Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]2[S:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Cc1ccc(N)c(S)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(-c3ccc(Br)cc3)sc2c1
Yield: 76.9 %

Procedure:
2-amino-5-methylthiophenol 10.02 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 16.85 g of product (yield=76.94%).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19](OC)=[O:20])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[NH3:25].CO>>[C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([NH2:25])=[O:20])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1cc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)ccc1F
Solvent: CO
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(F)c(C(N)=O)c1
Temperature: 90 °C

Procedure:
A mixture of methyl 3′-acetyl-5′-chloro-4-fluoro-2′-methoxy-6′-methylbiphenyl-3-carboxylate (50 mg, 0.1 mmol) and 7.0 M ammonia in methanol (2.0 mL, 14 mmol) was heated at 90° C. in a sealed tube overnight. After evaporating the mixture to dryness, the residue was used directly in next step. LCMS calculated for C17H16ClFNO3 (M+H)+: m/z=336.1. found: 336.0.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[F:14][CH:15]([F:18])[CH2:16]I.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:14][CH:15]([F:18])[CH2:16][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: FC(F)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(CC(F)F)C1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg) and 1,1-difluoro-2-iodoethane (618 mg) in N,N-dimethylformamide (6 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.403 ml) and the mixture was stirred at 70° C. for 72 hours. The reaction mixture was concentrated and the crude product was purified on silica gel with methanol/dichloromethane.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=O)[CH:27]=2)[CH:22]=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[CH:27]=2)[CH:22]=[CH:21]1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5cc[nH]c5c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-indole-6-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-indol-6-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[O:14])[O:12][CH:13]=2)=[CH:5][CH:4]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[O:14]=[C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)=[C:13]([CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20])[O:12]1
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)co1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1oc(=O)[nH]c1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 4-(4-trifluoromethylphenyl)-2-oxazolone (10.8 g), methyl acrylate (8.10 g), boron trifluoride diethyl ether complex (6.68 g) and toluene (50 mL) was stirred with heating under reflux for 3 h. The reaction mixture was concentrated and poured into iced water (200 mL). The precipitated solid was collected by filtration, washed with water and air-dried. Recrystallization from isopropyl alcohol-isopropyl ether gave the title compound as pale-yellow prism crystals (4.00 g, 27%). melting point: 156-157° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][OH:18])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH3:2].C(OC(C1C(C)=C2C(=CC=1C)N=[C:42]([CH2:48]OCC1C=CC=CC=1)[N:41](C1C=CC=CC=1S(=O)(=O)NC)[C:40]2=[O:68])=O)C.C(OCC)C>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][O:18][C:40](=[O:68])[NH:41][CH2:42][CH3:48])[N:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[C:9]2=[O:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Reactant: CCOC(=O)c1c(C)cc2nc(COCc3ccccc3)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Agent: [Pd]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCNC(=O)OCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1S(=O)(=O)NC
Reaction time: 8 h
Yield: 43 %

Procedure:
Preparation of 2-Hydroxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: A solution of 2-Benzyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester (15 g, 0.028 mol) in anhydrous THF (270 mL) is degassed under house vacuum. Palladium on activated charcoal (Acros, 10% Pd, 930 mg) is added and the suspension is flushed with hydrogen (balloon). The suspension is stirred under hydrogen overnight. TLC and LCMS analysis indicates that starting material remained. The reaction mixture is filtered through Celite, and the catalyst is washed sequentially with methanol, DCM and methanol. The filtrate is evaporated to give a cream solid. Trituration with diethyl ether provides a white solid which is removed by filtration and dried under high vacuum to provide the title compound (5.42 g, 0.012 mol, 43%). The ethereal filtrate, which contains un-reacted starting material, is evaporated in vacuo and the residue is subjected to a second cycle of hydrogenation (Pd—C, 920 mg): after stirring overnight under hydrogen TLC/LCMS indicated absence of starting material. The reaction mixture is worked-up as above to provide the title compound as a white solid (4.75 g, 0.01 mol, 38%). Total yield: 10.17 g, 0.022 mol, 82%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[CH3:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]=1)[CH3:11]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Yield: 28.7 %

Procedure:
2,6-Diacetylpyridine (7.3 g, 44.8 mmol) and 2,4,6-trimethylaniline (5.74 g, 42.55 mmol) were dissolved in 450 ml of toluene. To this solution, 4 Å molecular sieves and a small amount of p-toluenesulphonic acid (0.22 mmol) were added. The mixture was refluxed for 16 hours. After filtration the solvent was removed in vacuo. Several crystallisations from ethanol yielded 3.42 g (28.7%) of monoimine (1). 1H-NMR (CDCl3) δ 8.55 (d, 1H, Py-Hm), 8.11(d, 1H, Py-Hm), 7.92 (t, 1H, Py-Hp) 6.89 (s, 2H, ArH), 2.77(s, 3H, Me), 2.27 (s, 3H, Me), 2.22 (s, 3H, Me), 1.99 (s, 6H, Me).
Reaction SMILES: [OH:1][CH:2](/[CH:12]=[CH:13]/[C:14]1[C:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:18][N:17]2[C:26]=1[CH:27]([CH3:29])[CH3:28])[CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].CO.[BH4-].[Na+]>O>[OH:11][CH:4]([CH2:3][CH:2]([OH:1])/[CH:12]=[CH:13]/[C:14]1[C:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[N:18][N:17]2[C:26]=1[CH:27]([CH3:29])[CH3:28])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of ethyl (E)-5-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl) -3-oxohept-6-enoate [0.32 g; prepared as described in Reference Example 1(i)]in methanol (10 ml) under an atmosphere of argon was cooled to 0° C and treated with sodium borohydride (15.2 mg). The solution was stirred for 15 minutes and then it was poured into a mixture of ice and water (50 ml). The resulting mixture was extracted with diethyl ether (100 ml) and then with ethyl acetate (2×50 ml). The combined extracts were dried over magnesium sulphate, evaporated and subjected to flash chromatography on silica gel, using as eluant a mixture of petroleum ether (b.p. 40-60° C) and diethyl ether (1:1 v/v), to give ethyl (E)-3,5-dihydroxy-7-(3-isopropyl-1-phenylpyrrolo[2.1-a]phthalazin-2-yl)-hept -6-enoate (0.26 g) in the form of a yellow gum. [NMR (in a mixture of CDCl3 and D2O): 1.28 (3 H, t, J=7 Hz), 1.4-1.7 (2 H, m), 1.52 (6 H, d, J=7 Hz), 2.40-2.48 (2 H, m), 3.8 (1H, septet, J=7 Hz), 4.08-4.14 (3 H, m), 4.28-4.42 (1 H, m), 5.31 and 5.36 (1 H, two dd, J=16 Hz, 6 Hz), 6.63 and 6.65 (1 H, two dd, J=16 Hz, 1 Hz), 7.22-7.64 (9 H, m), 8.24 (1 H, s)].
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:3].[NH2:16][C:17]1[C:20](=[O:21])[C:19](=[O:22])[C:18]=1OC>CO>[NH2:16][C:17]1[C:20](=[O:21])[C:19](=[O:22])[C:18]=1[NH:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:13]=[CH:14][CH:15]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:6]=1
Reactant: COc1c(N)c(=O)c1=O
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: CO
Product: CN(C)Cc1cccc(OCCCNc2c(N)c(=O)c2=O)c1
Yield: 94.9 %

Procedure:
A mixture of 3-(3-dimethylaminomethylphenoxy)propylamine (1.41 g; 6.77 mmoles) [prepared according to the procedure described in Belgian Patent No. 867,106]and 1-amino-2-methoxycyclobutene-3,4-dione (0.86 g; 6.77 mmoles) in 40 mL of methanol was stirred at ambient temperature for 20 hours and then filtered to give 1.95 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[N:36]=[C:37](SC)SC>CN(C=O)C>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]1[O:11][C@:3]2([CH2:2][N:1]=1)[CH:8]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:9]1)[CH2:4]2
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1nc2ccccc2o1)SC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2oc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 10 ml-vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HCl salt (69.5 mg, 0.361 mmol), DMF (2 ml), DIEA (0.063 mL, 0.361 mmol) and Cs2CO3 (235 mg, 0.722 mmol) at room temperature, followed by dimethyl benzo[d]oxazol-2-ylcarbonimidodithioate (86 mg, 0.361 mmol). The resulting suspension was stirred at room temperature for 1 hr. LC/MS then indicated consumption of starting material. The mixture was diluted with MeOH and purified by preparative HPLC to afford the expected product, (R)—N-(benzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (101.5 mg, 0.323 mmol, 90% yield), as a tan gum. 1H NMR (400 MHz, Acetone-d6) δ ppm 2.07-2.14 (m, 2H) 2.20 (ddd, J=8.78, 5.27, 3.26 Hz, 2H) 2.33-2.45 (m, 1H) 2.62 (d, J=2.26 Hz, 1H) 3.34-3.47 (m, 3H) 3.48-3.58 (m, 1H) 3.75-3.88 (m, 2H) 4.15 (d, J=10.54 Hz, 1H) 4.32 (d, J=10.54 Hz, 1H) 7.13-7.26 (m, 2H) 7.41 (td, J=3.70, 1.63 Hz, 1H) 9.24 (br, s, 1H). MS (LC/MS) R.T.=0.792, [M+H]+=299.17.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:26]2[CH:25]=[C:24]([C:23]3[CH2:22][C:21](=[O:37])[NH:20][C:9]4[CH:10]=[C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(OCC(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M179) (266 mg, 0.5 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (175 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][NH:6]2.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][CH2:24][CH:23]([CH3:32])[N:22]3[CH:21]=1)=O>>[CH3:32][CH:23]1[CH2:24][CH2:25][C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:4]4[C:3]5[C:7](=[CH:8][CH:9]=[CH:10][C:2]=5[F:1])[NH:6][CH:5]=4)=[CH:21][N:22]13)[CH:29]=[CH:28][CH:27]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2C
Reactant: NC(=O)Cc1c[nH]c2cccc(F)c12
Product: CC1CCc2cccc3c(C4=C(c5c[nH]c6cccc(F)c56)C(=O)NC4=O)cn1c23

Procedure:
Beginning with (4-fluoroindol-3-yl)acetamide and (4-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxo-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:11](=[CH2:13])=[N-:12]>CCOCC>[N+:11](=[CH:13][C:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])=[N-:12]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)CC1CCCCC1
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)CC1CCCCC1

Procedure:
A solution of 19.8 g of cyclohexylacetyl chloride (b.p. 98°-100°/23 mm Hg) in 150 ml of dry ether is slowly added at 0°-5° with cooling in an ice-water bath to a vigorously stirred solution of 11 g of diazomethane in 500 ml of ether. The excess diazomethane and ether is distilled off under reduced pressure and cyclohexylmethyl diazomethyl ketone is obtained as residue; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.45μ, 3.52μ, 4.75μ and 6.12μ; the product is processed without any further purification. A solution of 20 g of cyclohexalmethyl diazomethyl ketone in 100 ml of ether is added in one portion, with stirring, to a solution of 32 g of triphenylphosphine in 450 ml of ether. After stirring for 30 minutes at room temperature, the solvent is evaporated under reduced pressure. The 1-cyclohexyl-3-(triphenylphosphoranylidene-hydrazono)-acetone obtainable as oily residue crystallises in the cold from ether; m.p. 58°-62°; ultra-violet absorption spectrum: λmax 314 mμ, 262-275 mμ and 223 mμ (in ethanol and in potassium hydroxide/ethanol), and λmax 257-275 mμ and 230 mμ (in hydrogen chloride/ethanol); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.43μ, 3.56μ, 4.76μ, 6.15μ and 6.67μ.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C2CCC(=O)CC2)cc1
Temperature: 100 °C
Yield: 95.6 %

Procedure:
A solution of 4-(4-hydroxyphenyl)cyclohexanone (6.0 g, 31.6 mmol) in DMF (90 mL) was treated with K2CO3 (21 g, 158 mmol, 5 equiv) and 2-iodopropane (15 mL, 26.8 g, 158 mmol, 5 equiv.). The reaction was heated at 100° C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-isopropoxyphenyl)cyclohexanone (7.02 g, 95%). 1H NMR (CDCl3): 7.14 (dt, 2H), 6.84 (dt, 2H), 4.3 (septet, 1H), 2.97 (tt, 1H), 2.46-2.52 (m, 4H), 2.16-2.24 (m, 2H), 1.83-1.98 (m, 2H) and 1.33 (d, 6H). Step 2:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[Cl:1][C:2]1[N:7]=[C:6](/[C:8](=[CH:20]\[N:21]([CH3:23])[CH3:22])/[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccnc(Cl)n1)c1ccc(F)cc1
Product: CN(C)/C=C(/C(=O)c1ccc(F)cc1)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound prepared in step 2 (4.7 g, 0.017 mol) in 100 mL of dimethylformamide dimethyl acetal was stirred at room temperature overnight. Excess dimethylformamide dimethyl acetal was removed under vacuum to give 4.5 g of crude product as a thick brown oil, which was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44])C>CCCCCC.C(OCC)(=O)C>[C:19]([CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([CH2:6][CH2:5][C:4]([OH:45])=[O:3])=[C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:41]=[CH:40][C:34]3[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=3[C:32]=1[CH2:42][CH2:43][CH3:44])[CH:9]=[CH:10]2)([OH:21])=[O:20]
Reactant: CCCc1c(OCCCCCOc2ccc3cc(OCC(=O)OCC)ccc3c2CCC(=O)OCC)ccc2c1OCCC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCOc2ccc3cc(OCC(=O)O)ccc3c2CCC(=O)O)ccc2c1OCCC2=O
Yield: 52.4 %

Procedure:
Starting with 0.736 g (1.19 mmol) of 2-[[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyl]oxy]-6-(2-ethoxy-2-oxoethoxy)-1-naphthalenepropanoic acid ethyl ester from the preceding example, the title compound (0.352 g; 52.6%) was obtained as a white solid, mp 160.5°-163° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 226.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([O:13]C1C=CC([N+]([O-])=O)=CC=1)=[O:12].O[C:41]1[CH:42]=[CH:43][C:44]([O:60][CH3:61])=[C:45]([N:47]([CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[S:48]([CH3:51])(=[O:50])=[O:49])[CH:46]=1.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:38][C:6]1[CH:5]=[N+:4]([O-:39])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:36][CH2:37]2)[CH:24]=1)[O:10][C:11]([O:13][C:41]1[CH:42]=[CH:43][C:44]([O:60][CH3:61])=[C:45]([N:47]([CH2:52][CH2:53][N:54]2[CH2:55][CH2:56][O:57][CH2:58][CH2:59]2)[S:48]([CH3:51])(=[O:50])=[O:49])[CH:46]=1)=[O:12]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc(O)cc1N(CCN1CCOCC1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 39.2 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine I-oxide (prepared in an analogous manner to that described in Scheme 3, Step 1) (0.250 g, 0.427 mmol) and DMAP (0.052 g, 0.427 mmol) in dry DMF (5 ml), N-(5-hydroxy-2-methoxyphenyl)-N-(2-morpholinoethyl)methanesulfonamide (0.180 g, 0.545 mmol) was added, and the resulting mixture was stirred at RT for 7 hours. The reaction mixture was treated with water and extracted with DCM (3×). The combined organic layers were washed with brine and dried over Na2SO4; the solvent was removed under vacuum and the crude was purified by flash chromatography on silica gel column (DCM:acetone=6:4) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)phenoxy)carbonyloxy)-ethyl)pyridine 1-oxide (0.130 g, 0.167 mmol, 39.2% yield, LC-MS purity (BPI): 100%, MS/ESI+ 776.34 [MH]+, [δD]−27.42, c=0.542, DCM).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O.[NH2:21][NH2:22]>>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][C:16](=[O:18])[NH:21][N:22]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: NN
Reactant: Cc1nccn1-c1ccc(C(=O)CCC(=O)O)cc1
Solvent: O
Product: Cc1nccn1-c1ccc(C2=NNC(=O)CC2)cc1

Procedure:
Similarly, the reaction of 4-(2-methyl-1H-imidazol-1yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone (3b).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CS(O[C@H:31]1[CH2:35][CH2:34][O:33][CH2:32]1)(=O)=O>CN(C=O)C>[O:33]1[CH2:34][CH2:35][C@@H:31]([N:12]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]3[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[N:11]2)[CH2:32]1
Reactant: CS(=O)(=O)O[C@H]1CCOC1
Reactant: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc([N+](=O)[O-])cc1)nn2[C@@H]1CCOC1
Reaction time: 3 h

Procedure:
A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (S)-tetrahydrofuran-3-yl methanesulfonate (0.389 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 3 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford 1-((R)-tetrahydrofuran-3-yl)-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. ESI-MS m/z [M+H]+ found 327.6, calculated 327.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([SH:21])[N:3]=1.Br[CH2:23][CH2:24][OH:25].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([S:21][CH2:23][CH2:24][OH:25])[N:3]=1
Reactant: OCCBr
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCCO)c(C#N)c1-c1ccc2c(c1)OCO2

Procedure:
75 mg (0.19 mmol) of 2-amino-4-(1,3-benzodioxol-5-yl)-6-sulfanyl-3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry 33 (7), 1014–1017 (1997); 34 (4), 557–563 (1998)] and 47 mg (0.38 mmol) of 2-bromoethanol and 63 mg (0.75 mmol) of sodium bicarbonate are stirred in 1 ml of DMF at room temperature overnight. Water is then added, and the precipitated product is filtered off with suction and dried under reduced pressure.