Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])[CH2:6][CH2:7]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCN(Cc2ccccc2F)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2F)CC1)c1ccccc1
Yield: 56.7 %

Procedure:
0.2 g (0.000956 mol) of 1-(2-fluoro-benzyl)-piperidin-4-ol and 0.16 ml (0.00147 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.122 ml (0.00105 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.17 g (57%) of 1-(2-fluoro-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:7]1=[N:6]2.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].C>CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]1[CH:12]=[C:13]([C:16]3[NH:21][N:20]=[N:19][N:17]=3)[CH:14]=[CH:15][C:7]1=[N:6]2
Reactant: Cc1sc(C)c2c(=O)n3cc(C#N)ccc3nc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1sc(C)c2c(=O)n3cc(-c4nnn[nH]4)ccc3nc12
Temperature: 120 °C
Yield: 60.4 %

Procedure:
A mixture of 4.4 g (0.0172 mol) of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile (Example 51), 6.5 g (0.1 mol) of sodium azide and 5.3 g (0.1 mol) of ammonium chloride in 180 ml of dimethylformamide is stirred and heated in a wax bath at 120° C. for seventeen hours under nitrogen. The reaction mixture is cooled, filtered and filtrate evaporated. The residue is treated with 250 ml of water and acidified with concentrated hydrochloric acid. This mixture is warmed on a steam bath, cooled and filtered to give 5.1 g of crude product. This material is dissolved in hot pyridine, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Mansville). The filtrate is cooled to give 3.1 g of 1,3-dimethyl-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno-[3,4-d]pyrimidin-10-one; mp 292° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39](O)=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>>[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccc(C)cc2)c2ccccc2C)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccc(C)cc2)c2ccccc2C)c1

Procedure:
0.38 g of compound 74 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.51 g of ethyl 4-(2-aminophenoxy)butyrate and 0.45 g of 3-[1-(2,4'-dimethylbenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.C(Cl)Cl>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: O=CO
Product: CCN(CC)C/C=C/c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCc1occc1-2
Temperature: 100 °C
Yield: 7.9 %

Procedure:
A mixture of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 4, 1.73 g) and lithium hydroxide monohydrate (1.41 g) in dioxane (27 mL) and water (9 mL) was heated to 100° C. for 16 hours, under an atmosphere of nitrogen. The mixture was cooled to room temperature and diluted with DCM (100 mL) and water (100 mL). This mixture was acidified to pH6 using formic acid and the layers were separated. The aqueous layer was extracted with a further 3×100 mL DCM. The combined organic layers were washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give a tan solid. This was purified by chromatography on silica, eluting with a mixture of 2M ammonia solution in methanol and DCM with a gradient of 10-20% to give 7-[2-((E)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl-amino]-4H-furo[2,3-c]chromene-6-carboxylic acid (0.133 g), isolated as the minor by-product of the reaction.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.Br[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36]>>[CH3:36][CH:35]([CH3:37])[CH2:34][CH2:33][CH2:32][O:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=1
Reactant: CC(C)CCCBr
Reactant: CCCCCCC(Oc1ccc(O)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCCC(Oc1ccc(OCCCC(C)C)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 92 starting from 3-{4-[1-(4-hydroxy-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl ester and 1-bromo-4-methyl-pentane. MS: 484.2 [M−H]−.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:19][OH:20])/[CH:7]=[CH:8]/[P:9](=[O:18])([O:14][CH:15]([CH3:17])[CH3:16])[O:10][CH:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2].N1C=CN=C1.[Si:26](Cl)([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:1]([O:4][CH2:5][CH:6]([CH2:19][O:20][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[CH:7]=[CH:8]/[P:9](=[O:18])([O:14][CH:15]([CH3:16])[CH3:17])[O:10][CH:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(/C=C/P(=O)(OC(C)C)OC(C)C)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(=O)OCC(/C=C/P(=O)(OC(C)C)OC(C)C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of diisopropyl (E)-3-acetoxymethyl-4-hydroxybut-1-enylphosphonate (3 g, 9.7 mmol ) and imidazole (1.7 g, 25 mmol) in anhydrous THF (60 ml) at 0° C. was added t-butyldiphenylsilylchloride (3.2 ml, 12.7 mmol). After stirring at room temperature for 3 h, the solvent was removed and the residue was partitioned between chloroform (100 ml) and brine (30 ml). The organic phase was dried (MgSo4), evaporated in vacuo and chromatographed on silica gel, eluting with chloroform of increasing polarity to chloroform-methanol (100:1) to give diisopropyl (E)-3-acetoxymethyl-4-t-butyldiphenylsilyloxybut-1-enylphosphonate as an oil (5 g, 94%); υmax (film) 3071, 3050, 2977, 2931, 2858, 1743, 1630, 1582, 1472,and 1425 cm-1 ; δH (CDCl3) 1.05 [9H, s, C(CH3)3 ], 1.26 (3H, d, J 6 Hz, CH3CH), 1.27 (3H, d, J 6 Hz, CH3CH), 1.32 [6H, d, J 6.3 Hz, (CH3)2CH], 1.98 (3H, s, CH3CO), 2.74 (1H, m, CH), 3.72 (2H, m, CH2), 4.22 (2H, m, CH2), 4.65 (2H, m, 2×CH(CH3)2 ], 5.76 (1H, ddd, J 1, 17 and 18 Hz, PCH=CH), 6.99 (1H, ddd, J 7, 17 and 22 Hz, PCH=CH), 7.3-7.7 (10H, m, 2×C6H5) (Found: C, 63.42; H, 8.22%. C29H43O6PSi requires C, 63.71; H, 7.93%.).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:31]([C:32]([O:34]C)=[O:33])=[C:30]2[C:21]([C:22]3[CH:23]=[CH:24][N:25]=[N:26][C:27]=3[CH2:28][O:29]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].O1CCOCC1.O>CO.CC(C)=O.C(O)=O>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:31]([C:32]([OH:34])=[O:33])=[C:30]2[C:21]([C:22]3[CH:23]=[CH:24][N:25]=[N:26][C:27]=3[CH2:28][O:29]2)=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:37]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1nnccc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O=CO
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCc1nnccc1-2
Yield: 73.4 %

Procedure:
A mixture of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl-amino]-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (Intermediate 1, 0.249 g), lithium hydroxide monohydrate (0.474 g), dioxan (9 mL) and water (2.25 mL) was irradiated in the microwave at 135° C. for 45 minutes. The resulting solution was diluted with methanol, acidified with formic acid and evaporated in vacuo. The residue was dissolved in ethanol and toluene and evaporated in vacuo. The residue was triturated with 20% methanol in dichloromethane and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-30% to give a gum which was dissolved in acetone. A solid precipitated out on standing. This was collected by filtration to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylic acid (0.178 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N+:27]([O-])=O)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.[H][H]>C(O)C.[Pd]>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[N:10]=[C:9]2[CH2:11][CH2:12][CH3:13])=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2N)cc1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 0.475 g (1.23 mmol) of 7-methyl-3-[(2'-nitrobiphen-4-yl)methyl]-2-propyl-3H-imidazo[4,5-b]pyridine in 15 mL of absolute ethanol was added 50 mg of 10% palladium on carbon catalyst and the mixture was hydrogenated at 40 psig of hydrogen on a Parr apparatus. Reduction was complete after 1 hour and the reaction mixture was filtered and evaporated in vacuo to afford a tan solid (0.416 g, 95%) which was used in the subsequent step without further purification: NMR (CDCl3) δ 0.98 (t, J=8 Hz, 3H), 1.70-1.86 (m, 3H), 2.66 (s, 3H), 2.83 (t, J=10 Hz, 2H), 3.64-3.72 (br s, 2H), 5.52 (s, 2H), 6.70-6.82 (m, 2H), 7.00-7.19 (m, 5H), 7.36 (d, J=10 Hz, 2H), 8.20 (d, J=6 Hz, 1H); MS (FAB) m/e 357 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(F)c1
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1cccc(F)c1
Temperature: 0 °C

Procedure:
Borane-dimethyl sulfide complex (9.15 ml, 96.5 mmol) is added dropwise and then faster as gas evolution slowed, to an ice-cooled mixture of 3-fluorophenyl acetic acid (XXXIX, 4.96 g, 32.2 mmol) in THF (30 ml). After 2 hr methanol is added dropwise over the course of several hours. The solvents are then removed under reduced pressure and methanol is again added and removed under reduced pressure. The methanol addition/removal is repeated three times and then the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated to give 2-(3-fluorophenyl)ethanol (LXV), MS (m/z) 140; IR (neat) 1590, 1046, 1450, 1141, 782, 1488 and 691 cm-1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccccc1C
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc([N+](=O)[O-])ccc1C
Temperature: 0 °C

Procedure:
To 120 ml of concentrated sulfuric acid is added 53.6 g of o-methylacetophenone, while cooling at -10°. To this cold, stirred solution is added a mixture of 32 ml of 70% nitric acid and 48 ml of concentrated sulfuric acid. The reaction solution is stirred for 21/2 hours between -9° and 0° and then poured over 800 g of ice. The mixture is extracted with ether and the organic phase washed with water, saturated Na2CO3 solutions, water and finally brine. The ether solution is dried over MgSO4 and evaporated to dryness to give 56.2 g of a pale yellow oil. The oil is crystallized from 95% ethanol to give 25.4 g of product, mp about 50° C. Recrystallization from hexane afforded product mp 53°-55° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5]1.[C:17]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].ClCCl>C(#N)C.O>[C:17]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][N:4]3[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:5]3)[CH2:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=c1ccc(-c2ccccc2)nn1CCCl
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=c1ccc(-c2ccccc2)nn1CCN1CCN(c2cccc3ccccc23)CC1
Yield: 68.2 %

Procedure:
A mixture of 2-(2-chloroethyl)-6-phenyl-3(2H)-pyridazinone (1.9 g, 7.5 mmol), 1-naphthylpiperazine (1.7 g, 8 mmol), K2CO3 (1.12 g, 8 mmol) and KI (10 mg) in acetonitrile (50 mL) was refluxed for 7 hours. When heating, was over, the solvent was eliminated at reduced pressure and distributed between dichloromethane and water; the aqueous phase was extracted with dichloromethane (twice). The organic extracts were collected, dried over anhydrous Na2SO4 and concentrated to dryness. The obtained residue was purified by flash chromatography (CH2Cl2/MeOH 97:3) yielding 2-[2-(4-naphthylpiperazine-1-yl)-ethyl]-6-phenyl-3(2H)-pyridazinone (2.1 g). The product was dissolved in ethanol and by adding hydrochloric acid concentrated up to pH=1 yielded a white solid, which was re-crystallised in methanol, yielding the hydrochloride of the title compound, presenting a M.P. higher than 260° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[Cl:26].C1COCC1.C(N(CC)CC)C>N1C=CC=CC=1>[Cl:26][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:20]=1[NH:19][C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: Nc1ccncc1Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)Nc3ccncc3Cl)s2)noc1C(F)(F)F
Yield: 83 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-amino-3-chloropyridine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and pyridine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a saturated aqueous NaHCO3 solution followed by water to afford product as a colorless solid (80 mg, 83%). 1H NMR (CDCl3) 2.40 (s, 3H), 7.59 (d, J=4.0, 1H), 7.73 (d, J=4.0, 1H), 8.46 (s, 3H), 8.59 (s, 1H). 13C NMR 7.9, 114.5, 114.7, 118.6 (q, J=271), 129.0, 129.7, 135.2, 140.4, 141.0, 149.4, 149.6, 155.6 (q, J=40), 157.6, 159.3. 19F NMR −63.1. LC/MS 6.68 min, [M+1]+388.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([S:13]([CH2:16][Cl:17])(=[O:15])=[O:14])[C:10](=[O:12])[CH3:11].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[N:9]([S:13]([CH2:16][Cl:17])(=[O:14])=[O:15])[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)N(c1ccc(F)cc1Cl)S(=O)(=O)CCl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CC(=O)N(c1cc([N+](=O)[O-])c(F)cc1Cl)S(=O)(=O)CCl
Temperature: 2.5 °C
Yield: 92 %

Procedure:
30 g (0.1 mol) of N-(2-chloro-4-fluorophenyl)-N-[(chloromethyl)sulfonyl]acetamide was dissolved in a mixture of 150 mL of concentrated sulfuric acid and 50 mL of 30% oleum with stirring. The mixture was cooled to 0-5° C. and 9.2 mL of the nitrating agent, made from equal volumes of concentrated sulfuric acid and fuming nitric acid, was added slowly keeping the temperature below 5° C. Another 50 mL of oleum and 30 g of the starting material were then added, followed by the further dropwise addition of 9.2 mL of the nitrating agent, allowing the mixture to warm up to 10° C. The mixture was stirred for an additional 40 minutes at 10-15° C. and poured with vigorous stirring onto ice. The precipitated yellow solid was filtered off, washed with water and dried to yield 63.5 g (92%) of the title compound as a solid, which was recrystallized from ethyl acetate, melting at 183-187° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.Br[C:37]1[S:41][CH:40]=[N:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:37]3[S:41][CH:40]=[N:39][CH:38]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: CC1(C)OB(c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)OC1(C)C
Reactant: Brc1cncs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncs2)c1
Reaction time: 0.17 h

Procedure:
(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 9.1, 60 mg, 0.122 mmol), 5-bromothiazole (29.9 mg, 0.182 mmol), PdCl2(dppf)-(CH2Cl2) (9.93 mg, 0.012 mmol), Na2CO3 (38.7 mg, 0.365 mmol) DME (627 μL) and water (111 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and was subjected to MW irradiation at 125° C. for 10 min. Additional 5-bromothiazole, (29.9 mg, 0.182 mmol) was added MW irradiation was continued at 125° C. for 10 min. The RM was stirred with Si-Thiol (1.27 mmol/g, 47.9 mg, 0.061 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 25% for 0.2 min then 25% to 55% in 14 min) to afford the title compound as a white solid. UPLC-MS (Condition 1) tR=2.17 min, m/z=451.0-452.0 [M+H]+, m/z=449.0-450.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.79 (m, 1H) 1.80-1.91 (m, 1H) 3.00 (d, J=11.49 Hz, 1H) 3.25-3.31 (m, 2H) 3.42-3.51 (m, 1H) 4.19-4.25 (m, 1H) 4.74-4.99 (m, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.82-7.88 (m, 2H) 7.91 (s, 1H) 8.08 (d, J=2.45 Hz, 1H) 8.78 (d, J=2.45 Hz, 1H) 9.19 (s, 1H), 10.19 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:22]=[N:23][C:24](Cl)=[N:25][CH:26]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[N:25]=[CH:26][C:21]([Br:20])=[CH:22][N:23]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ncc(Br)cn2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (7.84 g) synthesized in Example 4 and 5-bromo-2-chloropyrimidine (5.0 g) were dissolved in N,N-dimethylformamide (70 mL), potassium tert-butoxide (3.47 g) was added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (6.0 g) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([O:16]C)[CH:5]=1)([CH3:3])[CH3:2]>Br.C(O)(=O)C.O>[OH:16][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1cc(C(C)C)ccc1-c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1ccc(-c2ccccc2)c(O)c1

Procedure:
A mixture of 4-isopropyl-2-methoxybiphenyl (3.8g from Example 5) in aqueous hydrobromic acid (150ml; 48%) and acetic acid (glacial, 50ml) was stirred under reflux for 7 hours. The mixture was cooled, diluted with water and extracted with ether. The extract was washed with water, dried, evaporated and distilled to give 2-hydroxy-4-isopropylbiphenyl, b.p. 112°-113°/0.2 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[Cl:12]N1C(=O)CCC1=O.[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:12][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1ccc2cnccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc2cnccc2c1Cl
Temperature: 50 °C
Yield: 58.4 %

Procedure:
7.0 g (38.1 mmol) of 6-fluoroisoquinoline (3) were dissolved in 60 mL of concentrated sulfuric acid. At 0° C. 10.18 g of N-chloro succinimide were added. After 1 h another 5.2 g of N-chloro succiminide were added and the solution was heated to 50° C. Two more portions of 5.2 g N-chloro succinimide were added successively and stirring was continued at 50° C. until the reaction was complete. The reaction mixture was cooled to room temperature, was poured on ice and adjusted to pH 10 by addition of sodium hydroxide. The precipitate was filtered off, dissolved in dichloromethane and washed with aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate, evaporated and the crude product was purified by preparative HPLC to yield 4.04 g of 5-chloro-6-fluoro-isoquinoline (7) as trifluoroacetate. Rt=0.97 min (Method A). Detected mass: 182.0/184.0 (M+H+).