Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]4[CH3:40])[C:25]4[CH2:31][CH2:30][N:29]([CH:32]=[O:33])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.CO.C(O)(=O)C>[Pd]>[CH3:40][C@@H:35]1[N:34]([C:24]2[C:25]3[CH2:31][CH2:30][N:29]([CH:32]=[O:33])[CH2:28][C:26]=3[N:27]=[C:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:13]4[NH:14][C:9](=[O:8])[CH:10]=[CH:11][CH:12]=4)=[CH:21][CH:20]=3)[N:23]=2)[CH2:39][CH2:38][O:37][CH2:36]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(OCc4ccccc4)n3)cc2)nc2c1CCN(C=O)C2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cccc(=O)[nH]3)cc2)nc2c1CCN(C=O)C2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
(S)-2-(4-(6-(benzyloxy)pyridin-2-ylamino)phenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carbaldehyde (0.066 g, 0.00012 mol), Palladium on Carbon 10% (0.1:0.9, Palladium:carbon black, 0.094 g), dry Methanol (3.30 mL, 0.0815 mol) and Acetic acid (0.21 mL, 0.0037 mol) were combined under nitrogen then purged with hydrogen, heated at 40° C., and stirred overnight. The reaction mixture was purged with nitrogen, added celite, filtered through celite, concentrated, and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 9.14 (s, 1H), 8.31-8.16 (m, 3H), 7.76 (s, 2H), 7.42 (t, J=7.8, 1H), 6.31 (s, 1H), 6.00 (d, J=8.1, 1H), 4.69-4.39 (m, 2H), 4.07 (d, J=5.4, 2H), 3.89 (d, J=11.1, 1H), 3.75-3.38 (m, 4H), 3.18 (d, J=4.4, 2H), 2.74 (s, 1H), 2.66 (d, J=12.1, 1H), 1.27 (t, J=6.4, 3H). LC/MS-m/z+447.2 (M+H)+.
Reaction SMILES: O=[C:2]([CH3:22])[CH2:3][CH2:4][C:5]1[C:6](=[O:21])[C:7]2[C:12]([C:13](=[O:20])[C:14]=1[CH2:15][CH2:16][C:17](=O)[CH3:18])=[CH:11][CH:10]=[CH:9][CH:8]=2.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].[ClH:28].Cl>C(O)C>[ClH:28].[ClH:28].[C:23]([NH:26][N:27]=[C:2]([CH3:22])[CH2:3][CH2:4][C:5]1[C:6](=[O:21])[C:7]2[C:12]([C:13](=[O:20])[C:14]=1[CH2:15][CH2:16][C:17](=[N:27][NH:26][C:23](=[NH:24])[NH2:25])[CH3:18])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[NH:25])[NH2:24]
Reactant: N=C(N)NN
Reactant: CC(=O)CCC1=C(CCC(C)=O)C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Product: CC(CCC1=C(CCC(C)=NNC(=N)N)C(=O)c2ccccc2C1=O)=NNC(=N)N
Yield: 54.1 %

Procedure:
Naphthoquinone (3.12 g, 20 mmol), 4-oxopentanoic acid (13.9 g, 120 mmol) and silver nitrate (2.0 g, 11.8 mmole) are combined in 30% aqueous acetonitrile at 65° C. A solution of ammonium peroxydisulfate (12.0 g, 52.6 mmole) is added dropwise over 30 minutes while the stirred mixture is maintained at 65°-75° C. On cooling, the mixture is extracted with diethyl ether (300 ml). The extract is then washed with water (3×50 ml), 5% NaHCO3 (2×50 ml) and brine (50 ml) and dried over MgSO4. After filtration through active carbon, the ether solution is evaporated to give crude 2,3-bis(3-oxobutyl)-1,4-naphthoquinone which is recrystallized from aqueous ethanol to give 1.45 g product, mp 110°-112° C. This 2,3-bis(3-oxobutyl)-1,4-naphthoquinone (0.456 g, 1.53 mmole), aminoguanidine hydrochloride (0.46 g, 4.3 mmole) and a drop of concentrated HCl are combined in 5 ml of 90% ethanol and heated at reflux for 3 hours. On cooling, 2,3-bis(3-(2-amidinohydrazono)butyl)-1,4-naphthoquinone crystallizes from the reaction mixture, and recrystallization from ethanol gives 400 mg product, mp 181°-183° C.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14](N)[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].N(O)=O.C(OC(=O)C)(=O)C.CN(C)C1C=CN=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:40]>>[C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([SH:40])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: CN(C)c1ccncc1
Agent: O=NO
Solvent: CC(=O)OC(C)=O
Product: OC[C@H]1O[C@@H](n2cnc3c(S)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Concomitant hydrolysis of the nitrile function and the sugar protecting groups of compound 41 is carried out by the treatment with 0.1N NaOH solution to obtain 4-amino-3-(β-D-ribofuranosyl)-1,3-azaphospholine-5-carboxamide (compound 50). Compound 50 is ring closed with formamide or with triethyl orthoformate to obtain the inosine analog, compound S1 (X=O), which is also prepared by deamination of the adenosine analog, compound 44, with aqueous nitrous acid. Acetylation of the sugar hydroxyls with acetic anhydride/4-(dimethylamino)pyridine, followed by thiation with phosphorus pentasulfide and subsequent deacetylation provides the 6-thioinosine analog 3-(β-D-ribofuranosyl)-1,3-azaphospholo[4,5-d]pyrimidine-7(6H)-thione (compound 51, X=S).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][NH:12][CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C:5]2=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].C1(C)C=CC=CC=1.[C:41](Cl)([Cl:43])=[O:42]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:14]([CH2:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:13][N:12]([C:41]([Cl:43])=[O:42])[CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 6 (0.12 g, 0.28 mmol) in dichloromethane (3 mL) was added saturated aqueous NaHCO3 solution (3 mL). The temperature of the mixture was lowered to 0° C., and a toluene solution (Aldrich, 20%) of phosgene (0.27 mL, 0.51 mmol) was added dropwise via a syringe. The reaction mixture was stirred at room temperature for 30 min, then diluted dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichlormethane twice. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated to give crude rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride as a light yellow oil, which was used in the next step without further purification (0.14 g, 100%).
Reaction SMILES: OS(C(F)(F)F)(=O)=O.C(OC([N:19]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[C:28]3[S:34]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:20]1)=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl>[C:37]1([S:34]([C:28]2[C:27]3[C:31](=[CH:32][CH:33]=[C:25]([O:24][CH:21]4[CH2:22][CH2:23][NH:19][CH2:20]4)[CH:26]=3)[NH:30][N:29]=2)(=[O:35])=[O:36])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: COc1ccccc1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNC3)cc12
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 67.7 %

Procedure:
Triflic acid (1.6 mL, 18 mmol) was added to a solution of 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-pyrrolidine-1-carboxylic acid benzyl ester (1.35 g, 2.56 mmol) and anisole (0.83 mL, 7.7 mmol) in methylene chloride at 0° C. The reaction mixture was stirred at 0° C., under nitrogen, for 3.5 hours, treated with 2.5 N sodium hydroxide and extracted with warm ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography with 0.5-1.0% ammonium hydroxide/5.0-10% methanol in chloroform to give 3-(naphthalene-1-sulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole as a beige solid, 0.684 g (67.7% yield), mp 168-170° C. dec. A portion of the solid (110 mg) was treated with methanol and ethereal HCl; chloroform and more methanol were then added for better solubility. The resultant mixture was concentrated to dryness in vacuo at 82° C. for 12 hours to yield the title product as a cream-colored foam (0.108 g); Mass spectrum (+EI, [M+H]+) m/z 394. 1HNMR (500 MHz, DMSO-d6): δ14.15-14.28 (br, 1H), 9.21-9.45 (br, 2H), 8.74-8.76 (m, 1H), 8.56 (dd, 1H, J=7.32 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.71-7.75 (m, 1H), 7.55-7.64 (m, 3H), 7.29 (d, 1H, J=2.20 Hz), 7.11 (dd, 1H, J=9.15 Hz and 2.31 Hz), 5.19-5.21 (m, 1H), 3.43-3.47 (m, 1H), 3.28-3.34 (m, 2H), 2.16-2.25 (m, 1H), 2.04-2.10 ppm (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](F)(F)[CH2:13][CH:12]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[C:30][Si](C)(C)C)=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
To (1-{4,4-difluoro-2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (412 mg, 0.82 mmol) in MeOH (8 mL) was added K2CO3 (227 mg, 1.64 mmol). After stirring for 5 h, the reaction was filtered then concentrated. The residue was diluted with EtOAc then washed with H2O. The aqueous phase was back-extracted with EtOAc two times then the organic phases were combined, washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography (20-80% EtOAc-hexanes gradient) to afford (1-{2-[5-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (371 mg, 0.82 mmol, quantitative yield). LCMS-ESI+: calc'd for C22H25F2N4O3: 431.2 (M+H+); Found: 431.1 (M+H+).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=O)[CH3:10]>C(O)C.C(O)(=O)C>[CH:4]1[CH:5]=[C:6]2[CH:10]=[C:9]([C:12]3[O:13][C:14]4[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:16]=3)[NH:7][C:1]2=[CH:2][CH:3]=1
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc2[nH]c(-c3cc4ccccc4o3)cc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Phenylhydrazine (97%; 6.3 ml, 1 eq) is introduced into a solution of 2-acetylbenzofuran (10 g, 1 eq) in ethanol (25 ml). After adding 20 drops of glacial acetic acid, the mixture is stirred at 80° C. for 1 h. Subsequently, the solvent is distilled off. The residue is introduced gradually into polyphosphoric acid (100 g), heated to 120° C. and stirred for 1 h. The reaction output is added cautiously to ice-water and neutralized with 2M NaOH. The precipitate is filtered off and washed with distilled water. The residue is dried under reduced pressure. After recrystallization in ethyl acetate/n-hexane, 7.0 g are obtained. Yield: 48%
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:45][CH2:46][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:42][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)c1
Yield: 17.6 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3-methoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (12.3 mg, 17.6%) as light yellow oil. MS m/e=521.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].C(O)(=[O:24])C.OO>O>[OH:24][C:11]1[CH:12]=[N:13][C:5]([NH:4][C:3]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([F:19])([F:21])[F:20])[C:2]=2[CH3:1])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(=O)O
Reactant: Cc1c(Nc2ncccc2C(=O)O)cccc1C(F)(F)F
Agent: OO
Solvent: O
Product: Cc1c(Nc2ncc(O)cc2C(=O)O)cccc1C(F)(F)F

Procedure:
To a suspension of 10 g. of 2-(2-methyl-3-trifluoromethylanilino) nicotinic acid and 160 ml. of glacial acetic acid, add 9 ml. of 30% hydrogen peroxide solution at room temperature. Warm the reaction mixture on a steam bath for one hour and add an additional 5 ml. of 30% hydrogen peroxide. Heat the resulting mixture for three hours on a steam bath, dilute with water and filter. After recrystallization from acetic acid, the product, 5-hydroxy-2-(2-methyl-3-trifluoromethylanilino) nicotinic acid melts at 305°-308° (dec.)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:27][C:28]1[S:29][C:30]([CH2:33][NH2:34])=[CH:31][N:32]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:34][CH2:33][C:30]1[S:29][C:28]([CH3:27])=[N:32][CH:31]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc(CN)s1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ncc(CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)s1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A mixture of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (0.200 g, 0.605 mmol) and (2-methylthiazol-5-yl)methanamine dihydrochloride salt (0.135 g, 0.67 mmol) in acetonitrile (15 ml) was treated at 25° C. with triethylamine (0.40 ml, 2.9 mmol) followed by benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (0.30 g, 0.68 mmol). After 3 hours, the reaction mixture was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution ethyl acetate) followed by crystallization from ethyl acetate gave 0.246 g (92% yield) of the title amide as white crystals; mp 167° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.64 (6H, s, 2×CH3), 2.70 (3H, s, CH3), 4.0-4.08 (4H, m, 2×CH2), 4.68 (2H, d, J=5.8 Hz, NCH2), 5.32 (2H, s, OCH2), 7.34-7.39 (3H, m, aromatics), 7.49 (1H, s, CH), 7.50-7.53 (2H, m, aromatics), 7.72 (1H, broad t, NH). Anal. Calcd for C22H24N4O4S: C, 59.98; H, 5.49; N, 12.71; Found: C, 59.99; H, 5.31; N, 12.61.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[C:6]([OH:14])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([O:14][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:7]=[C:8]([O:10][CH:11]([CH3:12])[CH3:13])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(OC(C)C)c1
Yield: 99.7 %

Procedure:
To a solution of 3-hydroxy-5-isopropoxy-benzoic acid methyl ester (7.00 g, 33.3 mmol) in acetone (80 mL) was added K2CO3 (5.06 g, 36.6 mmol) and 1-fluoro-4-nitrobenzene (3.53 mL, 33.3 mmol) at rt. The resulting mixture was refluxed for 12 hr. Then the mixture was filtered through a pad of Celite to remove insoluble salts and the cake was rinsed with acetone. Combined filtrates were concentrated under vacuum to afford a residue which was purified by silica gel flash chromatography (7.5×30 cm, hexane/EtOAc, v/v 10:1, 5:1). Fractions containing the mono-alkylation product were pooled and concentrated to give 3-isopropoxy-5-(4-nitro-phenoxy)-benzoic acid methyl ester (11.0 g, 44%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 8.22 (d, J=9 Hz, 2H), 7.43 (dd, J=1, 2 Hz, 1H), 7.29 (dd, J=1, 2 Hz, 1H), 7.04 (d, J=9 Hz, 2H), 6.80 (dd, J=2, 2 Hz, 1H), 4.56-4.64 (m, 1H). 3.90 (s, 3H), 1.35 (d, J=6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br:27]N1C(=O)CCC1=O>>[Br:27][CH2:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(C)n(Cc2ccc([N+](=O)[O-])cc2)c1C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)c1nc(CBr)n(Cc2ccc([N+](=O)[O-])cc2)c1C(=O)OCC
Yield: 71.5 %

Procedure:
Following a procedure similar to that described in Preparation 42(ii), but brominating 6.6 g of diethyl 2-methyl-1-(4-nitrobenzyl)imidazole-4,5-dicarboxylate [prepared as described in step (i) above] with 3.9 g of N-bromosuccinimide, 5.75 g of the title compound were obtained as a syrup.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7]C)[C:4]=1[OH:5].Br>C(O)(=O)C>[OH:5][C:4]1[C:6]([OH:7])=[CH:9][CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: COc1cccc(C=O)c1O
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1cccc(O)c1O
Reaction time: 18 h
Yield: 27 %

Procedure:
Into a 500 ml round bottom flask fitted with a nitrogen inlet, condenser, and a magnetic stirring bar were placed o-vanillin (50 g, 330 mmol), 200 ml glacial acetic acid, and 60 ml of 48% hydrobromic acid. The mixture was heated to reflux and allowed to stir for 18 hours. The solvent was distilled off and the residue was taken up in methanol and filtered. The filtrate was concentrated and the residue taken up in methylene chloride. This solution was washed three times with sodium bicarbonate, twice with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was dissolved in 0-2% methanol in methylene chloride and chromatographed (100:10:1 methylene chloride:methanol:ammonium hydroxide) to give 12.49g. of subtitled product (27%) which was used directly in the next step.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C([Li])(C)(C)C.I[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:16][C:15]=1[C:26](=[O:28])[CH3:27].C(Cl)Cl>CCOCC.C1COCC1.CN(C)C(=O)C.[I-].[Zn+2].[I-].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].[Cu+]>[CH:2]1([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:16][C:15]=2[C:26](=[O:28])[CH3:27])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1cc(I)c(C(C)=O)cc1OC(C)C
Reactant: BrC1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Cu+]
Agent: [Fe+2]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1cc(C2CCCCC2)c(C(C)=O)cc1OC(C)C
Temperature: 18 °C
Reaction time: 0.17 h
Yield: 20.2 %

Procedure:
A magnetically stirred solution of bromocyclohexane (0.18 mL, 1.46 mmol) in dry Et2O (3.0 mL), under a nitrogen atmosphere, was cooled to −78° C. and treated, dropwise, with tert-butyllithium (1.7 M in pentane, 1.9 mL, 3.23 mmol). After 10 minutes, the mixture was treated, dropwise, with a solution of anhydrous zinc iodide (495 mg, 1.55 mmol) in dry THF (1.7 mL). After 10 minutes at −78° C., the reaction mixture was allowed to warm to 18° C. and then slowly transferred to a mixture of iodide 9 (370 mg, 1.11 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH2Cl2 (18 mg, 0.022 mmol) and copper(I) iodode (8 mg, 0,042 mmol) in N,N-dimethylacetamide (1.0 mL). The resulting mixture was then stirred at 60° C., under a nitrogen atmosphere, for 6 h. The cooled mixture was filtered through a pad of Celite™ and the solids thus retained washed with EtOAC (1×50 mL). The filtrate was then washed with HCl (1×10 mL of a 1.0 M aqueous solution) and brine (1×10 mL), then dried (MgSO4), filtered and concentrated under reduced pressure and the ensuing residue subjected to flash chromatography (1:19→1:9 v/v ethyl acetate/hexane gradient elution) to afford the title compound 52 (65 mg, 20%) as a yellow oil, Rf 0.7 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.O1CCCC1.[C:43]([O:47][C:48]([NH:50][C:51](=[N:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])SC)=[O:49])([CH3:46])([CH3:45])[CH3:44]>CO>[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([CH:6]3[CH2:7][CH2:8][CH:3]([NH:2][C:51]([NH:50][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[N:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:4][CH2:5]3)=[O:10])[CH2:16][CH2:15]1)(=[O:18])=[O:19])[CH:29]=[CH:28]2
Reactant: NC1CCC(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)NC1CCC(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
To a solution of 1-(4-aminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (220 mg) and triethylamine (232 mg) in methanol (10 ml)-tetrahydrofuran (10 ml) was added N,N′-di-tert-butoxycarbonyl-S-methylisothiourea (135 mg) and the solution was stirred at 40° C. for 24 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give a colorless solid of the title compound (170 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1)=O.[N:11]1[NH:12][C:13](=[O:17])[CH:14]=CC=1>>[I:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[CH:1]=[CH:14][C:13](=[O:17])[NH:12][N:11]=2)=[CH:5][CH:6]=1
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1ccc(I)cc1
Product: O=c1ccc(-c2ccc(I)cc2)n[nH]1

Procedure:
7.8 g of 4-iodoacetophenone are converted into the pyridazinone in accordance with GWP 1.