Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]2=[N:6][C:5]=1[C:16](Cl)=[O:17])[CH3:2].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:7]2=[N:6][C:5]=1[C:16]([NH:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1)=[O:17])[CH3:2]
Reactant: Nc1nccs1
Reactant: CCOc1nc2c(nc1C(=O)Cl)c(C)nn2CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1nc2c(nc1C(=O)Nc1nccs1)c(C)nn2CC
Reaction time: 1 h

Procedure:
15.75 g. of 6-ethoxy-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]-pyrazine-5-carbonyl chloride (0.058 mol.) are dissolved in 150 ml. of dry toluene. To this well cooled solution (ice/sodium chloride) a solution of 6.4 g. of 2-aminothiazole (0.638 mol.) and 6.5 g. of triethylamine (0.638 mol.) in 260 ml. of dry toluene is added dropwise under stirring. The reaction temperature is kept at -5° to -10°. Then stirring is continued at room temperature for 1 hour and at 50° for 1 hour. The precipitated triethylamine hydrochloride is filtered off and the toluene filtrate is removed in vacuo. Recrystallization of the residual 6-ethoxy-1-ethyl-3-methyl-N-2-thiazolyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxamide gives 15.4 g. of product (78%), m.p. 158°-159°.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][NH:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1O>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:19])[CH2:9][NH:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: Cn1nccc(NCC(=O)N2CCC(O)CC2)c1=O
Product: Cn1nccc(NCC(=O)N2CCC(Oc3cc([N+](=O)[O-])ccc3Cl)CC2)c1=O
Yield: 7 %

Procedure:
Compound 9 is prepared from intermediate 5b and from 2-chloro-5-nitro-phenol following synthesis method 3 (yield: 7%).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:6]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH2:2][C@H:3]([OH:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:6]=1)=[N+:22]=[N-:23]
Reactant: CCCC(CCC)COc1cccc(C[C@@H](O)CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCCC(CCC)COc1cccc(C[C@@H](O)CN=[N+]=[N-])c1

Procedure:
Treatment of (R)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol with sodium azide following the method used in Example 66 gave (R)-1-azido-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([CH3:12])=[C:9]([Cl:11])[CH:10]=1)=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[Cl:11][C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=1[CH3:12]
Reactant: CCOC(=O)c1cc(Cl)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
5-Methyl-2-thiophenecarboxylic acid (2.84 g) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (1.68 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3-thiophenecarboxylic acid ethyl ester (1.84 g). 5-Methyl-2-thiophenecarboxylic acid ethyl ester (1.84 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.31 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred for 1.5 hour over a water bath, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g). 4-Chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g) was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (16 ml) was added. The mixture was stirred at 60° C. for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid (0.98 g) as crystals.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:9]1[CH2:10][CH:11]=[C:12]([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Nc1ccc(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(C2=CCOCC2)cn1
Temperature: 120 °C
Yield: 110.7 %

Procedure:
0.220 g of 5-iodopyridin-2-amine (1.0 mmol), 0.315 g of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.50 mmol), 0.116 g of tetrakis(triphenylphosphine)palladium(0) (0.100 mmol) and 2.25 ml of a 2M sodium carbonate solution (4.50 mmol) were dissolved/suspended in 8.6 ml of DMF in a microwave vessel, flushed with vacuum/argon, and subsequently heated in the microwave for 20 min at 120° C. HPLC/MSD indicated almost complete formation of the desired product. The solvent was evaporated under reduced pressure, 2M HCl was added to the residue and the mixture extracted three times with DCM. To the acidic water phase 2M NaOH was added up to pH 9 and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate solutions were washed once with brine, dried over sodium sulfate and the solvent removed under reduced pressure. 195 mg of the desired product were obtained as yellow powder (yield: quant.). The quite pure raw material (about 90%) was used without further purification in the next step.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[CH2:10]1[CH2:34][O:33][C:12]2([CH2:17][CH2:16][C@H:15]3[C@H:18]4[C@H:28]([C@@H:29]([OH:31])[CH2:30][C@:13]23[CH3:14])[C@:26]2([CH3:27])[C:21]([CH2:22][C@@H:23]([OH:32])[CH2:24][CH2:25]2)=[CH:20][CH2:19]4)[O:11]1.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.O.N1C=CC=CC=1>[Br:7][C@@H:17]1[CH2:16][C@H:15]2[C@H:18]3[C@H:28]([C@@H:29]([OH:31])[CH2:30][C@:13]2([CH3:14])[C:12]21[O:11][CH2:10][CH2:34][O:33]2)[C@:26]1([CH3:27])[C:21]([CH2:22][C@@H:23]([OH:32])[CH2:24][CH2:25]1)=[CH:20][CH2:19]3
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CCC21OCCO1
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](Br)C21OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
36.3 g of pyridine hydrobromide perbromide are added to a solution of 16.8 g of 17,17-ethylenedioxyandrost-5-ene-3β,11β-diol in 102 ml of tetrahydrofuran and the whole is stirred at room temperature for 21/2 hours. 26.9 g of sodium iodide are added to the mixture, which is then stirred for a further 30 minutes; a solution of 36.3 g of sodium thiosulphate in 50.4 ml of water, and 100 ml of pyridine are added in succession to the mixture and stirring is continued for a further 2 hours at room temperature. The reaction mixture is diluted with 100 ml of water and concentrated under a water-jet vacuum at approximately 45°. The residue is taken up in ethyl acetate and washed in succession with saturated sodium chloride solution, ice-cold dilute hydrochloric acid, ice-cold dilute sodium hydroxide solution and again with saturated sodium chloride solution and dried over sodium sulphate. Distilling off the solvent under a water-jet vacuum results in an amorphous residue comprising crude 16α-bromo-17,17-ethylenedioxyandrost-5-ene-3β, 11β-diol. The resulting crude product (13 g) is dissolved in 143 ml of dimethyl sulphoxide, and, while stirring, a mixture of 7 g of potassium tert.-butoxide in 13 ml of dimethyl sulphoxide is added at 45° in the course of 30 minutes and stirring is continued for 20 hours at 50° (bath temperature). The mixture is cooled to room temperature, diluted with approximately 1300 ml of a saturated ammonium chloride solution and taken up in ethyl acetate; the organic phase is washed three times with saturated sodium chloride solution and dried over sodium sulphate. By distilling off the solvent under a water-jet vacuum there is obtained amorphous 17,17-ethylenedioxyandrosta-5,15-diene-3β,11β-diol of a purity adequate for further processing.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([N:13]([CH3:25])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To a solution of the compound (12.1 g) obtained in step 1 in DMF (55 mL) was added sodium hydride (1.82 g) at 0° C. The reaction mixture was stirred at 0° C. for 5 min, methyl iodide (11.4 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (10% ethyl acetate/hexane) to give tert-butyl [3,5-bis(trifluoromethyl)phenyl](methyl)carbamate (12.5 g, 99%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[CH2:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>O.C(O)C>[C:1]1([C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[CH2:9][CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1ccccc1-c1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1-c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A stirred solution of 149.0 g (0.456 mole) of diethyl (2-phenylbenzyl)malonate and 56.1 g (1.0 mole) of potassium hydroxide in 50 ml of water and 500 ml of ethanol was heated under reflux for 3 hours. The reaction mixture was allowed to cool to ambient temperature and stand for 60 hours. The ethanol was removed by distillation and the residue slurried in 400 ml of water. The mixture was extracted with one portion of 250 ml of diethyl ether. The aqueous phase was separated and acidified with concentrated hydrochloric acid, then extracted with two portions of 250 ml each of diethyl ether. The two extracts of the acidified aqueous phase were combined, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give (2-phenylbenzyl)malonic acid as a pale yellow oil. The oil was used directly in the next step of this reaction sequence.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C>CO>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)[CH:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(Cn2ccc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(C(=O)O)cc3)ccc2c1
Reaction time: 0.67 h

Procedure:
To a slurry of the product of step i) (1 g) in methanol (15 mL) at reflux was added sodium hydroxide solution (1N, 2.4 mL). The reaction mixture was then stirred at reflux for 90 minutes. Additional sodium hydroxide solution (1N, 0.5 mL) was added and heating continued for a further 40 minutes. Acetic acid (0.16 mL) was added and the reaction was stirred at room temperature for 17 hours.
Reaction SMILES: C(OC([O:6][CH2:7][C:8]#[C:9][C:10](=[O:25])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C.O1CCCC1.O>[OH:6][CH2:7][C:8]#[C:9][C:10](=[O:25])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1
Reactant: CCOC(C)OCC#CC(=O)/C=C/c1cc(OC)c(OC)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(/C=C/C(=O)C#CCO)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4 g (11.5 mmol) of (E)-6-(1-ethoxy-ethoxy)-1-(3,4,5-trimethoxyphenyl)-1-hexen-4-yn-3-one in 40 ml of ethanol/tetrahydrofuran (1:1) was treated at room temperature with 0.4 g (1.6 mmol) of pyridinium (toluene-4-sulphonate) and was stirred at room temperature for 20 hours. The reaction mixture was diluted with water and extracted twice with ether. The combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 200 g of silica gel (elution agent methylene chloride/ether 4:1) and was subsequently crystallized from methylene chloride/ether. There was obtained (E)-6-hydroxy-1-(3,4,5-trimethoxyphenyl)-1-hexen-4-yn-3-one of melting point 113°-115°.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[I-:10].CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.[Na+].O>CN(C=O)C>[I:10][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH3:8])[CH:2]=1
Reactant: [I-]
Reactant: Cc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.8 %

Procedure:
To a solution of 10 g of o-cresol and 16.5 g (1.2 equiv) NaI in 250 ml of DMF was added 31 g (1.2 equiv) of chloramine-T hydrate. The dark green solution was stirred at rt for 1.5 h. The mixture, now a heterogeneous light brown, was poured into water, acidified, extracted with ethyl acetate, and the organic phase washed with water and bisulfite solution. The organic phase was dried over MgSO4. Concentration, trituration with hexane, and flash chromatography (silica gel, hexane, hexane/ethyl acetate (5:1)) provided 13.6 g (63%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:38])[C@@H:27]([NH2:37])[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:22][CH2:21]1)=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:15]([O:17][C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:38])[C@@H:27]([NH:37][C:12]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)=[O:14])[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:24][CH2:25]1)=[O:19])[CH3:16]
Reactant: O=C(O)c1cc(O)c2ccccc2c1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 630 mg of 4-Hydroxy-naphthalene-2-carboxylic acid and 1.1 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DMF, 512 mg of HOBT and 641 mg of EDC was added and the reaction mixture was stirred for 4 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/2). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 246 mg.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:16]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:18])[CH3:17]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:22][CH2:21][CH2:20][O:19][CH:16]([CH3:18])[CH3:17])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)OCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Reaction time: 48 h

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (40 g) was dissolved in dichloromethane (1.4 L) and triethylamine (23.3 mL). 3-Isopropoxypropylamine (19.3 mL) was added dropwise. After 48 hours, the reaction mixture was washed successively with water and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. (7-Bromo-3-nitroquinolin-4-yl)-(3-isopropoxypropyl)amine was isolated as a tan solid (51.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccc(C(=O)O)cc2)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Sc2ccc(CO)cc2)cc1
Yield: 51.5 %

Procedure:
4-(4-Methoxyphenylsulfanyl)benzoic acid was reduced with sodium bis-(methoxyethoxy)-aluminum hydride to provide in 51.5% yield 4-(4-methoxyphenylsulfanyl)benzyl alcohol. Its reaction with thionyl chloride provided in 93.3% yield the corresponding benzyl chloride which treated with sodium cyanide provided in 71.1% 4-(4-methoxyphenylsulfanyl)phenylacetonitrile. Alkaline hydrolysis provided after work-up 47.5% yield of 4-(4-methoxyphenyl-sulfanyl)phenylacetic acid, m.p. 85-87° C. Demethylation of this acid with pyridine hydrochloride provided in 98.0% yield 4-(4-hydroxyphenylsulfanyl) phenylacetic acid, m.p. 83-85° C., which was esterified with methanol in the presence of 4-toluenesulfonic acid to give the required ester as an oil. For C15H14O3S (274.3) calculated: 11.67% S; found: 11.49%. 1H NMR spectrum (CDCl3): H(O) 5.63 bs; CH2 3.58 s; aromatic H on the phenolic nucleus: H(2,6) 6.76 d, J=8.8 Hz; H(3,5) 7.33 d, J=8.8 Hz.
Reaction SMILES: Cl.[CH2:2]([NH:4][N:5]=[CH:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH:21]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:20][CH2:19][C:18]=3[CH:29]=2)=[O:12])=[CH:9][CH:8]=1)[CH3:3].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[CH2:2]([NH:4][N:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH:21]([CH2:23][C:24]([OH:26])=[O:25])[CH2:20][CH2:19][C:18]=3[CH:29]=2)=[O:12])=[CH:30][CH:31]=1)[CH3:3]
Reactant: CCNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)OCC)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.8 g (1.8 mmol) of the ester from Example 71 were suspended in a mixture of 16 ml ethanol, 2 ml 2 N aqueous sodium hydroxide, and some drops of water. It was stirred overnight at room temperature, while the suspension became a solution, which was brought to pH 5 with 2 N acetic acid. The precipitate of the pure title compound was collected by filtration, washed successively with water and acetone, and dried in vacuo. Yield: 0.65 g (95%) of a yellow powder, m.p. 260-262° C.(dec.).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][C:14]([N:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[CH3:17])=[O:15]>>[CH2:24]([N:21]1[CH2:20][CH2:19][CH:18]([N:16]([CH3:17])[C:14](=[O:15])[CH2:13][NH:12][C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C(=O)CN)C1CCN(Cc2ccccc2)CC1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Product: Cc1cc([N+](=O)[O-])cnc1NCC(=O)N(C)C1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was synthesized from 2-chloro-3-methyl-5-nitropyridine and 2-amino-N-(1-benzylpiperidine-4-yl)-N-methylacetamide in the same manner as in Example 10.
Reaction SMILES: Cl[C:2]1[N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[N:3]=1.[N:32]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>COC(C)(C)C>[CH3:11][N:8]1[C:9](=[O:10])[C:4]2[NH:3][C:2]([N:35]3[CH2:34][CH2:33][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36]3)=[N:12][C:5]=2[CH:6]=[N:7]1
Reactant: Cn1ncc2c(nc(Cl)n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: COC(C)(C)C
Product: Cn1ncc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
69.7 g of 2-chloro-5-methyl-1-trityl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one was combined with 153.4 g of t-butyl piperazine-1-carboxylate, and the mixture was stirred and heated to 100° C. under nitrogen atmosphere. When the reaction mixture became easily stirrable, the temperature was raised to 150° C. The mixture was kept at this temperature for one hour. The reaction solution allowed to cool and then suspended in 250 ml of t-butyl methyl ether. The suspended material was collected by filtration. The solid was washed twice with 200 ml of t-butyl methyl ether and three times with 200 ml of water. The solid was again washed twice with 200 ml of t-butyl methyl ether, and dried to give 50.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10](I)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:12]B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:10]([CH3:12])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CB(O)O
Reactant: Clc1nn2ccccc2c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1c(Cl)nn2ccccc12
Temperature: 100 °C

Procedure:
A mixture of the title compound from Example 1 Step A (0.30 g, 1.077 mmol), palladium acetate (0.024 g, 0.108 mmol), methyl boronic acid (0.129 g, 2.155 mmol), cesium carbonate (1.053 g, 3.23 mol) and triphenylphosphine (0.057 g, 0.215 mmol) in tetrahydrofuran (5.39 mL) was heated in a sealed tube at 100° C. for 18 hours. The reaction was then cooled to room temperature, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (0-15% ethyl acetate in hexanes) provided the title compound: LCMS m/z 166.94 [M+H]+, 168.89 [M+2+H]+; 1H NMR (500 MHz, CDCl3) 8.30 (d, J=6.9 Hz, 1 H), 7.35 (d, J=8.9 Hz, 1 H), 7.10 (dd, J=7.7, 7.7 Hz, 1 H), 6.70 (dd, J=6.6, 6.6 Hz, 1 H), 2.30 (d, J=1.2 Hz, 3 H).