Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:22]=2[CH3:21])[CH2:11][CH2:10][N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)[C@@H](Cc3ccccc3)C2)c1C

Procedure:
The title compound was prepared according to the procedure described for Example 1, Step A except using 2(S)-benzyl-1-tert-butoxycarbonylpiperazine (0.292 g, 1.06 mmol), 2,3-dimethyl-benzoic acid (0.159 g, 1.06 mmol), HOBT (0.157 g, 1.02 mmol), EDC.HCl (0.213 g, 1.11 mmol) and triethylamine to adjust the pH to 7. The title compound was obtained as a thick oil (0.416 g). NMR (DMSO-d6, 300 MHz) δ 7.15 (2H, m), 6.06 (1H,m), 4.42 (1H,m), 3.6-4.2 (2H, m), 2.7-3.24 (4H, m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.6 (15H, m), 0.72-1.00 (3H, m).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH:18]1([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[B][B][B][B][B][B][B][B][B][B]>CO>[CH:18]1([C:24]2[CH:25]=[CH:26][C:27]([NH:28][CH:2]3[C:10]4[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:8][CH:9]=4)[CH2:4][CH2:3]3)=[CH:29][CH:30]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2=O
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCCCOC(=O)c1ccc2c(c1)CCC2Nc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1648 h

Procedure:
To a solution of butyl 1-oxoindane-5-carboxylate (2.0 g, 8.60 mmol) and 4-cyclohexylaniline (2.28 g, 20.64 mmol) in 30 mL of anhydrous MeOH was added decaborane B10H14 (0.32 g, 2.6 mmol) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 1648 h. Product butyl 1-[(4-cyclohexylphenyl)amino]indane-5-carboxylate was collected by filtration as a white solid. HPLC/MS: m/z=392.3 (M+1), Rt=4.97 min. 1H NMR (CDCl3): δ 7.80 (1H, s), 7.97 (1H, d, J=8.0 Hz), 7.48 (1H, d, J=8.0 Hz), 7.14 (2H, d, J=8.5 Hz), 6.74 (2H, d, J=8.5 Hz), 5.07 (1H, t, J=7.1 Hz), 4.39 (2H, t, J=6.7 Hz), 3.92 (1H, br s), 3.10 (1H, m), 2.97 (1H, m), 2.69 (1H, m), 2.49 (1H, m), 2.02-1.80 (8H, m), 1.60-1.31 (7H, m), 1.08 (3H, t, J=7.3 Hz).
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH:7]1[CH:11]=[C:12]([CH3:14])[CH3:13])=[O:5].[OH-].[Na+]>C(O)C>[CH3:13][C:12]([CH3:14])=[CH:11][C@H:7]1[C:8]([CH3:9])([CH3:10])[C@@H:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(C)C)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Yield: 90 %

Procedure:
In a 500 ml volume four-necked flask, there were charged ethyl chrysanthemate consisting of 33.6 % of the cis-isomer and 66.4 % of the trans-isomer (100 g; trans-isomer, 0.34 mol), a 25 % aqueous solution of sodium hydroxide (30 g; NaOH, 0.19 mol) and ethanol (50 g), and the mixture was stirred at 60°C for 5 hours as in Example 1. After removing ethanol by distillation, the reaction mixture was treated as in Example 1 to give trans-chrysanthemic acid (28.7 g; trans-isomer, 90.0 %) and unreacted ethyl chrysanthemate (64.0 g; cis/trans = 53.8/46.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][Br:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: BrCCCCCBr
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(O)ccc21
Product: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(OCCCCCBr)ccc21

Procedure:
In analogy to example 1.4, 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester and 1,5-dibromopentane (80%) were converted to yield 6-(5-Bromo-pentyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless oil, MS: 451 (M, 1Br, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([OH:26])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH2:12][CH2:11][CH2:10]1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:26])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCC(O)c1cccc2nc3n(c12)CCCCN3c1ccc(Cl)cc1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCC(=O)c1cccc2nc3n(c12)CCCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 32 h

Procedure:
A mixture of 1-[1-(2,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-yl]propan-1-ol (160 mg, 0.409 mmol), tetra-n-propylammonium perruthenate (144 mg, 0.409 mmol), 4-methylmorpholine N-oxide (47.9 mg, 0.409 mmol) and dichloromethane (2.0 mL) was stirred at room temperature for 32 hr. The precipitate was removed by filtration, and the mother solution was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless amorphous (11.0 mg, 0.0283 mmol, 7%).
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl[CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([O:23][CH2:22][O:19][C:18]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])=[O:29]
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 50 °C
Yield: 50.8 %

Procedure:
Stir at 50° C. a mixture of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (1.0 g, 3.43 mmol), KI (0.16 g) 2,2-dimethyl-propionic acid chloromethyl ester (0.63 g, 4.16 mmol) in DMF (20 mL) for 1.5 h. Cool, and partition between H2O-EtOAc. Wash the extract with aqueous NaHCO3 solution, dry the extract (MgSO4), filter and concentrate under vacuum to afford the crude product. Chromatography the product on a silica gel column eluting with 8% MeOH/EtOAc to obtain 0.64 g of the title compound as a solid; MS 326(M+H), m.p. 223–224° C. TLC (silica gel, 8% MeOH/EtOAc) Rf=0.30.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:20]=[C:19]([CH:21]([O:24][CH2:25][C:26]2([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH2:22][OH:23])[C:18]2[C:14](=[CH:15][N:16]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[N:17]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:20]=[C:19]([CH:21]([O:24][CH2:25][C:26]2([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:22]=[O:23])[C:18]2[C:14](=[CH:15][N:16]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[N:17]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COC(C=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To solution of Methyl Sulfoxide (0.197 ml, 2.77 mmol) in DCM (12 ml) at −78° C. was added oxalyl chloride (0.694 ml, 1.387 mmol) dropwise. The solution was stirred at −78° C. for 0.5 h. A solution of Tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (400 mg, 0.631 mmol) in DCM (12 ml) was then added dropwise. The slurry was stirred at −78° C. for 2 h before addition of N,N-Diisopropylethylamine (0.549 ml, 3.15 mmol) dropwise. The solution was slowly warmed up and stirred at room temperature for 3 h. It was then washed with iced 1M HCl and brine, dried over MgSO4, filtered and concentrated. The residual light yellow oil was purified by Biotage LC (35% EtOAc/Hexane) to afford title compound (286.3 mg, 0.453 mmol, 71.8% yield) as yellow foam solid. 1H-NMR (CDCl3, 500 MHz) δ 9.61 (s, 1H), 8.05, s, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.33 (m, 2H), 7.04 (m, 2H), 7.02 (buried, 1H), 5.67 (m, 2H), 3.60 (app t, J=8.3 Hz, 2H), 3.45-3.85 (m, 3H), 3.45 (d, J=9.1 Hz, 1H), 2.18 (m, 2H), 1.95 (m, 2H), 1.75 (m, 1H), 1.43 (s, 9H), 0.91 (app t, J=8.2 Hz, 2H), −0.04 (s, 9H). LC/MS (HPLC method 3): tR=4.11 min, 632.3(MH)+.
Reaction SMILES: O(CC(C)C)[C:2]([S-:4])=[S:3].[K+].Cl[C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=1[NH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:18][C:14]1[C:12]2[N:13]=[C:2]([SH:4])[S:3][C:11]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(Cl)c1N
Reactant: CC(C)COC(=S)[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2sc(S)nc12
Reaction time: 26 h
Yield: 94.9 %

Procedure:
A solution of 250 g of potassium isobutyl xanthate (about 90% pure) in 400 ml of dimethylformamide is added dropwise to a mixture of 141.5 g of 2-chloro-6-methylaniline and 276 g of potassium carbonate in 1 liter of dimethylformamide at 150° C. in the course of one hour, under a nitrogen atmosphere. The reaction mixture is stirred for about a further 26 hours, whilst cooling intensively. The batch is cooled, freed from salt and then concentrated to dryness. The residue is taken up in 400 ml of water and the mixture is acidified. The 4-methyl-2-mercaptobenzothiazole which precipitates is filtered off, washed with water and dried. 172 g (95% of theory) of 4-methyl-2-mercaptobenzothiazole of melting point 188°-190° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[O:17][C:16](=[O:18])[NH:15][N:14]=3)=[CH:11][C:10]([C:19]([F:22])([F:21])[F:20])=[N:9]2)=[N:6][CH:7]=1.[CH3:23]CN(C(C)C)C(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[O:17][C:16](=[O:18])[N:15]([CH3:23])[N:14]=3)=[CH:11][C:10]([C:19]([F:20])([F:21])[F:22])=[N:9]2)=[N:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1[nH]nc(-c2cc(C(F)(F)F)nn2-c2ccc(Br)cn2)o1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1nc(-c2cc(C(F)(F)F)nn2-c2ccc(Br)cn2)oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Step-5: 5-(1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3,4-oxadiazol-2(3H)-one: To a stirred and (0° C.) cooled solution of step-4 intermediate (4.0 g, 11.43 mmol) and DIPEA (3.99 mL, 22.85 mmol) in DCM (50 mL) was added a solution of triphosgene (1.35 g, 4.57 mmol) in DCM (20 mL) over a period of 10 min. Reaction mixture was warmed to room temperature and stirred overnight. The reaction was cooled to 0° C. and quenched with ice water (5 mL). Water (25 mL) was added to the above mixture followed by DCM (100 mL). The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 3.0 g (70%) of the title compound as pink semisolid. 1HNMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H, D2O exchangeable), 8.71 (d, J=2.5 Hz, 1H), 8.39 (dd, J=2.5 & 8.5 Hz, 1H), 7.90 (d, T=8.5 Hz, 1H), 7.70 (s, 1H); ESI-MS (m/z) 376, 378 [(MH)+, Br79,81].
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]([O:16][Si](CC)(CC)CC)[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]1)(=[O:3])=[O:4]
Reactant: CC[Si](CC)(CC)OC(C1CCN(S(C)(=O)=O)CC1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(C(O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
1-Methanesulfonyl-4-[2,2,2-trifluoro-1-(triethyl-siloxy)ethyl]piperidine (300 mg, 0.999 mmol) was dissolved in tetrahydrofuran (2.4 mL). To this, a 1 mol/L aqueous hydrogen chloride solution (2.4 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give Compound EAG (198 mg, yield: 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:17][CH2:16][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:9]
Reactant: Cc1ccc(F)cc1C(=O)N1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C(c1cc(F)ccc1CBr)N1CCOCC1
Yield: 38.3 %

Procedure:
A mixture of intermediate 41, (5-fluoro-2-methylphenyl)(morpholino)methanone, (2.1 g, 9.5 mmol) and N-bromosuccinimide (2.0 g, 11 mmol) in CCl14 (30 mL) was heated at reflux. To this mixture was added benzoylperoxide (242 mg, 1 mmol) and the mixture heated at reflux for 2 hrs. After cooling, the insoluble materials were filtered and the filtrate purified by column chromatography (SiO2, 0-10% ether in CH2Cl2) to give 1.1 g (Yield 38%) of the title compound as a clear oil: 1H NMR (300 MHz, CDCl3) δ ppm: 3.31 (2H, t, J=4.94 Hz) 3.55-4.02 (6H, m) 4.56 (2H, dd, J=128.81, 9.51 Hz) 6.89 (1H, dd, J=8.23, 2.74 Hz) 6.96-7.12 (1H, m) 7.33-7.49 (1H, m); LC/MS m/z 302 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16]O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][CH2:16][C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[C:7]2=[N:14][C:13]=1[CH3:15]
Reactant: Cc1nc2c(OCc3ccccc3F)cccn2c1CO
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(OCc3ccccc3F)cccn2c1CCl

Procedure:
A mixture of 8-(2-fluorobenzyloxy)3-hydroxymethyl-2-methyl-imidazo[1,2-a]pyridine from Example 5 (1 g) and phosphorylchloride (15 ml) was heated under reflux for1 hr. Excess phosphorylchloride was distilled off in vacuo, the residue dissolved in hot ethanolic HCL and the mixture filtered to give the title compound as the hydrochloride salt.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][OH:22])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:31](Br)[CH2:32][CH2:33][CH3:34]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][O:22][CH2:31][CH2:32][CH2:33][CH3:34])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCBr
Reactant: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccc2c(c1)OCO2
Product: CCCCOCc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 240 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-3-hydroxymethyl-4-phenyl-2H-isoquinolin-1-one (250 mg) and n-butylbromide. Colorless crystals (120 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([CH:21]=O)=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][O:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][O:25]/[N:24]=[CH:21]/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1
Reactant: O=Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NOCCO
Agent: Cl
Product: OCCO/N=C/c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 45 %

Procedure:
The title compound was prepared from 1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbaldehyde and 2-(aminooxy)ethanol hydrochloride in 45% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, CD3OD), δ ppm 9.27 (s, 1H), 8.84 (m, 1H), 8.36 (s, 1H), 8.34 (d, 1H), 8.01 (d, 1H), 8.00 (s, 1H), 7.85 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 4.39 (t, 2H), 3.87 (t, 2H). LCMS (method B): [MH]+=350, tR=1.94 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[O:8])[CH2:6]Br.C(N(CC)C(C)C)(C)C.[CH2:21]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH:22]=[CH2:23].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[CH2:21]([N:24]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH2:6][C:5]([C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=1)=[O:8])[CH:22]=[CH2:23]
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: C=CCNCc1ccc(OC)cc1OC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(CC(=O)c1cccc(Br)c1)Cc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
3-Bromophenacyl bromide (20.9 g) was dissolved in dichloromethane (400 mL). After ice-cooling the solution, N,N-diisopropylethylamine (14.3 mL) and allyl(2,4-dimethoxybenzyl)amine (18.7 g) were dissolved in dichloromethane (50 mL) and added dropwise. The reaction solution was gradually warmed to room temperature while dipping in an ice water bath, and stirred for about 20 hours. Chloroform, a saturated sodium bicarbonate solution and a saturated sodium chloride solution were sequentially added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate (2 g). The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a crude product. The product was subjected to silica gel column chromatography to obtain the title compound (29.88 g).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][C:8]([OH:10])=[O:9]>>[CH2:1]([NH:5][CH2:7][C:8]([OH:10])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=C(O)CBr
Product: CC(C)CNCC(=O)O
Reaction time: 8 h

Procedure:
Isobutylamine (50 mL, 0.5 mol) was cooled in an ice bath, and bromoacetic acid (6.1 g, 43.9 mmol) added slowly as a solid, insuring that each piece dissolved. After stirring overnight, the excess amine was removed and MeOH was added to the resulting oil. The resulting mixture was concentrated, and repeated using MeOH/HCl. Finally, a white solid was recrystallized from ethanol/ether to provide N-isobutylglycine.HCl (3.95 g, 53.7%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.O[CH2:14][CH:15]([CH2:17]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[CH3:9][C:8]1[C:2]([CH3:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]2[C:7]=1[CH:14]=[CH:15][CH:17]=[N:6]2
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])c2ncccc2c1C
Yield: 16.5 %

Procedure:
In a similar fashion using route 10 general procedure 20, 4,5-dimethyl-2-nitroaniline (1.0 g, 6.0 mmol), glycerol (1.0 g, 11.4 mmol), 3-nitrobenzenesulfonic acid sodium salt (2.2 g, 9.6 mmol) and H2SO4/H2O (3 ml, 7:1), further reagents added over 4 days, gave the title compound (200 mg, 16%) which was used in the next step without purification.
Reaction SMILES: [CH:1]1([N:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[C:13]3[C:8]([C:9]([F:23])=[CH:10][CH:11]=[CH:12]3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCCCC=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:1]1([N:6]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[C:13]3[C:8]([C:9]([F:23])=[CH:10][CH:11]=[CH:12]3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)cc1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A solution of 2-cyclopentyl-7-fluoro-3-(4-methoxyphenyl)-2H-indazole (0.055 g, 0.177 mmol) in CH2Cl2 containing excess equivalents of cyclohexene (0.3 mL) at −78° C. was treated with boron tribromide (0.70 mL, 0.74 mmol, 4 eq.) and slowly allowed to warm to ambient temperature. The reaction mixture was quenched by dropwise addition of CH3OH to the cooled reaction mixture. The solvent was removed in vacuo and the residue partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). Removal of the solvent in vacuo afforded the crude product. Pure product was obtained by crystallization or flash chromatography through water deactivated silica gel to give the product (0.03 g) as an amber solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[OH-].[Na+].[CH3:21]I.O>CS(C)=O>[CH3:21][N:7]1[C:6]2[CH:17]=[C:2]([CH3:1])[C:3]([CH3:18])=[CH:4][C:5]=2[NH:11][C:10]2[N:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]1=[O:16]
Reactant: Cc1cc2c(cc1C)Nc1ncccc1C(=O)N2
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(cc1C)N(C)C(=O)c1cccnc1N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4.55 g (0.019mol) of 6,11-dihydro-8,9-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one in 40 ml of dimethylsulfoxide was added 3.0 ml of a 30% NaOH solution (0.022 mol). After two hours at room temperature 5.0 ml (0.08 mol) of methyl iodide was added and the mixture stirred at room temperature overnight. It was then poured into water, the resulting precipitate collected, washed, dried and crystallized from ethanol to yield 3.3 g (69% of theory) of a crystallized solid melting at 206°-209° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[C:7]([CH3:18])([CH3:17])[CH2:6]1)(=[O:4])=[O:3].CC(O)=O>C1COCC1.[Zn]>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[C:7]([CH3:18])([CH3:17])[CH2:6]1)(=[O:4])=[O:3]
Reactant: CC1(C)CN(S(C)(=O)=O)c2cc([N+](=O)[O-])ccc21
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)CN(S(C)(=O)=O)c2cc(N)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-Methanesulfonyl-3,3-dimethyl-6-nitro-2,3-dihydro-1H-indole (0.88 mg, 3.22 mmol) and AcOH (3.5 mL) in THF (100 mL) was added Zinc dust (14 g, 247 mmol) by small portion. The resulting mixture was stirred at RT for 2 h and was filtered over a Celite® pad. Solvent was evaporated and residue was diluted in CH2Cl2 and washed with NaOH 1M. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to give 1-Methanesulfonyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-ylamine.