Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.CC(CC)=CC1C=CC(C)=CC=1.C([O-])([O-])=O.[K+].[K+]>[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[CH3:1][C:2]1[CH:11]=[CH:12][C:5]2[C:4](=[CH:9][CH:8]=[C:7]([CH3:10])[CH:6]=2)[CH:3]=1
Reactant: CCC(C)Cc1ccc(C)cc1
Agent: [Cr+3]
Agent: CCC(C)=Cc1ccc(C)cc1
Agent: O=C([O-])[O-]
Product: Cc1ccc2cc(C)ccc2c1

Procedure:
contacting p-(2-methylbutyl)toluene or p-(2-methylbutenyl)toluene under dehydrocyclization conditions with a catalyst comprising supported chromium oxide modified with K2CO3 to produce 2,6-dimethylnaphthalene with simultaneous fragmentation of C12-alkylindanes or -indenes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])=[CH:11][CH:10]=2
Reactant: Clc1cc2cc(Br)ccc2cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ccc2cnc(Cl)cc2c1
Temperature: 50 °C
Yield: 103.1 %

Procedure:
A solution of 6-bromo-3-chloro-isoquinoline (972 mg, 4 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (2.5 g, 2.5 mL, 7 mmol) in toluene (12 mL) was degassed with nitrogen for 30 minutes. Bis(triphenylphosphine)palladium(II) dichloride (280 mg, 0.4 mmol) was added and the reaction mixture was heated at 50° C. for 18 h. The reaction mixture was cooled to room temperature and the mixture was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 20:1 to 10:1 to afford the title compound (964 mg). 1H NMR (300 MHz, CDCl3) δ1.51 (t, J=7.0 Hz, 3H), 4.01 (q, J=7.0 Hz, 2H), 4.45 (d, J=2.8 Hz, 1H), 4.90 (d, J=2.8 Hz, 1H), 7.76 (s, 1H), 7.85-7.97 (m, 2H), 8.04 (s, 1H), 0.94 (s, 1H). LCMS (m/z) 234/236 [M+H], Tr=5.40 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([CH2:22][N:23]([CH3:25])[CH3:24])[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>[Fe].CO>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([CH2:22][N:23]([CH3:24])[CH3:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:26]#[N:27])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CN(C)Cc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)Cc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 59.8 %

Procedure:
A stirred mixture of 4-[(3-bromophenyl)amino]-8-dimethylaminomethyl-6-nitro-3-quinolinecarbonitrile (5.98 g, 14.1 mmol), iron powder (2.76 g, 49 mg-atoms), acetic acid (5.67 ml, 99 mmol), and 70 ml of methanol was refluxed for 2 h and then evaporated to remove methanol. The residue was stirred with water for 10 m, and the orange solid was filtered off and washed with 2% acetic acid. The total filtrate was basified to pH 10 with 5 N sodium hydroxide. The resulting precipitate was extracted with methylene chloride. The extract was washed with water, dried, and concentrated. The residue was subjected to chromatography on silica gel with ethyl acetate-methanol-triethylamine to give 3.34 g of amber solid; mass spectrum (electrospray, m/e) M+H 396.2, 398.1.
Reaction SMILES: C=O.[C:3](=O)([O-])[O-:4].[K+].[K+].[CH3:9][O:10][C:11]([C:13]1([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16][CH:15]([CH3:18])[C:14]1=[O:19])=[O:12]>O>[CH3:9][O:10][C:11]([C:13]1([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:17][CH2:16][C:15]([CH2:3][OH:4])([CH3:18])[C:14]1=[O:19])=[O:12]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)C1=O
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O

Procedure:
A 37% formaldehyde aqueous solution (0.90 ml) and potassium carbonate (2.00 mmol) were added to 1-(4-chlorobenzyl)-3-methyl-2-oxocyclopentanecarboxylic acid methyl ester (Compound VIII-1) (4.00 mmol), and the resultant mixture was stirred at room temperature for 4 hours. After the reaction, water was added to the resultant reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and thereafter dried over anhydrous sodium sulfate. The solvent was distilled off, and a residue was purified with the use of a silica gel column. In this way, Compound VII-1 in the form of two isomers (isomer VII-1a and isomer VII-1b) was obtained. Note that Compound VIII-1 was synthesized in accordance with a method described in Patent Literature 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([NH2:22])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:30]C(N1C[C@H](O)C[C@H]1C(OC(C)(C)C)=O)=O)C1C=CC=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:19]([C@H:18]2[CH2:17][CH2:16][CH2:20][NH:22]2)=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN2CCCC2C(N)=O)C1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)[C@H]2CCCN2)C1

Procedure:
The title compound was prepared by methods similar to Steps 1 and 2 of Example 45, using (2R)-N-({(3R)-1-(tert-butoxycarbonyl-3-piperidyl}methyl)pyrrolidine-2-carboxamide and N-benzyloxycarbonyl-O-(tert-butyl)-trans-4-hydroxy-L-proline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:24])[C:5]2[N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=3.C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:84]([N:91]1[CH2:97][CH2:96][CH2:95][NH:94][CH2:93][CH2:92]1)([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85]>>[C:84]([N:91]1[CH2:97][CH2:96][CH2:95][N:94]([C:2]2[CH:3]=[C:4]([F:24])[C:5]3[N:6]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[C:7]4[C:12]([S:13][C:14]=3[CH:15]=2)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=4)[CH2:93][CH2:92]1)([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CC(C)(C)OC(=O)N1c2ccc(Br)cc2Sc2cc(Br)cc(F)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(c2cc(F)c3c(c2)Sc2cc(Br)ccc2N3C(=O)OC(C)(C)C)CC1

Procedure:
To a stirred solution of 3,7-dibromo-1-fluoro-10-Boc-phenothiazine (950 mg, 2.0 mmol) in toluene (30 mL) Pd2(dba)3 (46 mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol) and N-Boc-homopiperazine (1-Boc-1,4-diazepane) (400 mg, 2.0 mmol) were added. The mixture was refluxed for 24 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].[OH-].[Na+]>CCO.O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COCc1cc(C(=O)OC)ccc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of methyl 2-(methoxymethyl)-2′-methylbiphenyl-4-carboxylate (40.0 g, 148.0 mmol) in EtOH (1.2 L) at RT was treated with a 5N aqueous solution of NaOH (90 mL, 450 mmol). The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to RT and concentrated to give a yellow solid which was taken up in water (800 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with a concentrated aqueous solution of HCl (40 mL, pH˜2) and it was extracted with EtOAc (2×400 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated affording the title compound as a yellow solid (35.1 g, 92%). 1H NMR (DMSO-d6, 300 MHz) δ 12.99 (br s, 1H), 8.09 (s, 1H), 7.91 (m, 1H), 7.33-7.22 (m, 4H), 7.09 (m, 1H), 4.11 (m, 2H), 3.18 (s, 3H), 1.99 (s, 3H). LC/MS (Method B): 255.2 (M−H)−. HPLC (Method A) Rt 4.52 min (Purity: 96.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12](OCC)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N2CCCC2)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and pyrrolidine (1 ml) was heated at 120° C. for 15 h to obtain 59 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)ethanone after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [ClH:1].C([O:6][CH:7](OCCCC)[C@H:8]([CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41])[NH:9][C:10](=[O:35])[C@H:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:12][C:13](=[O:30])[C@H:14]1[CH2:18][CH2:17][C:16](=[O:19])[N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])CCC.Cl.[OH-].[Na+]>C(#N)C>[ClH:1].[CH2:23]([O:22][C:20]([N:15]1[C:16](=[O:19])[CH2:17][CH2:18][C@@H:14]1[C:13]([NH:12][C@H:11]([C:10]([NH:9][C@H:8]([CH:7]=[O:6])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:42])=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:30])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)C[C@H](NC(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N[C@H](C=O)CCCNC(=N)N
Yield: 84.4 %

Procedure:
To a solution of N-benzyloxycarbonyl-D-pyroglutamyl-L-leucyl-L-argininal dibutylacetal hydrochloride (0.21 g, 0.30 mmol) in acetonitrile (30 ml) was added 1N hydrochloric acid aqueous solution (15 ml). The mixture was reacted at 36° C. for 2 hours with stirring. After completion of the reaction, pH of the reaction mixture was adjusted to 4.8 with 1N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and chloroform was added to the residue. Insoluble matters were removed by filtration. After the filtrate was concentrated, the residue was recrystallized from chloroform-hexane to give 0.14 g (83%) of N-benzyloxycarbonyl-D-pyroglutamyl-L-leucyl-L-argininal hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])([O-])=O.[Cl-].[NH4+].N.[S-2].[Na+].[Na+]>O.C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccccc1Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1Nc1ccccc1C(=O)O
Reaction time: 1 h
Yield: 67.1 %

Procedure:
1.80 g (6 mmol) of 2-(2,4-dinitrophenylamino) benzoic acid, 2.66 g (42.6 mmol) of ammonium chloride, 2.4 ml of ammonia, concentrated, 52 ml of ethanol, and 21 ml of distilled water are combined at an internal temperature of 78° C. (bath temperature 90° C.). To this batch is added, in 3 portions, 4.44 g (20 mmol) of sodium sulfide (35% strength) and the mixture is stirred for one hour. The batch is suctioned off at room temperature and washed in succession with water and ether. The filtrate is concentrated to the aqueous phase and extracted by shaking with ethyl acetate. The organic phase is dried, filtered, and concentrated. The aqueous phase is acidified with 1N hydrochloric acid and suctioned off, thus obtaining 1.1 g of 2-(2-amino-4-nitrophenylamino)benzoic acid (processed without purification).
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:6]#[N:5])=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CO
Product: N#Cc1ccc(CN)cc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
Next, 26.0 g (99 mmols) of 4-phthalimidomethylbenzonitrile prepared in the same manner as above was admixed with 6.32 ml (0.129 mol) of hydrazine hydrate and 300 ml of methanol. The mixture was refluxed for 1 hour, cooled to room temperature and concentrated. The residue was dissolved in 300 ml of 1 mol dm-3NaOH, followed by extraction with ether. The ethereal layer was washed with saturated aqueous solution of sodium chloride, dryed over MgSO4 and concentrated, affording 11.8 g (yield 90%) of 4-aminomethylbenzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.C(N(CC)CC)C.[I-].C([NH3+])(C)(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: COC(=O)CCCCCBr
Reactant: Sc1ccc(Cl)cc1
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCSc1ccc(Cl)cc1

Procedure:
To a solution of 6-bromohexanoic acid methyl ester (2.1 g, 10 mmol), triethylamine (1.6 mL, 11 mmol) and tert-butylammonium iodide (200 mg, 0.54 mmol) in freshly distilled THF (30 mL) was added 4-chlorothiophenol (1.45 g, 10 mmol) under an atmosphere of argon. The mixture was stirred at reflux for 2 hours after which it was concentrated under reduced pressure. The oil was dissolved in ethyl acetate (100 mL) and then washed successively with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL) and brine (50 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an yellow oil that was purified by flash chromatography (1:9 diethyl ether:40-60° C. petroleum ether). The title compound was obtained as a colourless oil (2.5 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[N+:6]([O-:11])=[CH:7][NH:8][C:9]=2[N:10]=1.[ClH:13]>>[ClH:13].[N:3]1[C:4](=[O:12])[C:5]2[C:9]([N:8]=[CH:7][N+:6]=2[O-:11])=[N:10][C:2]=1[NH2:1]
Reactant: Nc1nc2[nH]c[n+]([O-])c2c(=O)[nH]1
Agent: Cl
Product: NC1=NC(=O)C2=[N+]([O-])C=NC2=N1
Temperature: 25 °C

Procedure:
2-Amino-1,9-dihydro-6H-purin-6-one-7-oxide (52.3 mg, 0.31 mmol) was heated over a steam bath in 5 ml of 1.0M aqueous hydrochloric acid until it dissolved. The solution was filtered and allowed to cool to room temperature. Upon standing, 47.3 mg of the hydrochloride salt of 2-amino-1,9-dihydro-6H-purin-6-one-7-oxide precipitated as fine, white needles, mp >250° C.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([CH:12]=1)[OH:11])[CH:3]([CH3:5])[CH3:4].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[ClH:22]>C(O)(=O)C>[ClH:22].[CH3:14][N:15]1[CH2:16][CH:17]=[C:18]([C:9]2[C:10]([OH:11])=[CH:12][C:6]([CH:2]([CH3:1])[CH:3]([CH3:4])[CH3:5])=[CH:7][C:8]=2[OH:13])[CH2:19][CH2:20]1
Reactant: CC(C)C(C)c1cc(O)cc(O)c1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)C(C)c1cc(O)c(C2=CCN(C)CC2)c(O)c1

Procedure:
5-(1,2-Dimethylpropyl) resorcinol (15.7 g) and N-methyl-4-piperidone (9.8 g) were dissolved in 35 ml acetic acid and treated with HCl gas as described in Example VI giving 18.8 g of product, m.p. 241°-243°.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([NH:22][C:23]2[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][N:27]([C@H:35]([CH3:38])[CH2:36][OH:37])[C:28]3=[O:34])=[O:21])[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(Cl)Cl>CN(C)C1C=CN=CC=1>[CH3:39][S:40]([O:37][CH2:36][C@H:35]([N:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[C:32]([CH3:33])[C:23]=2[NH:22][C:20](=[O:21])[CH2:19][C:11]2[CH:12]=[CH:13][C:14]([C:15]([F:18])([F:16])[F:17])=[C:9]([F:8])[CH:10]=2)[C:28]1=[O:34])[CH3:38])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.2 g, 0.002 mol) was added to a solution of (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(2-(1-hydroxypropan-2-yl)-6-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)acetamide (0.5 g, 0.001 mol), methanesulfonyl chloride (0.16 g, 0.0014 mol) and 4-dimethylaminopyridine (10 mg, 0.0001 mol) in methylene chloride (10 mL, 0.2 mol). The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the mixture was purified via flash chromatography to afford the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.[Br:21][C:22]1[N:26]=[C:25](Cl)[S:24][N:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:21][C:22]1[N:26]=[C:25]([C:6]2[CH:7]=[C:2]([Cl:1])[C:3]([O:17][CH:18]([CH3:19])[CH3:20])=[N:4][CH:5]=2)[S:24][N:23]=1
Reactant: CC(C)Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: Clc1nc(Br)ns1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)Oc1ncc(-c2nc(Br)ns2)cc1Cl
Yield: 96.4 %

Procedure:
3-chloro-2-[(1-methylethyl)oxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (D108) (1.2 g, 4.03 mmol), 3-bromo-5-chloro-1,2,4-thiadiazole (1.609 g, 8.06 mmol), tripotassium phosphate (2.57 g, 12.10 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.329 g, 0.403 mmol) were heated by Biotage Initiator to 80° C. for 1 hr. The reaction mixture was concentrated and the slurry was diluted with ethyl acetate. The resulted solution was washed with water, dried and purified by ISCO column chromatography to afford 5-(3-bromo-1,2,4-thiadiazol-5-yl)-3-chloro-2-[(1-methylethyl)oxy]pyridine (D109) (1.3 g). δH (CDCl3, 400 MHz): 1.43 (6H, d), 5.45 (1H, m), 8.21 (1H, d), 8.59 (1H, d). MS (ES): C10H9BrClN3OS requires 332.9. found 334.0 (M+H+).
Reaction SMILES: [Br-].[Li+].C[Si](Cl)(C)C.C[SiH](C)O[SiH](C)C.Br[CH2:16][C:17]1[C:22]2[O:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=2[C:20]([O:28][CH3:29])=[CH:19][CH:18]=1.[C-:30]#[N:31].[Na+]>C(#N)C.C1(C)C=CC=CC=1.CN(C=O)C.O>[CH3:26][C:24]1([CH3:27])[O:25][C:21]2[C:20]([O:28][CH3:29])=[CH:19][CH:18]=[C:17]([CH2:16][C:30]#[N:31])[C:22]=2[O:23]1
Reactant: [C-]#N
Reactant: COc1ccc(CBr)c2c1OC(C)(C)O2
Agent: C[SiH](C)O[SiH](C)C
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(CC#N)c2c1OC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of 2,2-dimethyl-7-methoxy-1,3-benzodioxole-4-carbaldehyde (9.3 g, 45 mmol) obtained by the method mentioned in the Japanese Published Unexamined Patent Application No. 98/147585 and by a method similar thereto in acetonitrile (47 mL) was added lithium bromide (8.9 g, 85 mmol), and then trimethylsilyl chloride (8.5 mL, 67 mmol) was added dropwise. After 15 minutes, the mixture was ice-cooled, and 1,1,3,3-tetramethyldisiloxane (13 mL, 76 mmol) was added dropwise, followed by stirring at room temperature for 2 hours. The resulting mixture was diluted with toluene and filtered through Celite. The solvent was evaporated in vacuo from the filtrate to give a pale yellow oil. To a solution of this crude 7-bromomethyl-2,2-dimethyl-4-methoxy-1,3-benzodioxole in DMF (73 mL) was added sodium cyanide (5.0 g, 102 mmol), and the mixture was stirred at room temperature for18 hours. Under ice-cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=5/1) to give Compound 12a (9.1 g, 92%) as an ash-colored solid.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1)[C:13]([OH:15])=O)[CH2:3][CH2:2]2.[NH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1)[C:13]([NH:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[O:15])[CH2:3][CH2:2]2
Reactant: O=C(O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reactant: CC(C)(CN)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(CO)CNC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-nitroisonicotinic acid (Intermediate 29A) (2.0 g, 6.8 mmol) in DMF (25 mL) was added 3-amino-2,2-dimethylpropan-1-ol (0.85 g, 8.2 mmol), triethylamine (1 g, 10.3 mmol) and HATU (3.16, 10.3 mmol) under nitrogen, reaction then stirred overnight. The reaction mixture was concentrated and purified by HPLC to afford 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(3-hydroxy-2,2-dimethylpropyl)-5-nitroisonicotinamide.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C1COCC1.C(O)=O.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:23]=[C:24]([NH2:26])[CH:25]=1)=[O:19]>O>[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:23]=[C:24]([NH:26][CH:1]=[O:3])[CH:25]=1)=[O:19]
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: COC(=O)c1cc(NC=O)cc(-c2ccc(C)cc2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (11.0 g, 108 mmol) was added to THF (15 mL) followed by addition of formic acid (5.09 g, 133 mmol). The mixture was heated to 65° C. for 2.5 hours, then cooled to room temperature. 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (5.0 g, 21 mmol) was added, and the reaction mixture was stirred for three hours at 70° C., then cooled to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 5-formylamino-4′-methyl-biphenyl-3-carboxylic acid methyl ester, which was used directly in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].C[Al](C)C>C1(C)C=CC=CC=1>[Br:14][C:12]1[CH:11]=[CH:10][C:7]2[C:8](=[NH:9])[NH:2][CH2:3][CH2:4][O:5][C:6]=2[CH:13]=1
Reactant: N#Cc1ccc(Br)cc1OCCN
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: N=C1NCCOc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a flask was charged 37 (9.00 g, 32.4 mmol) and toluene (90.0 ml). The suspension was cooled to 0° C. and was added trimethylaluminum (1.8 equiv., 58.4 mmol, 2M in toluene) drop-wise over 30 minutes. The suspension was then stirred at room temperature for 1 h and then warmed to 100° C. After 5 h, the solution was cooled to 0° C. and quenched with aqueous NaOH (2N, 90.0 ml). The suspension was extracted with EtOAc (4×90 ml) and the combined extracts were dried over then filtered through Celite®. The solution was concentrated and the residue triturated with EtOAc to afford 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-imine 33 (6.26 g, 26.0 mmol, 80% yield) as white crystalline solid.