Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5](F)=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[C:7]([N:9]([CH2:11][CH2:12][OH:13])[CH3:10])=[O:8].O>CN(C=O)C>[Cl:3][C:4]1[C:5]2[O:13][CH2:12][CH2:11][N:9]([CH3:10])[C:7](=[O:8])[C:6]=2[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: CN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCOc2c(ccc(F)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
Sodium hydride (28 mg, 0.723 mmol, 60% dispersion in mineral oil) was added slowly to a solution of 3-chloro-2,4-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide (180 mg, 0.723 mmol) in DMF (4 mL) and the reaction stirred at room temperature for 16 hours. Water was added to the reaction and the mixture was subsequently extracted with DCM (3×30 mL). The combined organic phases were washed with water (5×25 mL) and saturated brine solution then dried (MgSO4), filtered and evaporated to give the desired product as an oil (140 mg). 1H NMR δ (CDCl3): 3.21 (s, 3H), 3.54 (t, 2H), 4.52 (t, 2H), 6.97 (dd, 1H), 7.72 (dd, 1H). m/z 230 (M+H)+
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([N+:25]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:28])[CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([NH2:25])[CH:9]=2)=[N:6][NH:5][C:4](=[O:28])[CH2:3]1
Reactant: COc1ccc(C(=O)Nc2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc(C3=NNC(=O)CC3C)cc2N)cc1

Procedure:
9.8 gm of 5-methyl-6-[3-nitro-4-(4-methoxy-benzoylamino)-phenyl]-3-oxo-4,5-dihydro-2H-pyridazine were dissolved in 1000 ml of ethanol and hydrogenated for 24 hours at room temperature with a hydrogen pressure of 5 bar in the presence of 1 gm of 10% palladium charcoal. The obtained precipitate was suction filtered and used in the next step without removing the catalyst. A further fraction of the product can be obtained from the mother liquors.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(OC([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:41][CH:42]([CH3:44])[CH3:43])[C:36]([O:38]CC)=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:41][CH:42]([CH3:44])[CH3:43])[C:36]([OH:38])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=[O:6]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1Cl
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(-c2ccccc2)cc1Cl

Procedure:
Using 2-chloro-4-phenylbenzoic acid and ethyl 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2-chloro-4-phenylbenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: [CH3:1][CH:2]1[C:19](=O)[C:5]2=[CH:6][C:7]3[C:8]([CH3:18])([CH3:17])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=4.[CH3:21][Mg]Br.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:21][C:19]1[C:5]2=[CH:6][C:7]3[C:8]([CH3:17])([CH3:18])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH2:3][C:2]=1[CH3:1])=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: CC1Cc2cc3c(cc2C1=O)C(C)(C)c1ccccc1-3
Reactant: C[Mg]Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1=C(C)c2cc3c(cc2C1)-c1ccccc1C3(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.6 %

Procedure:
In a 1000 mL round flask, 2,9,9-trimethyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (50 g, 190.6 mmol) was dissolved in 400 mL of toluene, and then the temperature was lowered to 0° C. Then, 76 mL of 3M methylmagnesium bromide (THF solution) was slowly injected thereto, followed by stirring at room temperature for 12 hours. The reaction product was poured into a mixture of 200 mL of 1N-HCl aqueous solution and 200 g of ice. The mixture was stirred for 1 hour, followed by extraction with toluene, and then the organic layer was dried over magnesium sulfate, followed by removal of volatile materials. The dried reaction product was dissolved in 320 mL of toluene, and then inputted to a 500 mL round flask. After that, p-toluene sulfonic acid (0.2 g) was inputted thereto, and then water was completely removed under reflux with Dean-Stark. The resultant material was cooled to room temperature, and then an aqueous ammonium chloride solution (150 mL) and 200 mL of diethyl ether were injected thereto, followed by separation of the organic layer. The organic layer collected by extracting the residue with diethyl ether was dried over magnesium sulfate, followed by removal of volatile materials, and then purified by using silica gel column chromatography, to thereby obtain 42.0 g of 1,2,9,9-tetramethyl-3,9-dihydrocyclopenta[b]fluorene (yield: 84.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].OS(O)(=O)=O.[C:26](=O)([O-])[O-:27].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:27][CH3:26])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: NC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
5 g of (S)-(+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 50 ml methanol and the solution was cooled till −15° C. 15 mL (0.28 mol) of conc. H2SO4 (98%) was added dropwise in 1 hr maintaining the temperature till −15° C. After the completion of addition the reaction mixture was gradually increased, and stirred at 31° C. for 30 min, and then refluxed at 70° C. for 21 hrs. The solvent was distilled off under reduced pressure and to the residue 50 mL of water was added and stirred for 30 min followed by cooling to −5° C. The pH of reaction mixture was adjusted between 9 to 10 using aq. sodium carbonate. The residue was extracted with 100 mL ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and evaporated under vacuum. The yield was 3.8 g of crude product purified by column, using hexane:ethyl acetate (9:1) as eluent.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4](Cl)[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:24]=[C:25]([CH:49]=[C:50]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:51]=1[OH:52])[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:29])([CH3:22])([CH3:21])[CH3:20]>C(N(CC)CC)C>[C:19]([C:23]1[CH:24]=[C:25]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:29])[CH:49]=[C:50]([C:53]([CH3:55])([CH3:54])[CH3:56])[C:51]=1[O:52][P:2]1[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[P:4]([O:52][C:51]2[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][C:25]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:29])=[CH:49][C:50]=2[C:53]([CH3:54])([CH3:56])[CH3:55])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:20])([CH3:21])[CH3:22]
Reactant: ClP1N(c2ccccc2)P(Cl)N1c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(OP2N(c3ccccc3)P(Oc3c(C(C)(C)C)cc(CCC(=O)OCCCCCCCCCCCCCCCCCC)cc3C(C)(C)C)N2c2ccccc2)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-diphenyl-1,3,2,4-diazadiphosphetidine, n-octadecyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and triethylamine to give the title compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N+:11]([O-])([O:13]C(C)C)=[O:12].S(=O)(=O)(O)O>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:4][C:3]1[C:5]([N+:11]([O-:13])=[O:12])=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)O[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
To a stirred suspension of salicylic acid (0.69 g, 5 mmol) in dichloromethane (10 mL) at room temperature was added tetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed by isopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.69 mL) was then added dropwise to the mixture which was allowed to stir at room temperature for thirty minutes (became a yellow solution, followed by formation of a yellow precipitate) and then poured onto water (50 mL). The yellow precipitate was filtered off and then triturated with water (10 mL). The insoluble material was filtered off and dried to afford yellow crystals, (0.42 g, 46%) of m.p. 121–122° C. identified by NMR as the title compound (lit. m.p. 123° C., Merck Index No. 6553). The mother liqours were concentrated on a rotary evaporator (60° C., water aspirator pressure) and recrystallised from a dichloromethane/petroleum ether mixture to give yellow/orange crystals (0.35 g, 39%) of m.p. 226–228° C., identified by NMR as 2-hydroxy-5-nitrobenzoic acid (5-nitrosalicylic acid) (lit. m.p. 228–230° C., Merck Index No. 6554). (85% combined yield, Ortho:Para selectivity, 1.2:1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:38])[C:18]([C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][C:30](=[O:33])[N:29](CC=C)[C:28]=4[CH:37]=3)([OH:23])[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:39])[CH:12]=2)=[CH:7][C:6]=1[F:40])=[O:4]>C(O)CC.[Rh](Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:38])[C:18]([OH:23])([C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=4[CH:37]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:39])[CH:12]=2)=[CH:7][C:6]=1[F:40])=[O:4]
Reactant: C=CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(C(=O)OC)c(F)c4)cc3Cl)C(F)(F)F)cc21
Agent: Cl[Rh](Cl)Cl
Solvent: CCCO
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)NC(=O)CO4)C(F)(F)F)c(Cl)c2)cc1F
Yield: 28.7 %

Procedure:
To a suspension of 3′-chloro-3-fluoro-4′-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-biphenyl-4-carboxylic acid methyl ester (255 mg, 0.44 mmol, Example 70, step 7) in n-propanol (5 ml) was added rhodium(III)chloride (10 mg, 0.04 mmol). The mixture was stirred under reflux for 18 h. The reaction mixture was concentrated. The crude product was purified by flash chromatography (silica gel, heptane/AcOEt 8:2=>7:3) to give the title compound (68 mg) as a white solid. MS (m/e)=538.3 [M+H+].
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccccc1Cl
Agent: S
Solvent: Cc1ccccc1C
Product: Clc1ccccc1-c1cc(-c2ccccc2)c(-c2ccccc2)s1
Yield: 67.3 %

Procedure:
A 1-liter stainless steel stirred autoclave was charged with 33 g. (0.0946 mole) of 1,2-diphenyl-4-o-chlorophenylbutane-1,4-dione, 100 ml. of xylene, 20 g of phosphorus pentasulfide and 125 g of hydrogen sulfide. The autoclave was then heated at 160°-187° C. for three hours. The autoclave was cooled and vented. The residue was washed with ethanol and filtered off to give 17 g (51.8%) of crude product, m.p. 103°-107° C. Recrystallization from 20 ml of dioxane and 40 ml of ethanol gave 10.5 g (32%) of pure product, m.p. 117°-118° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH:10]2[CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCCl.[CH:21](=O)[CH:22]([CH3:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([NH:7][C:8]([CH:10]2[CH2:16][C:13]3([CH2:14][CH2:15]3)[CH2:12][N:11]2[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCC1)C1CC2(CC2)CN1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CN1CC2(CC2)CC1C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-cyclohexyl-5-azaspiro[2.4]heptane-6-carboxamide (10.0 mg, 0.0000450 mol) in 1,2-dichloroethane (0.5 mL, 0.006 mol) was added isobutyraldehyde (4.9 μL, 0.000054 mol), TEA (10 μL, 0.00009 mol), and sodium triacetoxyborohydride (20 mg, 0.00009 mol). After stirring for 30 min. at RT, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, then dried (MgSO4), filtered and concentrated in vacuo. The concentrate was purified by prep.-LC/MS to afford the desired product. LC/MS: 279.3 (M+H)+.
Reaction SMILES: NN.[CH3:3][C:4]1[C:5]([N+:15]([O-])=O)=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14]>C(O)C.CN(C)C=O>[NH2:15][C:5]1[C:4]([CH3:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:14])[NH:8][CH:9]=[N:10]2
Reactant: Cc1ccc2nc[nH]c(=O)c2c1[N+](=O)[O-]
Agent: NN
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc2nc[nH]c(=O)c2c1N
Temperature: 25 °C

Procedure:
An aqueous hydrazine solution (83%, 10 ml) in ethanol (10 ml) was added carefully at 28° under a nitrogen atmosphere to a mixture of 6-methyl-5-nitroquinazoline-4-one (formula 16, prepared according to Example VI) (10.0 g, 490 m-mol) and palladium-one-charcoal (10%, 1.0 g) in ethanol (150 ml). The mixture was refluxed for 1 hour. Cooling of the mixture to room temperature yielded crystals which were dissolved in dimethyl formamide (150 ml) and separated from the catalyst by filtration. The filtrate was evaporated and the residue recrystallized from ethanol. This yielded 7.0 g (82%) of the formula 17 target compound in the form of light yellow crystals, m.p. 260°-261° (decomp.); ir (KBr): 3480, 3315 cm-1 (NH2); pmr (DMSO-d6): δ 2.13 (s, 3 CH3), 6.70 (d, 1, J=8.5 Hz, H7), 6.95 (m, 2, D2O-exchangeable NH2), 7.36 (d, 1, J=8.5 Hz, H8), 7.88 (s, 1, H2), 11.67 (m, 1, D2O-exchangeable NH); ms (70 eV): m/e 175 (100%, M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Li+].[Li+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.OP(O)(O)=O.CC#N.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O.Cl>CN(C)C=O>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 20 gallon glass-lined vessel was charged with N,N-dimethylformamide (15.9 1) and 4-hydroxyphenylacetic acid (3.969 kg, 26.09 moles). When solution was obtained, lithium carbonate (2.12 kg, 28.7 moles, 1.1 equivs.) was added in one portion and the resulting mixture stirred at room temperature for 10 minutes. Benzyl bromide (3.723 l, 31.3 moles, 1.2 equivs.) was added in one portion and the mixture heated to 100° C. (internal temperature) and held for 3 hours, when LC (40/60, 0.0025 M H3PO4 /CH3CN, 220 nm, 1.5 mlmin-1, Hypersil column) showed approx. 5% starting acid remained. The reaction was cooled to approx. 60° C. and 2N aqueous HCl solution (20 l ) was added and the solution extracted with ethyl acetate (2×10 l). The combined organic extracts were washed with saturated NaHCO3 solution (16 l) and water (3×16 l). Emulsions were encountered during water washing, which could be broken by the addition of toluene (20 l total). The ethyl acetate was removed by distillation until the level of residual ethyl acetate was<0.3% [additional toluene (5 l) was added during distillation]. The volume of the mixture was adjusted to approx. 16 l (by further distillation) and allowed to cool to room temperature when crystallisation occurred. The slurry was diluted by the addition of hexane (20 l) and aged at ambient temperature overnight. The slurry was cooled to 0° C., held for 1 hour and the product filtered, washed with a cold (0° C.) 1:1 toluene/hexane mixture (4 l) and dried in vacuo at 50° C. to give the product as a white solid. Yield: 5.283 kg, 83%. LC/GC>98%. NMR confirmed structure; only trace impurities noted.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].[OH-].[Na+].Cl>O.CS(C)=O.ClC1C=CC=CC=1Cl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)c1ccc(Oc2nnc(Cl)cc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
3.0 g (purity: 90%; 16.4 mmol) of 4-hydroxy-3,6-dichloropyridazine, 7.45 g (49.1 mmol) of 4-t-butylphenol, and 2.03 g (purity: 97%; 49.1 mmol) of sodium hydroxide were added to a mixture of 19.1 g of 1,2-dichlorobenzene and 3.0 g of dimethyl sulfoxide and matured at 180° C. for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 50 g of pure water was added to the cooled mixture. A 35% aqueous hydrochloric acid solution was added to the resultant mixture so that the pH of the aqueous phase was adjusted to 2.1, and then the deposited solids were taken out by filtration. The solids were dried under nitrogen gas for 24 hours, and then 25 mL of methyl t-butyl ether was added to the solids to obtain a slurry. After stirring for 1.5 hour, the obtained slurry was subjected to filtration, and the resultant solids were dried under a reduced pressure to obtain 2.61 g of 6-chloro-3-(4-t-butylphenoxy)-4-pyridazinol in the form of pale brown solids (yield: 57.2%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][C:13]=1[CH2:18][CH3:19])[CH3:2].[OH-].[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][C:13]=1[CH2:18][CH3:19])[CH3:2]
Reactant: CCc1cnn(C)c1-c1cc(C(=O)OC)sc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cnn(C)c1-c1cc(C(=O)O)sc1CC
Yield: 100 %

Procedure:
A solution of methyl 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (181 mg, 0.65 mmol) in 6N sodium hydroxide (2.16 ml, 13.0 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (175 mg, 0.65 mmol, 100% yield) as a white foam: LCMS (ES) m/e 265 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[N:25][N:26]=2)[N:23]=1>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[N:25][N:26]=2)[N:23]=1
Reactant: Clc1ccc2nncn2n1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc2nncn2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (100 mg, 0.53 mmol) in DMF (2 mL) was added sodium hydride (55% dispersion in mineral oil, 25.4 mg, 0.58 mmol). The mixture was stirred at room temperature for 15 min. After addition of 6-chloro-1,2,4-triazolo[4,3-b]pyridazine (90 mg, 0.58 mmol) the mixture was stirred at room temperature for another 2 h. Then the mixture was evaporated, extracted (ethyl acetate/water) and the organic phase was dried with sodium sulfate and concentrated. Chromatography (SiO2, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (80 mg, 51%) as a white solid. MS: m/e=308.4 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[C:14]3[C:8]([CH2:9][CH:10]([C:15]([OH:17])=O)[S:11][C:12]=3[N:13]=1)=[N:7][N:6]2[CH2:18][C:19]1[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=1.Cl.CN.O.O[N:34]1[C:38]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C)C=O>[NH2:2][C:3]1[N:4]=[C:5]2[C:14]3[C:8]([CH2:9][CH:10]([C:15]([NH:34][CH3:38])=[O:17])[S:11][C:12]=3[N:13]=1)=[N:7][N:6]2[CH2:18][C:19]1[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=1
Reactant: On1nnc2ccccc21
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)O)C3)c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)C1Cc2nn(Cc3ncc(C)c(OC)c3C)c3nc(N)nc(c23)S1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
A mixture composed of 4-amino-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carboxylic acid hydrochloride of Example 8 (42 mg), methylamine hydrochloride (13 mg), 1-hydroxybenzotriazole monohydrate (14 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg), diisopropylethylamine (79 μL) and dehydrated N,N-dimethylformamide (1 mL) was stirred at room temperature for 48 hours. A 0.5 N sodium hydroxide solution was added to the reaction mixture, and the solid was collected by filtration. The solid collected by filtration was dissolved in a mixed solvent of chloroform-methanol, followed by purification by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (17.9 mg, 49%) as a solid.
Reaction SMILES: [I-].[C:2]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N+:9]=2[CH3:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](OCC)C.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:19][C:8]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[CH3:18]
Reactant: C[N+]1=C(c2ccccc2)c2ccccc2CC1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCc2ccccc2C1(C)c1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 1-phenyl-2-methyl-3,4-dihydroisoquinolinium iodide (1.0 g) in tetrahydrofuran (15 ml) was added 3M diethyl ether solution of methyl magnesium bromide (1.9 ml) with stirring at room temperature. After stirring for 30 minutes, the mixture was poured into saturated ammonium chloride aqueous solution and ethyl acetate. The organic layer was washed with water, sodium chloride aqueous solution and dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from n-hexane to give 1,2-dimethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (0.6 g).