Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@@H:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25](=[O:29])[C:26]#[C:27][CH3:28])[CH3:23]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:22]([O:24][C:25](=[O:29])/[CH:26]=[C:27](/[O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@H:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:6]2)=[CH:9][CH:10]=1)\[CH3:28])[CH3:23]
Reactant: CC#CC(=O)OCC
Reactant: CC1(C)OC[C@H](Cc2ccc(O)cc2)O1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccc(C[C@H]2COC(C)(C)O2)cc1
Temperature: 80 °C
Yield: 6.9 %

Procedure:
A mixture of 4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenol (0.696 g, 3.34 mol), potassium carbonate (0.463 g, 0.003 mol), ethyl-2-butynoate (2.25 g, 0.020 mol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (15 mL) was placed in a sealed tube and heated at 80° C. for 6 h. The reaction mixture was cooled, filtered and the isolated solids washed with tetrahydrofuran. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) which afforded (E)-3-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenoxy]-but-2-enoic acid ethyl ester (0.440 g, 41%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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:32]([O:36][C:37]([N:39]1[CH2:40][CH:41]=[C:42]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=3)[CH:5]=[C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)[N:3]=2)[CH2:43][CH2:44]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)CC1

Procedure:
Heat a solution of 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (774 mg, 1.64 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (608 mg, 1.97 mmol (prepared essentially as described by Eastwood (2000) Tetrahedron Letters 41 (19):3705-3708), K3PO4 (2M, 1.64 mL) and Pd(PPh3)4 (76 mg, 0.07 mmol) in dioxane at 80° C. for 16 hours. Partition the reaction mixture between brine and EtOAc, dry the EtOAc layer (Na2SO4) and concentrate under reduced pressure. Flash chromatography (30% EtOAc in hexanes as eluent) yields 4-{4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.Cl.[CH3:11][P:12]1(=[O:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][N:15]2[CH2:16][CH2:17][P:12](=[O:18])([CH3:11])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Br)n1
Reactant: CP1(=O)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CP1(=O)CCN(Cc2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (500 mg, 1.99 mmol), 4-methyl-1,4-azaphosphinane 4-oxide hydrochloride (406 mg, 2.39 mmol, prepared according to the method described in WO 2008/010985), and DIEA (522 μL, 2.99 mmol) were combined in DMF (5.0 mL) and stirred at room temperature overnight. The solvent was then evaporated in vacuo and the crude residue was purified by reverse phase HPLC (MeCN/water w/0.025% TFA) to afford the title compound as a colorless foam.
Reaction SMILES: [CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.Cl[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1>CN(C=O)C>[CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][N:6]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Clc1ccncn1
Reactant: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCN(c2ccncn2)CC1
Temperature: 140 °C
Yield: 51.2 %

Procedure:
4-(4-Ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (10 mg, 0.035 mmol), triethylamine (0.049 mL, 0.352 mmol), and 4-chloropyrimidine (8 mg, 0.070 mmol) were dissolved in DMF (1.5 mL) and heated under microwave irradiation at 140° C. for 30 min. The solution was concentrated in vacuo and purified via preparative HPLC 10% to 40% B in A and gave 6.5 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8.14 (dd, 1H, J=7.6, 1.3 Hz), 7.51 (s, 1H), 7.37 (s, 1H), 7.11 (d, 1H, J=7.5 Hz), 5.14 (s, 2H), 4.27 (m, 1H), 4.11 (m, 1H), 3.86-3.87 (m, 1H), 3.80-3.82 (m, 1H), 2.86 (m, 1H), 2.73 (m, 1H), 2.38 (m, 1H), 2.24-2.31 (m, 4H), 0.99 (t, 3H, J=7.6 Hz). MS (ES) [M+H] found 363.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([CH3:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:21]([NH:23][CH3:24])[CH3:22])=[CH:5][CH:4]=1.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:23]([CH:21]([C:10]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:18](=[O:19])[C:17]3[C:12](=[C:13]([CH3:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH3:22])[CH3:24])(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC(C)c1nc2c(C)cccc2c(=O)n1-c1ccc(OC)cc1
Product: COc1ccc(-n2c(C(C)N(C)S(=O)(=O)c3ccc(C(C)(C)C)cc3)nc3c(C)cccc3c2=O)cc1

Procedure:
In a similar manner as described above, 3-(4-methoxyphenyl)-8-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one, as prepared above in Example 5, was condensed with 4-tert-butylbenzenesulfonyl chloride to yield 4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide; MS (ESI) 520 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1.[OH-].[K+].I[CH3:24]>CC(C)=O.O>[CH3:24][O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1
Reactant: CI
Reactant: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CON=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of 0.2 g (0.75 mmol) of 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide in 2 mL of acetone cooled to 0° C. was added a solution of 0.065 g (1.16 mmol) of potassium hydroxide in 1 mL of water followed by 0.164 g (1.16 mmol) of iodomethane. The resulting mixture was stirred at room temperature overnight then 10 mL of water was added. The mixture was extracted with ether and the organic layer was washed with water and brine, then dried by sodium sulphate and filtered. The solvent was removed by evaporation under reduced pressure and the residue chromatographed on silica gel with a 3% methanol-dichloromethane mixture. Chromatographically homogenous fractions were pooled, the solvents were removed under reduced pressure and the residue was crystallised from toluene to give the product as off-white crystals of m.p. 157.9°-159.4° C.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]=[O:22])[CH2:16][CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1COCC1>[CH2:4]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]([OH:22])[CH3:1])[CH2:16][CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=CCC1CCC(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CC(O)CC1CCC(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
Methylmagnesium bromide (1 M solution in THF, 0.526 ml, 0.526 mmol) was added dropwise to 4-(2-oxo-ethyl)-cyclohexanecarboxylic acid benzyl ester (114 mg, 0.439 mmol) in THF (2.2 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture at the same temperature and extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution, water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-(2-hydroxy-propyl)-cyclohexanecarboxylic acid benzyl ester (80.7 mg, 67%).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.Cl.[CH3:14][NH:15][O:16][CH3:17].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of Boc-Gly-OH (4250 g, 24.26 mol), N,O-dimethylhydroxylamine-HCl (2839 g, 29.10 mol) and DMAP (297 g, 2.43 mol) in dichloromethane (36 L), is added triethylamine (5.54 L) at 0° C. over a period of 90 min followed by the addition of EDC hydrochloride (5674 g, 29.60 mol). The mixture is stirred at 0° C. for 1 h then warmed to room temp for 24 h. The reaction mixture is cooled to 0° C. and quenched with 1.0M HCl to pH 3 to 4, stirred at room temp for 20 min, then allowed to stand and separate. The organic phase is washed successively with 1.0M HCl (15 L), water (15.0 L) and brine (8.0 L), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to provide the title compound (4985 g; 94% yield) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[NH3:24]>CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:24])=[O:2])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: N
Reactant: COC(=O)CC(=O)Nc1ccc(CCc2ccc(Cl)cc2)cc1
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(CCc2ccc(Cl)cc2)cc1
Yield: 65 %

Procedure:
Prepared in analogy to example 3 from N-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield=65%. Colorless solid. MS: m/e=317.1 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:22])([C:19]([OH:21])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:31][C:32]1[O:33][C:34](=[O:38])[O:35][C:36]=1[CH3:37]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:22])([C:19]([O:21][CH2:37][C:36]1[O:35][C:34](=[O:38])[O:33][C:32]=1[CH3:31])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1oc(=O)oc1CBr
Reactant: CC(C)(C)OC(=O)N[C@@](C)(Cc1ccc(O)c(O)c1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(=O)oc1COC(=O)[C@](C)(Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Yield: 31 %

Procedure:
A solution of N-(t-butoxycarbonyl)-3-hydroxy-α-methyltyrosine (760 mg, 2.44 mmol), triethylamine (263 mg, 2.60 mmol) and 4-bromomethyl-5-methyl-1,3-dioxol-2-one (500 mg, 2.60 mmol) in dimethylformamide, 10 mL, is stirred at 60° C. for 3 hours under nitrogen. Most of the dimethylformamide is removed at 50°-60° C. and 0.1 mm and the residue is partitioned between saturated sodium bicarbonate solution, 10 mL, and ethyl acetate, 50 mL. The ethyl acetate extract is washed with water saturated with sodium sulfate, filtered and concentrated at 40°-45° C. and 15 mm. Flash chromatography of the residue over 40 g of silica gel 60 (230-400 mesh) with 3% methanol-97% chloroform as eluent affords 320 mg of the desired ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2].[I:15]N1C(=O)CCC1=O.C(O)(=O)C>CO>[I:15][C:12]1[S:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1-c1cccs1
Reactant: O=C1CCC(=O)N1I
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1-c1ccc(I)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2-nitro-phenyl)-thiophene (23 g, 0.11 mol) and N-iodosuccinimide (37 g, 0.165 mol) were dissolved in 110 ml of methanol. To this solution, acetic acid (10 g, 0.165 mol) was added. After stirring the reaction mixture for 4 hours at room temperature, the solvent was evaporated. The remainder was taken up in a mixture of ice and water and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and evaporated, delivering 2-iodo-5-(2-nitro-phenyl)-thiophene (28 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[O:18][CH2:19][CH2:20][CH2:21]2)=[O:6]
Reactant: c1ccc2c(c1)CCCO2
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)CCCO2)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of 2-bromo-5-iodobenzoic acid (1.0 g, 3.06 mmol) in DCM (5 mL) was added DMF (0.2 mL) and oxalyl chloride (0.44 mL, 4.59 mmol) at 0° C. After complete addition, the reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure, and the crude product was dissolved in DCM (4 mL) and added to chroman (488 mg, 3.67 mmol) which had been cooled to 0° C. To this mixture was added aluminum chloride (488 mg, 3.67 mmol) in portions. After stirring for 4 h, the reaction was quenched by pouring it into crushed ice. This was extracted with dichloromethane (50 mL×2): The dichloromethane layers were combined and washed with water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL×2), and brine (20 mL), then dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to furnish (2-bromo-5-iodo-phenyl)-chroman-6-yl-methanone (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]=[N+:15]=[N-:16])[O:10][C:9]2=[O:17])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:22][CH:21]2[CH2:23][C:24]3([CH2:29][CH:20]2[CH2:19]1)[O:28][CH2:27][CH2:26][O:25]3.O.[C:31](OC=C)(=O)[CH3:32]>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:32]=[CH:31][N:16]=[N:15]3)[O:10][C:9]2=[O:17])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:22][CH:21]2[CH2:23][C:24]3([CH2:29][CH:20]2[CH2:19]1)[O:28][CH2:27][CH2:26][O:25]3
Reactant: C=COC(C)=O
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Solvent: O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1
Yield: 47 %

Procedure:
5.0 g (12.39 mmol) of 2-[2-fluoro-4-[(5R)-5-(azidomethyl)-2-oxo-3-oxazolidinyl]phenyl]hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 9 of the preparation example 1 was dissolved in 100 ml of vinyl acetate, and the solution was heated to reflux for 30 hours. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate, and then, the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 2.5 g (47%) of 2-[2-fluoro-4-[(5R)-5-(1,2,3-triazol-1-ylmethyl)-2-oxo-3-oxazolidinyl]phenyl]hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23](=[O:32])[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)/[C:24](=[C:25](/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)\[C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)/[C:23]2=[O:32])[CH:16]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(C(F)(F)F)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo-4-trifluoromethyl-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3) δppm 3.91 (s, 3H), 4.96 (s, 2H), 6.37 (d, 1H), 6.67 (dd, 2H), 7.08 (t, 1H), 7.35-7.40 (m, 7H), 7.49 (d, 2H), 7.71 (d, 2H), 7.95 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:6]([C:16]2[N:17]=[C:18]([NH2:24])[NH:19][C:20](=[O:23])[C:21]=2[N:22]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[CH:2]=[CH2:3].[CH2:25](Br)C=C>>[CH2:1]([S:4][C:5]1[N:6]([C:16]2[N:17]=[C:18]([NH2:24])[NH:19][C:20](=[O:23])[C:21]=2[N:22]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[CH:2]=[CH:3][CH3:25]
Reactant: C=CCBr
Reactant: C=CCSc1nc2c(=O)[nH]c(N)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CC=CCSc1nc2c(=O)[nH]c(N)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 48 %

Procedure:
Following the first procedure for the preparation of 8-(2-propenylmercapto)guanosine (Example 9), but substituting 2-butenyl chloride for allyl bromide, the title compound was obtained in 48 percent yield as a white powder, mp 210° C. (decomp.). NMR (DMSO-d6): δ 6.3 (bs, 2H); 5.6 (d, J=5 Hz, 1H); 1.6 (d, J=6 Hz, 3H). IR (KBr): 1690, 1630, 1600, 1510 and 1365 cm-1.
Reaction SMILES: N1C(C)=CC(C)=CC=1C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[Br:24][C:25]1[CH:43]=[CH:42][C:28]2[O:29][CH2:30][CH2:31][CH:32]=[C:33]([O:34][Si](C(C)(C)C)(C)C)[C:27]=2[CH:26]=1>C1(C)C=CC=CC=1>[Br:24][C:25]1[CH:43]=[CH:42][C:28]2[O:29][CH2:30][CH:31]=[CH:32][C:33](=[O:34])[C:27]=2[CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OC1=CCCOc2ccc(Br)cc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1
Product: O=C1C=CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 94 %

Procedure:
2,4,6-Collidine (5.6 ml), DDQ (9.0 g, 40 mmol) and (7-bromo-2,3-dihydrobenzo[b]oxepin-5-yloxy)(tert-butyl)dimethylsilane was dissolved in toluene, the mixture was stirred for 5.5 hours at room temperature. the mixture was concentrated in vacuo and then purified by column chromatography to give 7-bromobenzo[b]oxepin-5(2H)-one (4.5 g, 94%). 1H-NMR (MeOD): 4.71 (m, 2H), 6.38 (m, 1H), 6.76 (m, 1H), 6.99 (m, 1H), 7.54 (m, 1H), 8.06 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)[C:5]([C:6]=23)=[N:4][NH:3]1.ClCCl.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[BH4-].[Na+]>C(O)(=O)C>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:18][C:17]2[CH:16]=[C:15]([CH:14]3[C:5]4=[N:4][NH:3][C:2](=[O:1])[C:11]5[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=54)[NH:12][CH:13]3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:35][CH2:34]1
Reactant: O=Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Reactant: CN1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a stirred solution of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (150 mg, 0.4 mmol) in dryness dichloromethane (10 mL) was added acetic acid followed by 1-methylpiperazine (121 mg, 1.2 mmol). After the addition, the mixture was stirred at room temperature for 1 h, Then the mixture was cooled to 0° C. Sodium borohydride (130 mg, 0.2 mmol) was added. After the addition, the mixture was stirred at this temperature for 3 hr. Dichloromethane was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by pre-HPLC to give 9-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as white solid (22 mg, yield 12%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.31 (s, 3H), 2.36-2.48 (m, 8H), 3.37-3.48 (dd, 2H), 4.30 (dd, 1H), 4.71 (dd, 1H), 7.01 (s, 1H), 7.05 (dd, 1H), 7.17-7.23 (m, 5H), 7.25-7.28 (m, 2H), 7.56 (dd, 1H), 7.61-7.65 (t, 1H); LC-MS (ESI) m/z: 452 (M+1)+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH:11]1[CH2:12][CH2:13][C:8]2([C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]2)[CH2:9][CH2:10]1
Reactant: CC(=O)N[C@H]1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCC2(CCNCC2)c2ccccc21

Procedure:
At 0° C., a solution of (B4) (2.2 g, 6.1 mmol) in dichloromethane (20 ml) was treated with TFA (10 ml) for 1 hour, concentrated, co-evaporated with acetonitrile and dissolved in dichloromethane. The resulting solution washed with a mixture of brine (ca. 100 ml) and 6N NaOH (3 ml), dried over Na2SO4 and concentrated to give (S)-N-(3,4-dihydro-2H -spiro[naphthalene-1,4′-piperidine]-4-yl)acetamide (B5) as a white solid. LC-MS: m/e=258.9 (M+H). Rt=0.96 min. The crude was used directly for further reactions.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.N([O-])=O.[Na+].[N-:18]=[N+:19]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[N:1]([C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(N)c(I)cc1C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(N=[N+]=[N-])c(I)cc1C(=O)O
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of 4-amino-5-iodo-2-methoxybenzoic acid (300 mg, 1.02 mmol) in trifluoroacetic acid (4 ml) at 5° C., was added sodium nitrite (283 mg, 4.1 mmol) portionwise, and the mixture allowed to stir for 30 min. Sodium azide (200 mg, 3.07 mmol) was then added portionwise and the mixture stirred for a further 30 min at 0° C. The mixture was diluted with water, and a yellow solid precipithated. The solid was filtered, washed with cold water and dried, to afford the title compound (274 mg, 84%).