Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([O:13][CH3:14])[C:6]([O:11][CH3:12])=[CH:7][C:8]=1[CH2:9]Cl.[OH-].[Na+].C1(C)C=CC=CC=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=1>O>[CH3:14][O:13][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][C:6]=1[O:11][CH3:12])[CH2:9][N:33]([CH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([NH2:24])=[CH:26][CH:27]=1)[CH2:2]2
Reactant: NCCc1ccc(N)cc1
Reactant: COc1cc(CCl)c(CCl)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(cc1OC)CN(CCc1ccc(N)cc1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4,5-Bischloromethyl veratrol (2.35 g: S. H. Wood, M. A. Peny and C. C. Tung, J. A. C. S. (1950), 72, 2989-2991) was added at room temperature to a stirred suspension of 50% aqueous sodium hydroxide (5 ml), toluene (25 ml), 4-aminophenylethylamine (1.5 g) and Aliquat (0.2 g). The heterogeneous mixture was stirred at room temperature for 16 hours, poured in water and extracted with methylene chloride. The organic layer was dried and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene dichloride/methanol (95:5) to give the title compound as a solid (0.6 g), MP: 150°. NMR includes signals at d 2.7(4H,m,Ph--CH2 --CH2 --N); 4.6(2H,bs,NH2); 3.7(6H,s,2×OCH3); 3.8(4H,s,2×N--CH2Ph); 6.2-7.0(6H,m,aromatics).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12](F)[CH:11]=2)=[CH:6][CH:5]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:22][CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2cc(F)ncc2Cl)cc1
Reactant: CC(C)N
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2cc(NC(C)C)ncc2Cl)cc1
Temperature: 90 °C
Yield: 67 %

Procedure:
4-(5-Chloro-2-fluoropyridin-4-yl)-benzoic acid methyl ester (90 mg, 0.34 mmol) was dissolved in DMSO in a screw cap tube and 0.5 mL isopropylamine was added. The tube was sealed and heated to 90° C. for 2 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to an oil, which was purified by chromatography on silica (EtOAc 0 to 20%/hexanes) to give 70 mg of 4-(5-chloro-2-isopropylamino-pyridin-4-yl)-benzoic acid methyl ester, 0.23 mmol, 67% yield. 1H NMR 500 MHz (CDCl3): 8.08 (m, 3H), 7.45 (d, 2H), 6.22 (s, 1H), 4.37 (d, 1H), 3.88 (s, 3H), 3.80 (m, 1H), 1.17 (d, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[NH+:11][CH:10]=[CH:9]2)([O-])=O.[H][H]>[Pt]=O.CO>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][NH:11][CH2:10][CH2:9]2
Reactant: O=[N+]([O-])c1cccc2cc[nH+]cc12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: Nc1cccc2c1CNCC2

Procedure:
The 2-lower alkyl-5,6,7, or 8-nitroisoquinolinium salt can be catalytically hydrogenated directly to a 2-lower alkyl-5,6,7 or 8-amino-1,2,3,4-tetrahydroisquinoline. The hydrogenation can be readily effected by use of a platinum oxide catalyst in methanol and a hydrogen pressure of about 25 to 100 psi. The hydrogenation proceeds at room temperature. After filtering to remove the catalyst, the filtrate can be worked up to obtain the 2-lower alkyl-5,6,7 or 8-amino-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9]/[N:10]=[C:11](\[C:16](=[O:22])[CH2:17][C:18](OC)=[O:19])/[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].O>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18](=[O:19])[CH:17]=[C:16]([OH:22])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CC(=O)/C(=N\Nc1ccc(Cl)c(Cl)c1)C(=O)OC
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COC(=O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1O
Reaction time: 1 h
Yield: 61.3 %

Procedure:
(E)-Dimethyl 2-(2-(3,4-dichlorophenyl)hydrazono)-3-oxopentanedioate (6.7 g, 19.3 mmol) in 1, 2 dichlorobenzene (20 mL) was heated at 180° C. overnight. After cooling, the reaction to room temperature, water 50 mL was added to the reaction mixture and it was stirred for 1 hour. The product was collected by filtration and further washed with water 20 mL and methanol (10 mL×3), then dried overnight under reduce pressure to yield 3.73 g (55.2%) of methyl 1-(3,4-dichlorophenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate as a tan solid. MS (ESI) 315 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([NH:23][C:24]3[N:28]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=3)=[O:22])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][C:52](Cl)=[O:53].N>CO.CN(C=O)C.C(Cl)Cl>[C:36]([C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:52](=[O:53])[CH2:51][O:50][CH3:49])[CH:7]=3)=[CH:11][CH:12]=2)[N:28]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[N:27]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(N)c3)c3ccccc23)cc1
Reactant: COCC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a stirred solution of 1-{4-[(2-aminopyridin-4-yl)methoxy]naphthalen-1-yl}-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (5) (526 mg, 0.96 mmol) and DIPEA (184 μL, 1.06 mmol) in mixture of DCM and DMF (10:1, 11 mL) was added methoxyacetyl chloride (92 μL, 1.01 mmol). After 1 h at RT further aliquots, of DIPEA (184 μL, 1.06 mmol) and methoxyacetyl chloride (92 μL, 1.01 mmol) were added sequentially and stirring was continued for 1 h. A solution of 1% ammonia in MeOH (40 mL), was added and the mixture stirred for 15 mins and then concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage 40 g); eluting with 0 to 6% MeOH in DCM to furnish N-[4-({4-[3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido]naphthalen-1-yloxy}methyl)pyridin-2-yl]-2-methoxyacetamide (1) (286 mg, 49%): m/z 593 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 3.32 (3H, s), 4.08 (2H, s), 5.39 (2H, s), 6.36 (1H, s), 7.03 (1H, d), 7.28 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H, m), 7.93 (1H, m), 8.30-8.35 (3H, m), 8.58 (1H, s), 8.79 (1H, s) and 10.02 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:7][C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([OH:19])=O)=[C:12]3[N:11]=[CH:10][C:9]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:4][S:5][CH:6]=1.[CH:34]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH2:36][CH2:35]1>>[CH3:1][C:2]1[C:3]([NH:7][C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH:40][S:37]([CH:34]4[CH2:36][CH2:35]4)(=[O:39])=[O:38])=[O:19])=[C:12]3[N:11]=[CH:10][C:9]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:4][S:5][CH:6]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1cscc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1cscc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-methyl-3-thienylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.11 mmol) obtained in step 2 and cyclopropanesulfonamide (0.048 g, 0.44 mmol), the title compound (0.005 g, 8%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](F)[CH:7]=1.[OH:9][C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Li+].[Cl-]>[Br:1][C:2]1[CH:7]=[C:6]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Oc1cncnc1
Reactant: Fc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cncc(Oc2cncnc2)c1
Yield: 61.3 %

Procedure:
A mixture of 3-bromo-5-fluoropyridine (2.0 g, 11 mmol, 1.0 eq), 5-hydroxypyrimidine (1.3 g, 14 mmol, 1.2 eq), and potassium carbonate (2.4 g, 17 mmol, 1.5 eq) in DMF (40 mL) was microwaved at 200° C. for 30 minutes. The reaction was diluted with 3M LiCl and extracted (3×) with CH2Cl2. The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 1.7 g (92%) of the title compound as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.77 (s, 2H), 8.58 (d, J=1.8 Hz, 1H), 8.54 (d, J=2.4 Hz, 1H), 8.02 (t, J=2.1 Hz, 1H); ES-MS [M+1]+: 252.0.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:23]2[C:31](O)=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)([CH2:21][OH:22])[C:13]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2([C:23]3=[CH:24][C:25]4[O:29][CH2:28][O:27][C:26]=4[CH:30]=[C:31]3[O:22][CH2:21]2)[C:13]1=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(CCCOCc2ccccc2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1N(CCCOCc2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 98 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 1-[3-(benzyloxy)propyl]-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 98% yield as a pale yellow syrup: 1H NMR (300 MHz, CDCl3) δ 7.38-6.95 (m, 9H), 6.49 (s, 1H), 6.08 (s, 1H), 5.83 (dd, 2H), 5.86 (ABq, 1H), 4.58 (ABq, 1H), 3.96-3.79 (m, 2H), 3.53 (t, 2H), 2.06-2.00 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 155.9, 148.8, 142.5, 142.2, 138.1, 132.3, 128.9, 127.9, 127.6, 123.9, 123.1, 119.5, 108.7, 103.0, 101.4, 93.6, 80.4, 73.1, 67.4, 58.1, 37.7, 27.9; MS (ES+) m/z 430.3 (M+1).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1.[OH-:20].[Na+]>O.Cl>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:6]1([OH:20])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1
Reactant: NC1(c2ccccc2Cl)CCC=CC1=O
Reactant: [OH-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1C=CCCC1(O)c1ccccc1Cl
Temperature: 25 °C
Yield: 28 %

Procedure:
Sodium nitrite (16 mg, 0.23 mmol) in water (0.5 ml) was added to a stirred solution of 6-amino-6-(2-chlorophenyl)-2-cyclohexen-1-one (50 mg, 0.23 mmol) in 1/3N HCl (1.5 ml) at 0° C. After 1 h the reaction was neutralized with sodium hydroxide and allowed to warm to room temperature for 30 minutes. The reaction was partitioned between saturated bicarbonate and ethyl acetate, the organic phase was washed with brine, dried (Na2SO4), and the solvent removed by evaporation. Purification was achieved by preparative thin layer chromatography on silica gel eluting with 3:2 ethyl acetate/hexane. Isolation of the UV active band at Rf 0.7 gave 6-(2-Chlorophenyl)-6-hydroxy-2-cyclohexen-1-one (14.2 mg, 28%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)C(O)=O.CN(C)C=O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:1]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1ccc(OCC2CC2)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OCC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
Oxalyl chloride (0.053 mL, 0.6 mmol) was added to a stirred solution of 3-chloro-4-[(cyclopropylmethyl)oxy]benzoic acid (WO 2005058848; 68 mg, 0.3 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at 0° under nitrogen, and the mixture was allowed to warm to room temperature with stirring overnight. The solvent was evaporated to give the title compound as a yellow oil (ca 80 mg) which was used crude in the subsequent reaction (D46).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]#[CH:15])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.C(N=[C:21]=[O:22])CCC.C(Cl)(Cl)=O>N12CCN(CC1)CC2.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]#[CH:15])=[C:6]([S:8]([N:11]=[C:21]=[O:22])(=[O:9])=[O:10])[CH:7]=1
Reactant: C#CCOc1ccc(C)cc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: C#CCOc1ccc(C)cc1S(=O)(=O)N=C=O
Temperature: 25 °C
Yield: 112.5 %

Procedure:
A mixture of 22.4 g of 5-methyl-2-propargyloxyphenylsulfonamide, 9.9 g of n-butylisocyanate, 0.3 g of 1,4-diazabicyclo(2,2,2)octane and 350 ml of absolute xylene is refluxed for 30 minutes; and about 20 g of phosgene are subsequently introduced at 115°-120° C. during 2 hours. After the excess of phosgene has been removed from the reaction mixture by feeding in nitrogen, the mixture is cooled to room temperature, filtered, and concentrated in vacuo. There is thus obtained as crude product 28.1 g of 5-methyl-2-propargyloxyphenylsulfonylisocyanate in the form of brown oil. This crude product is used, without further purification, in the subsequent stage.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.3 %

Procedure:
To an ice cold solution of 4-hydroxybenzonitrile (0.50 g, 4.19 mmol) in 10 ml of acetone was added potassium carbonate (0.76 g, 5.49 mmol) followed by benzyl bromide (0.32 ml, 2.73 mmol). The reaction mixture was stirred at 25° C. overnight under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 50 ml water and extracted with ethyl acetate (3×40 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 10% EtOAc-Hexane) to get the desired product (0.75 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH:16][CH3:17])[CH:10]=2)=[C:4]([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:3]=1.[N:24]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:15]=[CH:14][C:12]3[N:13]=[N:24][N:16]([CH3:17])[C:11]=3[CH:10]=2)=[C:4]([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:3]=1
Reactant: O=N[O-]
Reactant: CNc1cc(Sc2ccc(Cl)cc2Cn2cncn2)ccc1N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cn1nnc2ccc(Sc3ccc(Cl)cc3Cn3cncn3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
The aniline derivative was dissolved in 10% H2SO4 (2 ml) under ice cooling, followed by addition of an aqueous solution (0.5 ml) of sodium nitrite (50 mg), and the temperature of the resulting solution was raised up to room temperature for subsequent stirring for 20 hours. The solution was neutralized with an aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (methylene chloride:methanol=99:1 to 98:2), to give the title compound (55 mg; 41%). The purity of the compound was 100 % by HPLC.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][S:15][CH3:16])=[CH:9][CH:10]=2)[C:5](=[O:17])[N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.CC(C)([O-])C.[Na+].[NH2:27][C:28]1[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)C>[CH:18]([N:4]1[N:3]=[C:2]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][S:15][CH3:16])=[CH:9][CH:10]=2)[C:5]1=[O:17])([CH3:20])[CH3:19]
Reactant: Cc1cc(N)n[nH]1
Reactant: CSCCOc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Product: CSCCOc1ccc2c(Nc3cc(C)[nH]n3)nn(C(C)C)c(=O)c2c1
Temperature: 100 °C
Yield: 23.4 %

Procedure:
Degassed toluene (6 ml) and EtOH (3 ml) were added in one portion to a mixture of 4-bromo-2-isopropyl-7-(2-methylsulfanyl-ethoxy)-2H-phthalazin-1-one (0.3 g, 0.8 mmol), sodium t-butoxide (0.112 g, 1.2 mmol), 3-amino-5-methyl pyrazole (0.107 g, 1.2 mmol), tris-(dibenzylideneacetone)-dipalladium (0.038 g, 0.042 mmol) and 2-(di-t-butylphosphino)-biphenyl (0.025 g, 0.084 mmol) under nitrogen. The reaction mixture was heated to 100° C. for 20 hours with stirring and then cooled to RT. Diethyl ether (10 ml) was added and the precipitated solid was filtered to give the crude product as a grey solid. Flash column chromatography (elution: 95% EtOAc, 5% MeOH) afforded the title compound as a white solid (0.070 g, 7% yield).
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:11][C:12]1[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1>C(N(CC)CC)C>[OH:21][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: CCCCCCCC(=O)Cl
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
In the manner of Example 57 were reacted 3.4 ml of octanoyl chloride, 3.0 g of 5-amino salicylic acid and 2.8 ml of triethylamine. Recrystallization from methanol gave the title compound--m.p. ca. 200°-204° C.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+]=[N-].CCO.C(N(CC)C(C)C)(C)C.[CH3:32][C:33]([CH:35]1[C:41](=[O:42])[CH2:40][C:39]([CH3:44])([CH3:43])[CH2:38][C:36]1=[O:37])=O>CO.[Pd]>[CH3:44][C:39]1([CH3:43])[CH2:40][C:41](=[O:42])[C:35](=[C:33]([NH:1][C@@H:4]2[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]3[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]3=[O:13])[CH2:5]2)[CH3:32])[C:36](=[O:37])[CH2:38]1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(N[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO)=C1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
3′-Deoxy-3′-azido-thymidine (200 mg, 0.75 mmol) was dissolved in MeOH (25 ml) and Pd/C (40 mg) was added. The suspension was stirred over a constant stream of H2 overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was taken up in abs. EtOH (5 ml), N,N-diisopropylethylamine (0.1 ml) and 2-acetyldimedone (204 mg, 1.12 mmol) were added and the solution was refluxed for 5 h. The reaction mixture was cooled to room temperature and the product was precipitated by adding ether (50 ml) giving 3′-deoxy-3′-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-thymidine (24) (200 mg, 66%).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[O:5][CH:4]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[CH2:3]1.C[Si]([N:30]=[C:31]=[N:32][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:15]([C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][CH:4]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[CH2:3][C:2]3=[N:32][C:31]#[N:30])[CH:19]=[CH:18][CH:17]=1)#[N:16]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC(CC2CCCO2)O3)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(CC2CCCO2)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-oxo-2-((tetrahydrofuran-2-yl)methyl)chroman-6-yl)benzonitrile (233 mg, 0.70 mmol) in anhydrous DCM (18 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 1.4 mL, 1.4 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.287 g, 0.35 mL, 1.54 mmol) dropwise. The resulting mixture was stirred overnight after the addition. The reaction mixture was poured into ice-water (25 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted twice with DCM (2×30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give N-(6-(3-cyanophenyl)-2-((tetrahydrofuran-2-yl)methyl)chroman-4-ylidene)cyanamide as light brown solid, which was used for next step without further purification. MS ESI +ve m/z 358 (M+H)+.
Reaction SMILES: C1(OC([N:10]2[CH2:15][CH2:14][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C(C)C)[CH:20]=3)([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=O)C=CC=CC=1.Br.C(O)(=O)C>O>[OH:25][C:21]1[CH:20]=[C:19]([C:13]2([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCCC1(c2cccc(OC(C)C)c2)CCN(C(=O)Oc2ccccc2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCC1(c2cccc(O)c2)CCNCC1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
A solution of 4-(3-(1-methylethoxy)phenyl)-4-n-propyl-1-piperidinecarboxylic acid phenyl ester (Preparation 66, 6.7 g, 17.6 mmol) in 1:1 47% aqueous hydrobromic acid:glacial acetic acid (20 ml) was heated under reflux overnight. The solution was allowed to cool to room temperature and water (10 ml) was added. The aqueous layer was extracted with methyl tert-butyl ether (3×20 ml) to remove phenol as by-product. The aqueous layer was basified with 10M aqueous sodium hydroxide solution. At approximately pH 4, a biphasic solution developed as more methyl tert-butyl ether came out of solution. The layers were separated, and the aqueous layer was further diluted with water (10 ml) to solubilise a red oily deposit. The pH was adjusted to 10.3-10.5 with 10M aqueous sodium hydroxide and the precipitate was filtered and dried in vacuo at 50° C. to give the title compound as a pale brown solid (1.87 g, 48%).
Reaction SMILES: [C:1]1([C:7]2([CH2:11][C:12]([OH:14])=O)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[CH3:19][O:18][N:17]([CH3:16])[C:12](=[O:14])[CH2:11][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: CNOC
Reactant: O=C(O)CC1(c2ccccc2)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)CC1(c2ccccc2)CCC1
Yield: 89.5 %

Procedure:
A suspension of Example 68C (2.0 g, 10.5 mmol), N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.8 mmol), HATU (4.8 g, 12.6 mmol) and triethylamine (2.1 g, 21.0 mmol) in 100 mL dichloromethane was stirred at room temperature overnight. The resulting mixture was diluted with water (100 mL) and the aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layer was dried over Na2SO4, filtered, and concentrated to afford yellow oil. The crude product was purified by reserve-phase C18 column chromatography (H2O/CH3OH=1:4) to afford desired compound (2.2 g, 9.4 mmol, 89.5%) of title compound. LC-MS: m/e=234.1 (M+H+).