Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]1([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][C:23](O)([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])=[CH:28][C:27]=3[F:43])[CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[C:10]1([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][C:23]([F:7])([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])=[CH:28][C:27]=3[F:43])[CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(C2(F)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethylaminosulfur trifluoride (DAST, 0.65 mL) in dry methylene chloride (49 mL) at -78° C. under N2 is added a solution of 4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 1, 2.25 g) in dry methylene chloride (47 mL) over 2 mins. The resulting mixture is stirred at -78° C. for 1 hr and at ambient temperature for 30 mins and is then adjusted to pH 8 with saturated aqueous sodium bicarbonate (50 mL), diluted with water (50 mL), and the layers are separated. The organic phase is washed with water (25 mL) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with methanol/methylene chloride (0.5/99.5). Those fractions with an Rf =0.27 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound (contaminated with approx. 15% of the elimination side product). An analytical sample is prepared by radial chromatography (1000μ silica gel rotor, ethyl acetate/hexane (20/80) eluent), mp 116-118° C.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][C:14]=2[F:24])[N:5]=1)(=[O:3])[CH3:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>C(#N)C>[CH3:27][N:28]([CH3:30])[CH:29]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][C:14]=2[F:24])[N:5]=1)=[O:3]
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(C)=O)c1=O
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)C=CN(C)C)c1=O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 3-acetyl-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxypyridazin-4(1H)-one (600 mg), N,N-dimethylformamide dimethyl acetal (3 mL) and acetonitrile (3 mL) was stirred at 80° C. for 12 hr, allowed to be cooled to room temperature, and stirred for 12 hr. The precipitate was collected by filtration, and washed with diisopropyl ether to give the title compound (600 mg).
Reaction SMILES: N1CCCC1.C(N)CCC.N1(C2C=CC3N(C(=O)NN=3)N=2)CCCC1.[N:26]1([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([C:37](=O)[N:38]([CH2:40][CH3:41])[N:39]=3)[N:36]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH2:37][N:38]([CH2:40][CH3:41])[N:39]=3)[N:36]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCn1nc2ccc(N3CCCC3)nn2c1=O
Agent: O=c1[nH]nc2ccc(N3CCCC3)nn12
Solvent: CCCCN
Solvent: C1CCNC1
Product: CCN1CN2N=C(N3CCCC3)C=CC2=N1

Procedure:
By substituting pyrrolidine for the butylamine in the procedure of Example 3 and then continuing with the procedure of Example 4, 6-pyrrolidino-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one and 6-pyrrolidino-2-ethyl-1,2,4-triazolo[4,3-b]-pyridazin-3(2H)-one, respectively, are obtained.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]1[S:16](=O)[CH2:15][CH2:14][CH2:13]1.Cl.[F:19][C:20]([F:43])([S:39]([O-:42])(=[O:41])=[O:40])[CH:21]([O:26][C:27]([C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:28])[C:22]([F:25])([F:24])[F:23].[Na+]>CO>[C:29]12([C:27]([O:26][CH:21]([C:22]([F:25])([F:23])[F:24])[C:20]([F:19])([F:43])[S:39]([O-:42])(=[O:40])=[O:41])=[O:28])[CH2:30][CH:31]3[CH2:37][CH:35]([CH2:34][CH:33]([CH2:32]3)[CH2:38]1)[CH2:36]2.[OH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S+:16]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:3][CH:2]=1
Reactant: O=S1CCCC1
Reactant: Oc1cccc2ccccc12
Agent: Cl
Agent: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Solvent: CO
Product: Oc1ccc([S+]2CCCC2)c2ccccc12
Temperature: -16 °C

Procedure:
First 10 g (0.069 mol) of 1-naphthol and 7.2 g (0.069 mol) of tetramethylene sulfoxide were dissolved in 50 g of methanol and cooled at −16° C. An excess amount of hydrogen chloride gas was fed into the solution at a temperature below 20° C. Nitrogen was bubbled into the solution to expel the excess of hydrogen chloride gas whereupon the reaction solution was concentrated. Water and diisopropyl ether were added to the concentrate, from which a water layer, aqueous solution of 4-hydroxynaphthyl-1-tetrahydrothiophenium chloride was separated. Next, the aqueous solution (corresponding to 0.023 mol) of 4-hydroxynaphthyl-1-tetrahydrothlophenium chloride was mixed with an aqueous solution (corresponding to 0.021 mol) of sodium 1,1,3,3,3-pentafluoro-2-(adamantane-1-carbonyloxy)propanesulfonate which was synthesized according to the formulation described in JP-A 2007-145797 (or U.S. Pat. No. 7,511,169). The mixture was extracted with 100 g of dichloromethane and 50 g of methyl isobutyl ketone. The organic layer was washed with water, the solvents were distilled off in vacuum, and isopropyl ether was added to the residue for crystallization. Subsequent filtration and drying gave the target compound. White crystal, 6.2 g, yield 43%.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][N:25]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>C1COCC1.CO>[CH3:31][S:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:32])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[N:25][CH:26]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(SC)cn4)cn3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ccc(Nc2ccc(-c3ccc(C4CCC(CC(=O)O)CC4)cc3)nc2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude (4-{4-[5-(5-Methylsulfanyl-pyridin-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester was dissolved in THF/MeOH (4:1, 2.5 mL) and to it was added aqueous LiOH (4M, 0.5 mL). The mixture was stirred at room temperature for 18 hours, then was immediately purified via reverse-phase HPLC to yield the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 2 H) 1.44-1.57 (m, 2 H) 1.84 (m, 5 H) 2.16 (d, J=6.82 Hz, 2 H) 2.50 (m, 1 H) 6.91 (d, J=8.59 Hz, 1 H) 7.36 (d, J=8.34 Hz, 2 H) 7.70 (dd, J=8.59, 2.53 Hz, 1 H) 7.91 (d, J=8.34 Hz, 2 H) 7.95 (d, J=8.84 Hz, 1 H) 8.21 (d, J=2.27 Hz, 1 H) 8.33 (dd, J=9.09, 2.53 Hz, 1 H) 8.98 (br. s., 1 H) 9.64 (br. s., 1 H); MS (M+H)+ 434.2.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C.[C:21]1([C:26](Cl)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCCSc1cccnc1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1cccnc1)c1cccs1
Yield: 85.4 %

Procedure:
To a solution of 2.00 g (8.29 mmol) of 3-(3-aminopropylthio)pyridine dihydrochloride and 4.16 ml (29.9 mmol) of triethylamine in 80 ml of methylene chloride, 1.06 ml (9.95 mmol) of 2-thenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.97 g of the desired compound (yield: 85.3%, yellow powder).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][NH:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCN
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCNCC(OC)OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 2-methoxyethanamine (100 mg, 1.33 mmol) in DMF (2 mL) was added K2CO3 (276 mg, 1.99 mmol) and 2-bromo-1,1-dimethoxyethane (236 mg, 1.39 mmol). The mixture was stirred at 80° C. for 3 h. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was concentrated to give 2,2-dimethoxy-N-(2-methoxyethyl)ethanamine as a yellow oil in 91% yield and used in the next step without purification.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([CH3:11])=[O:10])=[CH:4][N:3]=1.[Cl:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16](B(O)O)=[C:15]([F:24])[CH:14]=1.C(=O)([O-])O.[Na+]>O.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>[Cl:8][C:7]1[C:2]([C:16]2[CH:17]=[C:18]([O:19][CH3:20])[C:13]([Cl:12])=[CH:14][C:15]=2[F:24])=[N:3][CH:4]=[C:5]([S:9]([CH3:11])=[O:10])[CH:6]=1
Reactant: COc1cc(B(O)O)c(F)cc1Cl
Reactant: CS(=O)c1cnc(Cl)c(Cl)c1
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: O
Product: COc1cc(-c2ncc(S(C)=O)cc2Cl)c(F)cc1Cl
Yield: 30.1 %

Procedure:
4.6 g of 2,3-dichloro-5-methylsulfinylpyridine, 4.5 g of 4-chloro-2-fluoro-5-methoxybenzeneboronic acid, 5.5 g of sodium hydrogen carbonate and 1.0 g of tetrakis(triphenylphosphine)palladium(0) were refluxed for 180 hours in a mixture of 100 ml of water and 100 ml of tetrahdyrofuran. After the tetrahydrofuran has been evaporated, the residue was extracted four times with in each case 70 ml of MTB. The combined organic phases were then dried over sodium sulfate and finally concentrated. The resulting oil was purified by means of chromatography on silica gel (eluent: cyclohexane/MTB=7:3→1:1 and cyclohexane/ethyl acetate=2:1). Stirring this purified oil with diethyl ether gave 2.2 g (30%) of white crystals.; m.p.: 117-118° C.
Reaction SMILES: [C:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].Br.[C:16]([O:20][C:21]([CH2:23][N:24]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31][N:30]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:29][CH2:28][N:27]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:16]([O:20][C:21](=[O:22])[CH2:23][N:24]1[CH2:35][CH2:34][N:33]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH2:32][CH2:31][N:30]([CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:29][CH2:28][N:27]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:26][CH2:25]1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: C=C(C)C(=O)NCCCCCC(=O)O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)NCCCCCC(=O)N1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Yield: 113.8 %

Procedure:
A suspension of 6-(methacryloylamino)caproic acid (2.80 g, 14.0 mmol), 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane hydrobromide (7.75 g, 13.0 mmol), N,N-dimethylaminopyridine (1.83 g, 15.0 mmol) and 5 mg BHT in 60 ml dichloromethane was cooled to −5° C. and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.88 g, 15.0 mmol) was added portionwise under stirring. To complete the reaction, the mixture was stirred for 2 h at −5° C. and over night at room temperature. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.00 g, 6.44 mmol) and N,N-dimethylaminopyridine (0.6 g, 4.9 mmol) each time were then added 3 more times at intervals of 2 h and finally left to be stirred for 6 h. The solution was washed 3 times with in each case 50 ml saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated on the rotary evaporator after the addition of 5 mg BHT and dried under fine vacuum. 10.3 g of a yellowish oil was obtained which was purified twice by chromatography (silica gel 60, 0.015-0.040 mm, acetone). The acetone was again distilled off on the rotary evaporator after the addition of 5 mg BHT and the product dried in fine vacuum. 6.13 g (8.8 mmol, 68% yield) of a yellow, highly viscous oil was obtained (HPLC purity: 95%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:39])[CH2:15][NH:16][C:17]([C:19]2[C:20]([O:37][CH3:38])=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:39]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][NH:16][C:17]([C:19]1[C:20]([O:37][CH3:38])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[C:22]2/[CH:28]=[CH:29]/[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)=[O:18]
Reactant: COc1c(C(=O)NCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C(=O)NCC(=O)N2CCNCC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[2-({3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonyl}-amino)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester obtained by Example 1215 was dissolved in 1 mL of dichloromethane, added with 1 mL of trifluoroacetic acid, and stirred at room temperature for 2 hours. The solvent was evaporated, followed by purification by LC-MS, to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C(OCC)(=O)C.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].O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:4]3[CH:3]=[C:2]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:18]=[O:19])[CH:7]=[CH:6][N:5]3[N:8]=2)=[CH:12][CH:13]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Fc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1-c1ccn2nc(-c3ccc(F)cc3)cc2c1
Yield: 78 %

Procedure:
The procedure described in stage 2.4 is followed, starting with 0.300 g (1.03 mmol) of 5-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine obtained in stage 2.3, 0.170 g (1.13 mmol) of 2-formylphenylboronic acid, 1.00 g (3.09 mmol) of caesium carbonate and 0.084 g (0.10 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in 5 ml of a 9/1 mixture of tetrahydrofuran and water. After chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15), 0.254 g (77%) of the expected product is obtained in the form of a beige powder.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH2:5][S:6]([NH2:9])(=[O:8])=[O:7].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:31][O:32][C:33]1[N:38]=[C:37]([CH3:39])[N:36]=[C:35]([C:40](O)=[O:41])[CH:34]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:2]([F:14])([F:1])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH2:5][S:6]([NH:9][C:40]([C:35]1[CH:34]=[C:33]([O:32][CH3:31])[N:38]=[C:37]([CH3:39])[N:36]=1)=[O:41])(=[O:7])=[O:8]
Reactant: COc1cc(C(=O)O)nc(C)n1
Reactant: NS(=O)(=O)Cc1ccccc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)Cc2ccccc2C(F)(F)F)nc(C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.4 g of 2-trifluoromethylbenzylsulfonamide are added in portions at 0°-2° C. to a mixture of 2.3 g of dicyclohexylcarbodiimide, 120 mg of 4-dimethylaminopyridine and 2.0 g of 6-methoxy-2-methylpyrimidine-4-carboxylic acid in 80 ml of abs. dichloromethane. The mixture is then stirred at 0° C. for 1/2 h, allowed to warm to room temperature and then stirred for 14 h. The precipitated urea is filtered off with suction, the solvent is distilled off under reduced pressure, and the residue is dissolved in acetone and stirred with 100 ml of 1N aqueous sodium carbonate solution for 1/2 h. The solid is filtered off, the filtrate is extracted with diethyl ether and acidified with conc. hydrochloric acid, and the product is filtered off with suction and dried at 50° C./20 mbar [lacuna] 2-Trifluoromethyl-N-[(6-methoxy-2-methylpyrimidin-4-yl)carbonyl]benzylsulfonamide of melting point 120°-122° C. is obtained in this way.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]#[C:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:16]=2)=[C:7]([NH:31][C:32]([NH:34][C:35]2[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:38]=[CH:37][C:36]=2[CH:44]([CH3:46])[CH3:45])=[O:33])[C:6]1=[O:47])[CH2:2][CH2:3][CH3:4]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[CH:16]=2)=[C:7]([NH:31][C:32]([NH:34][C:35]2[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:38]=[CH:37][C:36]=2[CH:44]([CH3:46])[CH3:45])=[O:33])[C:6]1=[O:47])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCC#CCN(CC)CC)c2)c2cccnc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OC/C=C\CN(CC)CC)c2)c2cccnc21
Yield: 95.6 %

Procedure:
A suspension of N-[1-butyl-4-[3-{(4-diethylamino-2-butynyl)oxy}-phenyl]-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (300 mg, 0.45 mmol), a Lindlar catalyst (distributed by Sigma Alderich Japan, 20 mg) in methanol (20 ml) was stirred at room temperature under hydrogen atmosphere for six hours. The mixture was filtered through a cerite pad, and the filtrate was concentrated under reduced pressure. The resultant was dissolved in chloroform, and the mixture was washed with a dilute aqueous ammonia, washed with water, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3-8% methanol in chloroform) to give the title compound (280 mg, 0.43 mmol).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:11][CH2:10]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:18]=2)[C@@H:6]1[O:32][C:33](=[O:35])[CH3:34])(=[O:3])[CH3:2].[N+:36]([O-])([OH:38])=[O:37]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:4][C@H:5]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:10][CH2:11]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[C:29]([N+:36]([O-:38])=[O:37])[CH:30]=3)[CH:18]=2)[C@@H:6]1[O:32][C:33](=[O:35])[CH3:34])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 109.5 %

Procedure:
To a stirred solution of acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester (Example 5, 104 mg, 2 mmol) in dichloromethane (25 ml) was added HNO3 (6% aqueous solution, 5.6 ml, 3.8 mmol) in a drop wise fashion, followed by the addition of tetrabutyl ammonium bromide (100 mg). The reaction mixture was stirred at room temperature until the complete conversion. The reaction mixture was diluted with DCM, washed with water, brine, concentrated and purified by silica gel chromatography to give 1.2 g of acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-hydroxy-3-nitro-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3]C.[H-].[Na+].[CH3:8][C:9]1[C:14]([C:15]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH3:25])=[C:19]([O:26][CH3:27])[C:18]=2[O:28][CH3:29])=[O:16])=[C:13]([O:30][CH3:31])[CH:12]=[CH:11][CH:10]=1.C(COC)OC>C(OCC)(=O)C.O>[CH3:8][C:9]1[C:14]([C:15]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH3:25])=[C:19]([O:26][CH3:27])[C:18]=2[O:28][CH2:29][CH2:1][CH2:2][CH3:3])=[O:16])=[C:13]([O:30][CH3:31])[CH:12]=[CH:11][CH:10]=1
Reactant: CCCCO
Reactant: COc1cc(C)c(C(=O)c2c(C)cccc2OC)c(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(C)cccc1OC

Procedure:
A mixture of n-butanol (5 ml) and sodium hydride (60% in oil, 10 mmol) is stirred until the formation of H2 gas ceases. A mixture of 1C (0.7 g, 2.2 mmol) and dimethoxyethane (15 ml) is added to the resulting reaction mixture. Subsequently, the reaction mixture is heated under reflux with stirring for 24 hours. A mixture of water and ethyl acetate (1:1 v/v; 100 ml) is then slowly added at room temperature. The organic phase is separated, concentrated and the residue is purified by column chromatography (petrol ether:ethyl acetate, 95:5 v/v) yielding the pure product as a yellow oil, 0.2 g, (24.4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:19][CH2:18]1>>[CH3:15][O:14][C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[C:11]2[C:6]=1[CH:5]=[N:4][N:3]=[C:2]2[NH:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:21][CH2:22]1
Reactant: COc1cc(OC)c2cnnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1cc(OC)c2cnnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 2.4 by reacting 1-chloro-5,7-dimethoxyphthalazine described in 13.2 with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl.[Ag]=O>[CH3:17][S:18]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:16])(=[O:20])=[O:19]
Reactant: OCCOCCOCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Agent: O=[Ag]
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
80 mL of dichloromethane was added to 10 g of pentaethyleneglycol and 10.7 g of silver oxide, and then 5.8 g of methanesulfonyl chloride dissolved in 16 ml of dichloromethane was added dropwise. After stirring the reaction solution at room temperature for 2 days, the solution was filtered with a celite, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 7.8 g of the objective compound.