Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[C:4]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[NH:5][CH:6]=1.C([Mg]Br)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[CH3:29])[O:25][CH2:24][CH2:23][C:22]2=[O:30].[Cl-].[NH4+]>C(Cl)Cl>[OH:30][C:22]1([C:2]2[N:3]=[C:4]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[NH:5][CH:6]=2)[C:21]2[C:26](=[CH:27][C:28]([CH3:29])=[C:19]([O:18][CH3:17])[CH:20]=2)[O:25][CH2:24][CH2:23]1
Reactant: COc1cc2c(cc1C)OCCC2=O
Reactant: CN(C)S(=O)(=O)c1nc(I)c[nH]1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1cc2c(cc1C)OCCC2(O)c1c[nH]c(S(=O)(=O)N(C)C)n1
Reaction time: 2.5 h
Yield: 56.1 %

Procedure:
A solution of 4.6 grams (0.016 mole) of [(4-iodoimidazolyl)sulfonyl]dimethylamine (commercially available) in 10 mL of dry methylene chloride was stirred and 5.7 mL (0.018 mole) of ethylmagnesium bromide (3M in diethyl ether) was added. Upon completion of addition, the reaction mixture was stirred during a 2.5 hour period. After this time, 3.0 grams (0.016 mole) of 6-methoxy-7-methylchroman-4-one (ii) (prepared in Step C of Example 5) was added, and the reaction mixture was stirred for an additional 18 hours. After this time, the reaction mixture was poured into 100 mL of an aqueous solution of ammonium chloride and extracted with three 100 mL portions of methylene chloride. The combined extracts were washed with one 50 mL portion of water, and dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on Grade II basic alumina (3% water) using a 99:1 mixture of methylene chloride and methanol, respectively, as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 3.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1C2C(=CC=CC=2)C=CC=1S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH2:41][C:42]([F:45])([F:44])[F:43])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: O=S(=O)(OCC(F)(F)F)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(CC(F)(F)F)c4=O)cc3)CC2)cc1
Yield: 42.4 %

Procedure:
A mixture of 17.5 parts of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-3H-1,2,4-triazol-3-one prepared as described in example XVII of U.S. Pat. No. 4,267,179, 19.5 parts of 2,2,2-trifluoroethyl 2-naphthalenesulfonate, 10.0 parts of potassium carbonate and 135 parts of N,N-dimethylformamide was stirred overnight at 145° C. After cooling, water was added. The crystallized product was filtered off under pressure and dissolved in dichloromethane. The organic layer was dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-butanone. The product was filtered off and dried, yielding 9.2 parts (42.4%) of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-(2,2,2-trifluoroethyl)-3H-1,2,4-triazol-3-one; mp. 208.0° C. (int. 37).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH3:2].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]1[S:12][C:11]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:30][CH2:31][N:32]([S:35]([CH2:38][CH3:39])(=[O:36])=[O:37])[CH2:33][CH2:34]2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCOCCNCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 7 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [2-(ethyloxy)ethyl]amine (30 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown for preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide to give 6 mg of the title compound (7%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][CH2:31][S:32][C:33]1[N:40]2[C:36]([S:37][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:39]2)=[C:35]([C:54]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)=[O:55])[N:34]=1)=[N+:28]=[N-:29]>>[N:27]([CH2:30][CH2:31][S:32][C:33]1[N:40]2[C:36]([S:37][C:38]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[CH:39]2)=[C:35]([C:54]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)=[O:55])[N:34]=1)=[N+:28]=[N-:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(SCCN=[N+]=[N-])nc(C(=O)c3cccnc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(SCCN=[N+]=[N-])nc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Yield: 50.3 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[5-(2-azidoethyl)thio-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (853 mg) was prepared in the same manner as in step a) of Example 1, except that 910 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.59 g of 5-(2-azidoethyl)thio-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)=[CH:4][C:3]=1[C:19]#[N:20].I([O-])(=O)(=O)=[O:22].[Na+]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:22])=[O:14])=[CH:11][C:10]([C:15]([F:17])([F:16])[F:18])=[N:9]2)=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2CO)ccc1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)ccc1F
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxymethylpyrazole (0.45 g, 1.58 mmol) in acetonitrile (10 mL) was added catalytic amount of ruthenium chloride at 0° C. followed by addition of a solution sodium periodate (0.71 g, 3.32 mmol) in water. The reaction was stirred at 0° C. to room temperature overnight. The next day the acetonitrile was evaporated and the residue was partitioned between ethyl acetate and water, washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxycarbonylpyrazole (0.27 g, 57% yield) as pure compound: MS (ES−): 298 (M−H)− (40%).
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].C(O[CH:9](OCC)[CH2:10][CH:11](OCC)OCC)C.[ClH:21]>>[ClH:21].[N+:2]1([O-:1])[C:3]([OH:4])=[N:5][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)NO
Reactant: CCOC(CC(OCC)OCC)OCC
Agent: Cl
Product: [O-][n+]1cccnc1O
Temperature: 1.5 °C

Procedure:
0.261 mol (19.85 g) hydroxy urea have been dissolved in 390 ml 1 M HCl and 0.235 mol (51.77 g) 1,1,3,3-tetraethoxypropane were added dropwise under ice cooling, with the internal temperature being maintained at 1-2° C. The solution was thawed in an ice bath to room temperature and stirred over night, then evaporated to dryness. The residue was suspended with 250 ml of acetone, the mixture was cooled in an ice/ethanol bath, the solid filtered off and washed with a little ice-cold acetone. After drying, 24.5 g of crude product were obtained. The crude product was recrystallized with 460 ml of methanol from the boiling heat, cooled in an ice/ethanol bath, filtered off and dried. The mother liquor was concentrated on a rotary evaporator until again product started to precipitate, then a second fraction was crystallized similarly. After drying 11.8 g (1. fraction) and 5.9 g (2. fraction) the title compound were obtained.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.Br[CH2:9][C:10]([O:12]CC)=[O:11].Cl>O.CS(C)=O>[N:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: CCOC(=O)CBr
Reactant: c1cc[nH]c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cn1cccc1
Reaction time: 1 h

Procedure:
To a mixture of potassium hydroxide (16.7 g) and dry DMSO (150 mL), pyrrole (5 g) was added dropwise at 20-25° C., with stirring under nitrogen atmosphere. Stirring was continued for 1 hr at 20-25° C. Ethyl bromoacetate (24.5 g) was added dropwise at 20-25° C. and stirring was continued for 2 hr. In the reaction mixture (150 mL) DM water was added and pH was made acidic (pH=3) with 20% HCl (50 mL). The reaction mixture was extracted with diethyl ether (2×100 mL). The combined organic extract was washed with DM water (100 mL), saturated brine (100 mL) and dried over Na2SO4. The solvent was evaporated to obtain pyrrol-1-yl-acetic acid.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][C:23]([OH:25])=O)[CH:16]=3)=[N:9][C:8]=2[N:7]([CH2:26][CH:27]=[CH2:28])[C:5]1=[O:6])[CH:2]=[CH2:3].[C:29]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:20][N:19]1[NH:18][C:17]([O:21][CH2:22][C:23]([N:38]2[CH2:39][CH2:40][N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[O:25])=[CH:16]/[C:15]/1=[C:10]1\[N:11]=[C:12]2[C:13](=[O:14])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:6])[N:7]([CH2:26][CH:27]=[CH2:28])[C:8]2=[N:9]\1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C=CCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC=C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c2c(n(CC=C)c1=O)=N/C(=C1/C=C(OCC(=O)N3CCN(c4ccccc4)CC3)NN1C)N=2
Yield: 27 %

Procedure:
Condensation of 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (0.5 mmol) and N-phenyl-piperazine (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][O:33][CH2:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][O:33][CH2:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCCCC1CCCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCCOC1

Procedure:
Prepared similarly to Intermediate 243 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.[S-:14][C:15]#[N:16].[K+].BrBr>C(O)(=O)C>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]2[N:9]=[C:15]([NH2:16])[S:14][C:7]=2[CH:6]=1
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(OCC(F)(F)F)cc2s1

Procedure:
The procedure is as in Example 1, starting with 4-(2,2,2-trifluoroethoxy)aniline, potassium thiocyanate and bromine in acetic acid, to obtain 6-(2,2,2-trifluoroethoxy)-2-benzothiazolamine, m.p. 134° C.
Reaction SMILES: [Li+].[BH4-].[F:3][C:4]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH3:16])[C:5]=1[C:6](OC)=[O:7].O>C1COCC1>[F:3][C:4]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH3:16])[C:5]=1[CH2:6][OH:7]
Reactant: COC(=O)c1c(F)cc(F)cc1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)cc(F)c1CO
Temperature: 25 °C
Reaction time: 23 h
Yield: 98.4 %

Procedure:
A solution of LiBH4 (2M in THF, 6.28 mL, 12.6 mmol) was added to a solution of methyl 2,4-difluoro-6-methoxybenzoate (1.15 g, 5.71 mmol) in THF (30 mL). The solution was stirred at rt for 23 h, then at 60° C. for 4.5 h, and reflux for 18.5 h. After cooling to rt, H2O (20 mL) was added dropwise and the mixture stirred for 5 min before being partially concentrated in vacuo. DCM (20 mL) was added, the phases were separated, and the aqueous phase was extracted with DCM (2×10 mL). The organic layers were concentrated in vacuo to yield the title compound (978 mg, 5.62 mmol).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:15][O:14][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[CH:2][N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:5]=3[C:6]=2[CH:7]=1
Reactant: C[C@@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)CC2
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-7-methoxy-1-tetralone and 100 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.78 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.25 g (94%) of (R)-1-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl)-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1)=[O:2].C([OH:18])(C)C>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[C:13]([C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([C:1]([OH:18])=[O:2])=[CH:12]2)=[CH:7][CH:8]=1)#[N:14]
Reactant: CC(C)O
Reactant: N#Cc1ccc2ccc(C=O)cc2c1
Agent: [Cr+3]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc2ccc(C(=O)O)cc2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
7-Formyl-2-naphthalenecarbonitrile obtained in Reference Example 1 (3.0 g) was dissolved in 50 ml of acetone. The solution was cooled to 0° C. with stirring, and a solution prepared by dissolving 10 g of chromium oxide (IV) in 11 ml of concentrated sulfuric acid and 50 ml of water was added until the mixture becomes orange yellow. The reaction solution was stirred at 0° C. for 90 minutes and then at room temperature for 45 minutes, followed by the addition of 2 ml of isopropyl alcohol. The reaction solution was evaporated, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was extracted with saturated sodium bicarbonate aqueous solution, the saturated sodium bicarbonate layer was adjusted to pH 1 by adding concentrated sulfuric acid, and the thus precipitated solid matter was collected by filtration to give 1.94 g of 7-cyano-2-naphthalenecarboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:12]I>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][CH3:12])=[N:6][CH:7]=1
Reactant: CI
Reactant: OCc1ccc(Br)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(Br)cn1
Reaction time: 8 h
Yield: 102.6 %

Procedure:
A solution of this (5-bromo-pyridin-2-yl)-methanol (4.80 g, 23.0 mmol) in DMF (25 mL) was added drop wise over 5 minutes to a slurry of sodium hydride (1.10 g, 27.6 mmol) in DMF (50 mL) at 0° C. under N2. The mixture was stirred for 15 minutes before the drop wise addition of a solution of methyl iodide (1.57 mL, 25.3 mmol) in DMF (25 mL). The mixture was allowed to reach room temperature and was then stirred overnight. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were thoroughly washed with brine, dried over MgSO4 and evaporated to dryness to give the title compound as a yellow oil (4.77 g, 98%) sufficiently pure for the next step.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21]3[N:22]4[CH:28]=[C:27]([NH:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:26]=[CH:25][C:23]4=[N:24][C:20]=3[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:37])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:38]I.O>CN(C=O)C>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:21]3[N:22]4[CH:28]=[C:27]([N:29]([CH3:38])[C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:26]=[CH:25][C:23]4=[N:24][C:20]=3[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:37])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CI
Reactant: CCCCCC(=O)Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(=O)N(C)c1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Sodium hydride (1.6 equiv., 1.029 mmol, 0.041 g (60%)) was added to a solution of 86 (1.0 equiv., 0.643 mmol, 0.302 g) in DMF (15 ml), the reaction mixture was stirred for 1 h at room temperature. Methyl iodide (1.2 equiv., 0.772 mmol, 0.110 g) was added and the mixture was stirred at room temperature for 24 h. Water was added to the reaction mixture, and the formed precipitate was filtered off and washed with water and isopropyl ether to give N-[5,6-dihydro-6-(4-nitrophenyl)-5-oxo-pyrido[2′,1′:2,3]-imidazo[4,5-c]isoquinolin-9-yl]-N-methyl-hexanamide (87) (0.296 g, yield=95%, purity (LC)=93%).
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=[C:8]([CH2:20][CH2:21][CH3:22])[C:7]=1[C:23]#[N:24])(=[O:3])[NH2:2].Cl.Cl.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH2:30][CH2:29]1.C[O-].[Na+].CO>CN(C=O)C>[NH2:24][C:23]1[C:7]2[C:6](=[N:11][C:10]([N:28]3[CH2:33][CH2:32][CH:31]([NH:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]4[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=4)[CH2:30][CH2:29]3)=[CH:9][C:8]=2[CH2:20][CH2:21][CH3:22])[S:5][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: CCCc1cc(OS(=O)(=O)C(F)(F)F)nc(SCC(N)=O)c1C#N
Reactant: OC(CNC1CCNCC1)COc1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCc1cc(N2CCC(NCC(O)COc3ccncc3)CC2)nc2sc(C(N)=O)c(N)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
To a sealed tube was added trifluoro-methanesulfonic acid 6-carbamoylmethylsulfanyl-5-cyano-4-propyl-pyridin-2-yl ester (66.7 mg, 0.174 mmol) in 4 mL of dry DMF, followed by the addition of 1-(piperidin-4-ylamino)-3-(pyridin-4-yloxy)-propan-2-ol trihydrochloride salt (69 mg, 0.191 mmol) and N-N-diisopropylethylamine (180 mg, 1.39 mmol). The reaction mixture was stirred at 70° C. for 2 h. DMF was removed in vacuo. The residue was dissolved in 5 mL of MeOH, followed by the addition of sodium methoxide, 0.5 M solution in MeOH (1.74 mL, 0.86 mmol). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was loaded onto a flash chromatography column. The column was eluted with 0–5% 2M NH3 in MeOH/CH2Cl2. The product fractions were collected, concentrated and dried under high vacuum pump to afford 24 mg (28.5%) of the title compound as a light brown solid product. (TLC: Rf=0.4, 5% 2M NH3 in MeOH/CH2Cl2, UV). ES+ 485.29 m/z (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:5](=[CH:6][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=2)[CH:4]=1.[Li]CCCC.[C:27](Cl)(=[O:29])[CH3:28].[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:5](=[C:6]([C:27](=[O:29])[CH3:28])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1cc2cn(COCC[Si](C)(C)C)nc2cc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc2nn(COCC[Si](C)(C)C)c(C(C)=O)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
The title compound was prepared in a similar manner as described by G. Luo et al., J. Org. Chem. 2006, 71, 5392-5395: To a solution of 5,6-dimethoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (200 mg, 0.65 mmol) in THF (5 mL) at −78° C. was added dropwise a 2.5 M solution of n-BuLi in hexanes (0.29 mL, 0.71 mmol). The reaction mixture was stirred at −78° C. for 20 min. Acetyl chloride (0.07 mL, 0.97 mmol) was then added dropwise, and the mixture was stirred at RT for 16 h. Saturated aqueous NH4Cl solution was added to the reaction mixture, followed by stirring for 30 min. The aqueous phase was extracted twice with EtOAc and the combined organics were washed with brine, dried (Phase separator) and evaporated to give the crude title compound which was used directly in the next step without further purification.