Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH:12]=[CH2:13])=[C:9]([OH:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].I[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:35]=[CH:34][C:23]2[CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[O:27][C:22]=2[C:21]=1[CH2:36][CH2:37][CH3:38]>>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][C:9]([O:14][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:35]=[CH:34][C:23]3[CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[O:27][C:22]=3[C:21]=2[CH2:36][CH2:37][CH3:38])=[C:10]([CH2:11][CH:12]=[CH2:13])[C:2]=1[OH:1])=[O:5]
Reactant: C=CCc1c(O)ccc(C(N)=O)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OC)CC2
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(CCC(=O)OC)CC3)ccc(C(N)=O)c1O

Procedure:
The compound of Example 20 and the compound of Example 3 are coupled as described in Example 60. Chromatographic purification of the crude phenolic ester on silica gel using ethyl acetate/hexane (3:7) as eluant affords the product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1nc(-c2ccccc2)cs1
Product: O=C(Nc1nc(-c2ccccc2)cs1)c1cc(Br)ccc1O
Yield: 16 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1[C:24]2[C:16]3[C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[O:19][C:15]=3[C:14](B(O)O)=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:2]1([C:14]2[C:15]3[O:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc2ccccc2c2c1oc1ccccc12
Reactant: Brc1ccccc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2cc3ccccc3c3c2oc2ccccc23)cc1
Yield: 56 %

Procedure:
Into a 200 mL three-neck flask were placed 0.90 g (5.7 mmol) of bromobenzene and 1.5 g (5.7 mol) of benzo[b]naphtho[1,2-d]furan-6-boronic acid, and the air in the flask was replaced with nitrogen. To this mixture were added 20 mL of toluene, 10 mL of ethanol, and 6.0 mL of an aqueous solution of sodium carbonate (2.0 mol/L). While the pressure was reduced, this mixture was stirred to be degassed. To this mixture was added 0.33 g (0.28 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 80° C. for 2 hours under a nitrogen stream. After that, the aqueous layer of this mixture was subjected to extraction with toluene, and the obtained solution of the extract and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate, and this mixture was gravity-filtered. An oily substance obtained by concentration of the obtained filtrate was purified by silica gel column chromatography (a developing solvent in which the ratio of hexane to toluene was 19:1) to give a white solid. The obtained solid was recrystallized with a mixed solvent of toluene and hexane, so that 0.95 g of white needle-like crystals of the object of the synthesis were obtained in 56% yield. The reaction scheme is illustrated in (R-1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH:35][CH2:36][CH2:37][CH3:38]>CN(C=O)C>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:35]([CH3:34])[CH2:36][CH2:37][CH3:38])[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: CCCNC
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN(C)c1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methyl-N-propylamine in DMF. ES-MS m/e (%): 442 (M+H+, 100).
Reaction SMILES: [C:1]([C@H:5]([NH:9][NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C@H:5]([NH:9][NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH2:7][CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C=CC[C@@H](NNC(=O)c1cccc(OC)c1C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCC[C@@H](NNC(=O)c1cccc(OC)c1C)C(C)(C)C
Reaction time: 2.5 h

Procedure:
(R)-3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-but-3-enyl)-hydrazide (3.05 g, 10.5 mmol) was dissolved in 100 mL methanol. Palladium on charcoal (1%, 240 mg) was carefully added, and the mixture was shaken on a Parr hydrogenator for 2.5 hours at a starting pressure of 55 psi. Decrease in pressure was monitored as a measure of the reaction progress; after 1.5 hours, hydrogen uptake ceased. The mixture was filtered through a pad of Celite, and solvent was removed in vacuo. Analysis by TLC using several solvents was largely unsuccessful in distinguishing between the two hydrazide spots, although 3:1 hexanes:ethyl acetate (Rf=0.28) was marginally successful. The crude product was crystallized twice from 2:1 pentane:hexanes to provide >0.6 g of (R)-3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-butyl)-hydrazide. 1H NMR (400 MHz, CDCl3) δ 7.05 (t, 1H), 6.79 (d, 1H), 6.76 (d, 1H), 3.7 (s, 3H), 2.37 (m, 1H), 2.12 (s, 3H), 1.7-1.1 (m, 4H), 0.90 (s, 9H), 0.82 (t, 3H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH:26]=O)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[C:30]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[C:30]=1[N:38]1[CH2:43][CH2:42][N:41]([CH2:26][CH2:25][CH2:24][N:11]2[C:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]=3[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12]2)[CH2:40][CH2:39]1
Reactant: O=[N+]([O-])c1cccc(Cl)c1N1CCNCC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a stirred solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (0.5 g, 1.25 mmol) and 1-(2-chloro-6-nitrophenyl)-piperazine (0.301 g, 1.25 mmol) in CH2Cl2 (6 mL) was added sodium sulfate (0.354 g, 2.50 mmol) and sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The mixture was allowed to stir at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with water. The CH2Cl2 layer was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica, 10% acetone/CH2Cl2) to afford of 1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0.380 g, 49%). MS (electrospray): exact mass calculated for C27H30ClF3N6O4S, 626.2; m/z found, 627.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.73 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.54 (dd, J=8.2, 1.2 Hz, 1H), 7.49 (dd, J=8.2, 1.2 Hz, 1H), 7.10 (t, J=8.2 Hz, 1H), 4.58 (s, 2H), 4.13 (t, J=6.5 Hz, 2H), 3.71 (t, J=5.9 Hz, 2H), 3.01-3.11 (m, 4H), 2.95 (t, J=5.9 Hz, 2H), 2.92 (s, 3H), 2.42-2.53 (m, 4H), 2.40 (t, J=6.5 Hz, 2H), 2.12 (q, J=6.5 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37](Cl)[N:36]=[N:35][C:34]=2[CH2:40][CH2:41][CH2:42][CH3:43])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:15][OH:16])[C@H:11]([CH2:13][O:14][C:37]2[N:36]=[N:35][C:34]([CH2:40][CH2:41][CH2:42][CH3:43])=[C:33]([C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:32][CH:31]=3)[CH:38]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-trans-3,4-bis-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 mmol, 462 mg) in THF (4.0 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 2.5 mmol, 100 mg) and stirring continued for 10 min at room temperature, then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 1.0 mmol, 352 mg) was added. The resulting mixture was stirred at 50° C. for 1 hour, poured into water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 1% methanol in ethyl acetate to give (±)-trans-3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to give (±)-trans-{4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-pyrrolidin-3-yl}-methanol dihydrochloride.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>ClCCl>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][N:11]=1)=[O:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(-c2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
5-phenylpyridin-2-amine (2.4 g, 14.10 mmol) was dissolved in 75 ml of dichloromethane. The solution was treated with triethylamine (1.57 g, 15.51 mmol) and trimethylacetylchloride (1.87 g, 15.51 mmol) and the mixture was stirred at room temperature for 1 hour. Silica gel (9 g) was added and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (5:1) to afford 2,2-dimethyl-N-(5-phenylpyridin-2-yl)propanamide (2.58 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:11])[NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:7][CH:8]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 12 h
Yield: 87.8 %

Procedure:
4-(Trifluoromethyl)phenyl isocyanate (1.068 g, 5.71 mmol) and 4-amino-1-Boc-piperidine (1.0 g, 5 mmol) was dissolved in CH2Cl2 (100 mL) and stirred for 12 h. The reaction was quenched by addition of water. The organic layer was isolated and the aqueous layer was extracted with EtOAc for 4 times. The combined organic layer was concentrated under vacuo and was further purified by flash chromatography (EtOAc:Hex/1:1) yielding final product (1) (1.7 g, 4.39 mmol, 88%). 1H NMR (d6-DMSO, 300 Mhz): ∂ 8.77 (s, 1H), 7.55 (s, 4H), 6.26 (d, J=10 Hz, 1H), 3.80 (d, J=Hz, 2H), 3.64 (m, 1H), 2.88 (br, 2H), 1.78 (d, J=5 Hz, 2H), 1.38 (s, 9H), 1.23 (m, 2H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3=[N:19][CH:20]=[CH:21][C:16]([C:8]4[CH:9]=[C:10]([F:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:17]3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f26) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:24]=[C:23]([O:25]COC)[CH:22]=[C:21]([O:29]COC)[C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([O:8][CH2:9][C:10]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([OH:29])[C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cc(COCc2ccccc2)c(C(=O)Nc2ccccc2)c(OCOC)c1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1ccccc1)c1c(O)cc(O)cc1COCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
The above-obtained 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)-N-phenylbenzamide (18 mg, 0.043 mmol) was dissolved in ethanol (4 mL) and the obtained solution was added with concentrated hydrochloric acid (0.10 mL) followed by stirring at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain Compound 1 (14 mg, 92%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].C([O-])([O-])=O.[K+].[K+].[C:13]([O:17][C:18]([N:20]([CH3:30])[CH2:21][CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(#N)C>[C:13]([O:17][C:18](=[O:19])[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])[CH3:30])([CH3:16])([CH3:15])[CH3:14]
Reactant: NCCCCN
Reactant: CN(CCCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCCNCCCCN)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Putrescine (9.45 g, 107 mmol) was dissolved in acetonitrile (200 mL) with K2CO3 (14.79 g, 107 mmol) and stirred under N2. Mesylate 22 (6.03 g, 21.4 mmol) dissolved in acetonitrile (60 mL) was added dropwise over 30 min while stirring under N2. After 30 min, the reaction mixture was brought to reflux and stirred overnight. The reaction mixture was then cooled, solid K2CO3 was filtered off and the filtrate concentrated in vacuo. The residue was re-dissolved in CH2Cl2 (200 mL) and washed six times with sat. aqueous Na2CO3 to remove the unreacted putrescine. The organic layer was then dried over anhydrous Na2SO4, filtered, and concentrated to give the product 23 as a clear oil that was used in the next step without further purification, yield: 5.31 g (90%); 1H NMR (CDCl3) δ 3.21 (t, 2H), 2.84 (s, 3H), 2.71 (t, 2H), 2.62 (t, 4H), 1.40-1.60 (m, 17H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[O:20][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(F)c(F)c1
Product: N#Cc1cc(C=O)ccc1Oc1ccc(F)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 3,4-difluorophenol.
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][CH:12]=[O:13])[O:8][C:7](=[O:14])[NH:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:15]([Mg]Br)[CH2:16][CH:17]([CH3:19])[CH3:18].Cl>C1COCC1.CC(C)=O>[CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][C:12](=[O:13])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[O:8][C:7](=[O:14])[NH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@@H]1NC(=O)O[C@H]1CCC=O
Reactant: CC(C)CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)CCC(=O)CC[C@@H]1OC(=O)N[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A 2 g (0.01 mole) portion of the compound from Example 26 was dissolved in THF (50 mL) and treated at 0°-5° C. with 37.5 mL of an 0.8 M solution of isopentyl magnesium bromide in THF. The reaction was stirred for 2 hours at room temperature and then poured into ice water which contained 6.5 mL of 6 N HCl. The mixture was extracted with methylene chloride. Evaporation of the dried methylene chloride solution gave a quantitative yield of the Grignard adduct. This material was dissolved in 300 mL of acetone and treated by dropwise addition with Jones solution until the orange color persisted. The chromium salts were filtered and the filtrate was evaporated. The residue was diluted with ether and the resulting solution was washed successively with aqueous NaHCO3 and brine solution. After drying over MgSO4, the solvent was evaporated to give 1.7 g (66%) of product as an oil. NMR (300 MHz, CDCl3, ppm): 0.86-0.96 (m, 12H), 2.41 (M, 2H), 2.67 (m, 2H), 3.5 (m, 1H), 4.15 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH2:57])[CH2:56][CH2:55]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:65])([F:64])[F:63])[CH:42]=1>CN(C=O)C>[CH3:39][O:40][C:41]1[CH:61]=[CH:60][C:44]([O:45][C:46]2[CH:59]=[CH:58][C:49]([CH2:50][NH:51][C:52]([C:54]3([NH:57][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][N:2]([CH3:9])[CH3:1])[CH2:55][CH2:56]3)=[O:53])=[CH:48][CH:47]=2)=[C:43]([C:62]([F:63])([F:64])[F:65])[CH:42]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: CN(C)CCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)CCCN(C)C)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.44 mg (11 μMol) 4-dimethylamino-butyric acid was dissolved in 100 μL DMF, 3.5 μL (24.95 μMol) triethylamine and 3.37 mg (10.5 μMol) TBTU in 100 μL DMF were added and the mixture was stirred for 10 min at RT. Then 3.80 mg (10 μMol) 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide in 100 μL DMF was added and the mixture was shaken for 3 days at ambient temperature. Filtered through Alox B, washed with DMF/MeOH=9/1 and the filtrate was evaporated down.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:4](=[O:21])[C:3]=1[C:22](=O)[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.O.[NH2:33][NH2:34]>C(O)C>[N+:18]([C:14]1[CH:13]=[C:12]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:33][N:34]=[C:22]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:3]=3[C:4]2=[O:21])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1c2c(CCc3ccncc3)n[nH]c2c2cccnc2n1-c1cccc([N+](=O)[O-])c1
Yield: 95.5 %

Procedure:
To a suspension of 4-hydroxy-1-(3-nitrophenyl)-3-[1-oxo-3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2 (1H)-one (416 mg, 1.0 mmol, prepared in Synthetic Example 4) in ethanol (15 ml) was added hydrazine monohydrate (80%, 180 μl, 4.5 mmol, 4.5 eq.), and the resultant mixture was treated in the same manner as in Example 1 to give 5-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (394 mg, 96%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[NH:29][C:30]([CH2:32][CH:33]([CH2:37][CH:38]=[CH:39][CH2:40][CH2:41][CH3:42])[C:34]([OH:36])=O)=[O:31]>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[N:29]1[C:30](=[O:31])[CH2:32][CH:33]([CH2:37][CH:38]=[CH:39][CH2:40][CH2:41][CH3:42])[C:34]1=[O:36]
Reactant: CCCC=CCC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC=CCC1CC(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.8 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.047 g, 0.15 mmol) and diisopropylethylamine (0.043 g, 0.25 mmol) were added sequentially at ambient temperature to a stirred solution 2-{[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]methyl}oct-4-enoic acid (0.051 g, 0.11 mmol) in dimethylformamide (2 ml), the mixture was stirred at ambient temperature for 48 hours, then it was added dropwise to ice-cold water (10 ml). The resulting solid was collected by filtration and dried in vacuo to give 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-hex-2-enylpyrrolidine-2,5-dione (0.029 g) as an off-white solid, m.pt. 146–149° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 0.8–1.0 (m, 3H) (CH3), 1.2–1.4 (m, 2H) (—CH2CH3), 1.9–2.1 (m, 2H) (—CH2CH2CH3), 2.3–2.5 (m, 2H) (—CH2CH═CH—), 2.5–2.6 (m, 1H) (ring CH), 2.8–3.0 and 3.0–3.2 (2×m, 2H) (ring CH2), 4.4 (s, 2H) (ArCH2—), 5.25–5.45 and 5.45–5.7 (2×m, 2×1H) (—CH═CH—) 7.2–7.3 (m, 1H) (ArH), 7.3–7.5 (m, 1H) (ArH), 7.5–7.6 (m, 1H) (ArH), 7.8–8.05 (m, 3H) (3×ArH), 8.3 (d, 1H) (ArH), 12.65 (s, 1H) (CONH); m/z (M+H)+. 434, 95.8% purity.
Reaction SMILES: N[C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[FH:17].N([O-])=O.[Na+]>>[Cl:8][C:6]1[CH:7]=[C:2]([F:17])[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=1
Reactant: F
Reactant: Nc1cc(Cl)cnc1Oc1ccc(O)cc1
Agent: O=N[O-]
Agent: [Na+]
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
122.5 g (0.518 mole) of 4-(3-amino-5-chloropyridin-2-yloxy)phenol are introduced at -8° to 0° C. into a vessel charged with 400 g (20 moles) of hydrogen fluoride. Then 37.3 g (0.540 mole) of sodium nitrite are added in portions over one hour. The mixture is stirred for 2 hours at 0° C. and slowly heated to 55° C. in an autoclave. Excess hydrogen fluoride is removed by distillation and the residue is taken up in 200 ml of methylene chloride and the solution is neutralised with ice-water and ammonia, the organic phase is dried and concentrated by evaporation, affording 112 g of 4-(5-chloro-3-fluoropyridin-2-yloxy)phenol with a melting point of 97°-98° C.