was added a solution of methyl 2,2-diethoxyacetimidate (295 mg, 1.83 mmol) in MeOH (1 mL) and the resulting mixture was heated with stirring in an oil bath at 70° C. for 2 hrs and allowed to cool to room temperature over 3 days. The solvent was removed in vacuo and the residue was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH2:13][N:14]([CH3:16])C)=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:16]([NH:14][CH2:13][CH2:12][C:8]1[C:7]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][C:9]=1[OH:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(C)CCc1ccc(C(C)(C)C)cc1O
Reactant: O=Cc1ccccc1
Product: CC(C)(C)c1cc(O)c(CCNCc2ccccc2)c(C(C)(C)C)c1

Procedure:
The product of Example 75 (0.143 g) was treated with 0.060 g (0.58 mmol) of benzaldehyde according to the procedure described in Example 3. The product was purified on a silica gel flash chromatography column eluted with 5% isopropanol in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][N:26]([CH2:34][CH2:35][CH2:36][O:37][CH3:38])C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[N:6][C:7]=1[C:8](=[O:16])[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.Cl.[OH-].[Na+]>CCOC(C)=O.O>[NH2:1][C:2]1[C:7]([C:8]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:16])=[N:6][C:5]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][NH:26][CH2:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:21][CH:22]=2)=[CH:4][N:3]=1
Reactant: COCCCN(CCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCNCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Reaction time: 3 h

Procedure:
A mixture of the product of step (v) (300 g, 0.58 mol) in 4N—HCl in EtOAc (3 L) was stirred for 3 hours. The suspension was filtered and the yellow solid obtained. The solid was dissolved in H2O (1.2 L). 2N—NaOH was added dropwise into the solution to basified to pH=11. The mixture was extracted with a mixture of THF and EtOAc (5 L×2, 1:1) and the organic phase washed with aqueous 10%—NaCl and concentrated in vacuo. The subtitle compound (vi) was obtained (pale yellow solid, 210 g).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:30])=[C:5]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8]>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[S:3][C:4]([Br:30])=[C:5]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Br)sc(Br)c2Cc2cccc(Cl)c2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)c1c(Br)sc(Br)c1Cc1cccc(Cl)c1)c1ccc(C(=O)O)cc1

Procedure:
Methyl 4-[(1S)-1-({[2,5-dibromo-4-(3-chlorobenzyl)-3-thienyl]carbonyl}amino)ethyl]benzoate from Example 5, Step 1 (27.0 mg, 0.0472 mmol) was reacted under conditions similar to Example 1, Step 11. After trituration of the crude product in 1:9 EtOAc/hexane, the desired product was obtained as a white solid. MS (−APCI): m/z 554 (M−1)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)C(O)=COC=1CO.COC1C(OC(C(O)C2C=CC(O)=C(OC)C=2)CO)=CC=CC=1.[NH3:51]>C(O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[NH:51][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Agent: COc1cc(C(O)C(CO)Oc2ccccc2OC)ccc1O
Agent: O=c1cc(CO)occ1O
Solvent: CCO
Product: O=c1cc(CO)[nH]cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5-benzyloxy-2-hydroxymethyl-4-pyrone (prepared from Kojic acid by the method of D. Erol, J. Med. Chem., 1994, 29, 893) (9.7 g, 40 mmol), concentrated aqueous (880) ammonia (100 mL), and ethanol (20 mL) was heated to reflux overnight. The mixture was allowed to cool to room temperature then filtered. The resultant solid was washed with ether and dried in vacuo (5.9 g); MS (APCl+) m/z 232 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([OH:8])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
3-Methyl-2-nitrophenol (11.4 g, 74.4 mmol) was dissolved in chloroform (11 ml) and cooled on an ice-water bath. Bromine (3.8 ml, 74.4 mmol) in HOAc (9 ml) was added drop wise to the stirred, cooled solution. The solution was stirred at 0° for 2 h. Ice was added to the reaction mixture. The organic phase was separated and the water phase was extracted with chloroform. The combined organic phase was washed with brine and water. Evaporation gave 17.2 g. MS (ESI+) for C7H6BrNO3 m/z 232, 234 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:13][C:14]([N:16]([CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17][C:18]([O:20]C)=[O:19])=[O:15])[C:6](=[O:12])[NH:7]2.[Li+].[OH-].O>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:13][C:14]([N:16]([CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:6](=[O:12])[NH:7]2
Reactant: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Cc1cc2c(C)ccnc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc2[nH]c(=O)c(CC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.5 %

Procedure:
To a solution of methyl N-((5-methyl-1,8-naphthyridin-2(1H)-on-3-yl)acetyl)-N-(2-(tert-butyloxycarbonyl)aminoethyl)glycinate (0.72 g, 1.70 mmol) in THF (10 mL) was added LiOH (aqueous, 2M) (2.0 mL). The resulting solution was stirred at rt. for 45 min. then additional water was added, the THF was evaporated in vacuo and the pH of the aqueous solution was adjusted to 3.0. The resulting precipitate was washed with water (2×10 mL), collected by centrifugation and dried in vacuo to yield the desired product (366 mg, 53%) as a white powder (mp 133-36° C.). 1H NMR (DMSO-d6; this compound exist as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 12.12 (s br, 1H), 8.33 (d, J=4.9 Hz, 1H), 8.00 (s, 1H), 7.09 (d, J=4.9 Hz, 1H), 6.92 (6.70) (m, 1H), 3.99 (4.26) (s, 2H), 3.62 (s, 2H), 3.45 (m, 2H+H2O), 3.17 (m, 2H), 2.53 (2.52) (s, 3H), 1.36 (1.34) (s, 9H) 13C NMR (DMSO-d6): δ 171.07 (171.31), 170.23 (170.54), 162.36, 155.80, 149.53, 149.27, 145.30, 132.67 (133.55), 129.35 (129.20), 119.92, 113.44, 78.01, 48.13, 47.33, 38.60 (38.36), 34.07, 28.27, 17.76. FAB− HRMS (m/z): 417.1798, calc. C20H26N4O6−H 417.1774.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][O:25][C:21](=[O:24])[CH:22]=[CH:23][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1cccc(Sc2cccc(-c3ccccc3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cccc(Sc2cccc(-c3ccccc3)n2)c1
Reaction time: 0.33 h

Procedure:
Crude aryl bromide (14) (100 mg, 0.18 mmol), methyl acrylate (18 mg, 0.21 mmol), triethylamine (71 mg, 0.70 mmol), tri(o-toly)phosphine (5 mg, 0.016 mmol) and palladium(II) acetate (12 mg, 0.054 mmol) in acetonitrile (2 mL) was heated in a CEM Discover microwave for 45 minutes at 90° C. More tri(o-toly)phosphine (3 mg) and palladium(II) acetate (3 mg) were added and the reaction mixture retreated in the microwave for 20 minutes; palladium(II) acetate (2 mg) was then added and the process repeated for a further 25 minutes. The solvent was removed under a stream of nitrogen gas, water was added, and the organics extracted with EtOAc, washed with water, dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was partially purified by column chromatography. Yield: 51 mg, 60%; LC-MS tr 1.82 min; HPLC Purity: 70%; MS (ES+) m/z 348 (M+H)
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[N:16]1[C:21]2[N:22]=[C:23]([NH:34][CH2:35][C:36]([O:38]C)=O)[N:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH3:33])[C:20]=2[CH:19]=[CH:18][C:17]1=[O:40]>>[F:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[N:16]1[C:21]2[N:22]=[C:23]([NH:34][CH2:35][C:36]([N:2]([CH3:3])[CH3:1])=[O:38])[N:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH3:33])[C:20]=2[CH:19]=[CH:18][C:17]1=[O:40]
Reactant: CNC
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 54.5 %

Procedure:
Following the general procedure outlined in Example 193, dimethylamine (1.1 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2 mmol) and the product of Example 190 (100 mg, 0.22 mmol) were reacted to give the desired product 56 mg (54%). LC-MS: 468.2 (MH+, m/z), 2.00 (Rt, min).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][C@@H:14]([CH3:18])[NH:13]1.ClCCl>O>[CH3:11][C@H:12]1[NH:13][C@@H:14]([CH3:18])[CH2:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Temperature: 45 °C
Yield: 103.3 %

Procedure:
A suspension of 6.74 g (47.8 mmol) of 4-fluoro-nitro-benzene and 10.91 g (95.5 mmol) of cis-2,6-dimethyl-piperazine is heated at 45° C. for 1 hour. The reaction mixture is cooled and shaken with dichloromethane and water. The organic layer is dried (magnesium sulfate) and concentrated to give 11.62 g (>100%) of the product as a solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH2:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>ClCCl>[Br:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][C:19](=[O:22])[CH2:20][CH3:21])[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: NC1CCc2nc(Br)sc2C1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1CCc2nc(Br)sc2C1
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A solution of 2-Bromo-4,5,6,7-tetrahydro-benzothiazol-6-ylamine (0.36 grams, 1.5 mmol, obtained in above step) and triethylamine (0.43 mL, mmol) in dichloromethane (15 mL) was cooled to 0° C. Propionylchloride (0.17 mL, 1.8 mmol) in dichloromethane (2 mL) were added and stirred the reaction mass for 30 minutes. After completion of reaction, the mass was poured onto ice cold water and the product was extracted with ethyl acetate (3×15 mL). The combined organics were washed with water followed by brine, dried over anhydrous sodium sulphate and the organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (methanol/chloroform, 2/98) to obtain the title compound (0.4 grams).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=[C:20]([CH:24]=1)[C:21]([OH:23])=[O:22].O>CO.[N+]([O-])([O-])=O.[Ag+]>[C:21]([C:20]1[CH:24]=[C:16]([N:15]=[C:3]2[CH:4]=[C:5]3[C:14](=[N:13][C:12]4[C:7]([S:6]3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=[CH:2]2)[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=1)([OH:23])=[O:22]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(N=c2ccc3nc4ccccc4sc-3c2)cc(C(=O)O)c1
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
Phenothiazine (1.0 g, 5.0 mmol) and 5-aminoisophthalic acid (0.9 g, 5.0 mmol) were dissolved in MeOH (200 mL), cooled to 10° C. and treated with 1 M aqueous AgNO3 (30 mL, 30 mmol). After stirring at 10° C. for 30 minutes H2O (40 mL) was added and stirring continued for an additional 5 minutes. The solid product was then collected by filtration and washed with H2O (50 mL). The solid was dissolved in MeOH (500 mL) containing concentrated aqueous NH4OH (10 mL), stirred for 20 minutes then filtered to remove Ag. The filtrate was concentrated to ca. half its original volume under reduced pressure and refrigerated overnight at 5° C. The mixture was then filtered through Celite (Celite Corp.) and concentrated in vacuo until solid began to separate. The resulting solution (ca. 100 mL) was again filtered through Celite, diluted with ethyl acetate (900 mL) and allowed to stand for 15 minutes. The red solid that separated was collected by filtration, washed with ethyl acetate and dried to give 18(1.55 g, 82.5%).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C1C=CC=CN=1)C.N1C=CN=C1.[Si:52](Cl)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]>N1C=CC=CC=1>[Si:52]([O:4][C@@H:3]1[C@@H:5]([CH2:6][OH:7])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a solution of thymidine (10.00 g, 41 mmol) in pyridine (50 ml) was added triphenylmethyl chloride (13.81 g, 50 mmol) and dimethylaminopyridine (0.4 g, 3.0 mmol). The mixture was allowed to stir at 80° C. for 30 min. The pyridine was removed under reduced pressure and the residue dissolved in DMF (80 ml). Imidazole (6.14 g, 90 mmol) and t-butyldimethylsilyl chloride (6.18 g, 41 mmol) were added, and the mixture was allowed to stir overnight at room temperature. The DMF was removed under reduced pressure, and the residue was dissolved in 80% aqueous acetic acid (60 ml). The mixture was allowed to reflux for 30 min, cooled, and neutralized with NaOH. The mixture was lyophilized, and the residue was purified by chromatography (1:1 EtOAc: hexanes) to give 21 as a white solid (10.35 g, 71%): mp 60° C. (softens), 90° C. (melts); Rf 0.69 (1:9 MeOH:CH2Cl2); 1H NMR (CDCl3) 7.33(m, 1H), 6.13(t, 1H, J=6.75 Hz), 4.48(m, 1H), 3.90(m, 2H), 3.74(m, 1H), 2.32(m, 1H), 2.22(m, 1H), 1.89(s, 3H), 0.88(s, 9H), 0.07(s, 6H)ppm.
Reaction SMILES: O.O.[Sn](Cl)Cl.Cl.[Cl:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)(O)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[N:16]([CH3:37])[C:15](=[O:38])[CH:14]=1>CC(O)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=2)[N:16]([CH3:37])[C:15](=[O:38])[CH:14]=1
Reactant: Cn1c(=O)cc(CCc2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)cc(CCc2cccc(Cl)c2)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc21
Temperature: 110 °C

Procedure:
To a solution of tin(II) chloride dihydrate (268 mg, 1.189 mmol, 4 equip) and concentrated HCl (0.373 ml) in AcOH (4 ml) was added 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(hydroxy)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one (160 mg, 0.307 mmol, 1 equip). The resulting solution was heated to 110° C. for 45 minutes. The reaction was cooled to room temperature and concentrated. The residue was purified by MPLC using dichloromethane-methanol as the eluent to yield 4-(3-chlorophenethyl)-6-((4-chlorophenyl)(thiazol-2-yl)methyl)-1-methylquinolin-2(1H)-one.