Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:50])[NH:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1)([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:28]([O:32][C:33](=[O:50])[NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](=[O:19])[NH:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)=[CH:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:37][N:36]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1)NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)cc2)cn1
Temperature: 90 °C
Yield: 81.8 %

Procedure:
(E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (0.95 g) and [5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester (1.00 g) are dissolved under an inert gas atmosphere in dimethylethylenglycole (35 mL), and Pd(PPh3)3Cl2 (0.22 g) and a sodium carbonate solution (2.21 g dissolved in 21 water) is added and it is heated for 0.5 h at 90° C. After cooling the mixture is diluted with water, extracted with chloroform, and the combined organic phases are dried and evaporated. The residue is purified by silica gel flash chromatography CHCl3/THF (4:1). 0.97 g of the title compound are obtained with a melting point of 140-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[CH:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O.N1C=CC=CC=1>>[Cl:17][C:12]1[C:11](=[O:13])[O:10][C:9](=[O:14])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1C=C(c2ccc(Cl)cc2)C(=O)O1
Solvent: c1ccncc1
Product: O=C1OC(=O)C(c2ccc(Cl)cc2)=C1Cl
Temperature: 11 °C
Reaction time: 0.5 h

Procedure:
With ice-cooling, 15.0 g (72 mmol) of 3-(4-chlorophenyl)furan-2,5-dione were added to 72 ml of thionyl chloride, and the mixture was admixed dropwise over a period 10 min with 11.5 g (145 mmol) of pyridine, the temperature being maintained at 10-12° C. The mixture was stirred at 10-12° C. for 30 min, heated at 75° C. for 10 min using a preheated heating bath and allowed to cool, and excess thionyl chloride was removed at 60° C. under reduced pressure. The residue was boiled with 200 ml of toluene and filtered, and the residue was again boiled with 100 ml of toluene and filtered whilst still hot. The filtrate was concentrated under reduced pressure and the residue was boiled with 100 ml of petroleum ether, cooled, filtered off, washed once more with petroleum ether and dried under reduced pressure. Yield: 16.2 g, m.p. 110-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11]C)=[O:10])[S:8][C:4]=2[CH:3]=1.[OH-].[K+]>C1COCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc2ccc(Br)cc2s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.0 g (14.8 mmol) of methyl 6-bromo-1-benzothiophene-2-carboxylate in 40 ml of a 1:1 mixture of THF and 2 N potassium hydroxide solution is stirred at room temperature for 2 h. The solvent is removed in vacuo, and the residue is acidified with concentrated hydrochloric acid. The resulting precipitate is filtered off with suction, washed with water and dried in vacuo at 50° C. 3.55 g (93.5% of theory) of the desired product are obtained.
Reaction SMILES: [C:1]([C:4]#[N:5])(=O)[CH3:2].[NH2:6]/[C:7](/[C:12]#[N:13])=[C:8](\[NH2:11])/[C:9]#[N:10]>CO.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[C:4]([C:1](=[N:11]/[C:8](=[C:7](\[NH2:6])/[C:12]#[N:13])/[C:9]#[N:10])[CH3:2])#[N:5]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CC(=O)C#N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CO
Product: CC(C#N)=N/C(C#N)=C(\N)C#N
Yield: 26.3 %

Procedure:
To a mixture of 22.1 g of acetyl cyanide and 16.3 g of diaminomaleonitrile were added dropwise a solution of 0.5 g of phosphorus pentoxide in 3 ml of methanol. The crude product thus obtained was recrystallized from aqueous methanol to obtain 6.3 g (26% yield) of α-cyanoethylidenediaminomaleonitrile.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:12])(=O)[C:8]([CH3:10])=[O:9].CN(C=O)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1COCC1>[O:21]1[CH2:22][CH2:23][N:18]([C:7](=[O:12])[C:8](=[O:9])[CH3:10])[CH2:19][CH2:20]1
Reactant: C1COCCN1
Reactant: CC(=O)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (8.75 mL) was added to a solution of pyruvic acid (6.96 mL) and DMF (77 μL) in THF (200 mL) at room temperature, and the mixture was stirred at room temperature for 20 min. Under a nitrogen atmosphere, morpholine (18.4 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (11.0 g) as a colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47](Cl)=[O:48].C(N(CC)CC)C>CN(C)C=O>[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)=[O:48]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccc5ccccc5c4)cc3)cc21
Yield: 73.4 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), 2-naphthoylchloride (153 mg), triethylamine (232 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (337 mg).
Reaction SMILES: P([O-])([O-])([O-])=O.[CH3:6][C@@H:7]1[O:11][C@@H:10]([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([OH:20])[C@H:16]([N:21]=[C:22]([NH2:24])[NH2:23])[C@@H:15]([OH:25])[C@@H:14]2[N:26]=[C:27]([NH2:29])[NH2:28])[C@H:9]([O:30][C@@H:31]2[O:36][C@@H:35]([CH2:37][OH:38])[C@H:34]([OH:39])[C@@H:33]([OH:40])[C@@H:32]2[NH:41][CH3:42])[C@@:8]1([OH:45])[CH:43]=[O:44].OS(O)(=O)=O>>[CH3:6][C@@H:7]1[O:11][C@@H:10]([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([OH:20])[C@H:16]([NH:21][C:22]([NH2:24])=[NH:23])[C@@H:15]([OH:25])[C@@H:14]2[NH:26][C:27]([NH2:29])=[NH:28])[C@H:9]([O:30][C@@H:31]2[O:36][C@@H:35]([CH2:37][OH:38])[C@H:34]([OH:39])[C@@H:33]([OH:40])[C@@H:32]2[NH:41][CH3:42])[C@@:8]1([OH:45])[CH:43]=[O:44]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]3N=C(N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Product: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O

Procedure:
The thus-obtained cell was suspended in 600 ml of a 0.1M phosphate buffer solution, and broken by the use of a Dyno-mill. After the removal of insoluble materials by centrifugal separation, a crude extract containing adenylate kinase was obtained. Then, 200 ml of a 10% streptomycin sulfate solution was added to 400 ml of the crude extract. Precipitates formed were removed by centrifugal separation to thereby obtain a streptomycin supernatant liquid. This supernatant liquid was subjected to ammonium sulfate fractionation, and a fraction from 30% saturation (4° C.) to 60% saturation (4° C.) was obtained. This fraction was dissolved in a 50 mM Tris-hydrochloric acid buffer solution (pH 8.0) and passed through a DEAE-Sephadex column which had been equilibrated with the same buffer solution as above, and thereafter it was eluted with a solution prepared by adding sodium chloride to the above buffer solution. Near a concentration of sodium chloride of 0.2M, the desired adenylate kinase was eluted. The thus-eluted fraction was subjected to hydroxyapatite column chromatography under the same conditions as in Example 1, passed through a Sephadex G-75 column, and eluted with a 30 mM Tris-hydrochloric acid buffer solution (pH 8.0) containing 0.1M sodium chloride to thereby obtain an adenylate kinase sample which provided a single band by acrylamide disc electrophoresis as in the case of Example 1. Furthermore, as in the case of Example 1, the adenylate kinase sample provided a single peak at a molecular weight of about 22,000 as determined by Sephadex G-100 chromatography.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:66]([O:68][C:69](=[O:73])[CH2:70][CH2:71][NH2:72])[CH3:67]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([NH:72][CH2:71][CH2:70][C:69]([O:68][CH2:66][CH3:67])=[O:73])=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: CCOC(=O)CCN
Reactant: COCc1cc(-c2nc(-c3cccc(CC(=O)O)c3)no2)ccc1-c1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)Cc1cccc(-c2noc(-c3ccc(-c4ccccc4C)c(COC)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
To a solution (3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetic acid (preparation described in Example 24 Step 1, 209 mg, 0.48 mmol) in DMF (2 mL) at 0° C. was added DIEA (252 μL, 1.5 mmol) and HATU (183 mg, 0.48 mmol). After 10 min, a solution of beta-alanine ethyl ester hydrochloride (82 mg, 0.53 mmol) in DMF (1 mL) was added and the reaction mixture stirred at RT overnight. EtOAc was added and the mixture was washed with water. The organic phase was then dried over MgSO4, filtered and concentrated in vacuo affording the title compound (100 mg, 40%). LC/MS (Method B): 514.1 (M+H)+. HPLC (Method A) Rt 4.73 min (Purity: 99.5%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[CH3:33][CH:34]([C:36]1[NH:40][N:39]=[C:38]([C:41](O)=[O:42])[CH:37]=1)[CH3:35].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([C:20]([NH:19][C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([NH:11][C:6]3[N:7]=[CH:8][C:9]4[N:10]=[C:2]([NH:1][C:41]([C:38]5[CH:37]=[C:36]([CH:34]([CH3:35])[CH3:33])[NH:40][N:39]=5)=[O:42])[S:3][C:4]=4[N:5]=3)[CH:13]=2)=[O:32])[CH:26]=[CH:25][CH:24]=1)([CH3:29])[CH3:28])#[N:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Reactant: CC(C)c1cc(C(=O)O)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)c3cc(C(C)C)[nH]n3)sc2n1
Temperature: 90 °C
Reaction time: 21 h
Yield: 31.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (82 mg, 185 μmol) produced in Example D25(iii) in pyridine (3 mL) were added 5-(1-methylethyl)-1H-pyrazole-3-carboxylic acid (57 mg, 370 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (211 mg, 555 μmol), and the mixture was stirred at 90° C. for 21 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→92/8), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from N,N-dimethylformamide and diethyl ether to give the title compound (34 mg, 32%) as pale-yellow crystals.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
To a solution of ethyl(1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (100 mg, 0.23 mmol) in CH2Cl2 (5 ml) was added triethylsilane (32 mg, 0.28 mmol), followed by boron trifluoride etherate (0.13 ml, 1.05 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to provide the title compound (91 mg, 96%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13]>[Ni].CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:4]=1
Reactant: CCCS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1C
Agent: [Ni]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cc(N)ccc1C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
Propane-1-sulfonic acid (2-methyl-5-nitro-phenyl)-amide (10 g, 39 mmol) was hydrogenated over Raney nickel (1.0 g) in methanol at 50° C. and 70 psi for 4 h. Then, the catalyst was filtered out, washed with warm methanol, and the combined filtrates were evaporated to give 8.0 g (90%) of propane-1-sulfonic acid (5-amino-2-methyl-phenyl)-amide as colorless solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:11]=2[N:10]=1)=[O:7])([CH3:4])[CH3:3].[H][H]>CN(C)C=O.[Pd]>[CH3:4][C:2]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:11]=2[N:10]=1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc2ccc(N)cc2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
6-Nitrobenzothiazol-2-yl tert-butyl carbamate (4.68 g, 15.8 mmol) was dissolved in dimethylformamide (120 mL) and palladium on charcoal (841 mg, 10% Pd, 0.79 mmol Pd) was added. The air was replaced with hydrogen (1 bar) and the mixture was vigorously stirred at 60° C. until completion of the reaction (2 h). The palladium was removed by filtration through a pad of celite and the solution was concentrated to 20 mL. Water (200 mL) was added. After stirring for 1 h, the precipitated 6-aminobenzothiazol-2-yl tert-butyl carbamate was filtered off and washed with water. Additional product was obtained by repeated filtration of the mother liquor. A total of 3.24 g (12.2 mmol, 77%) of a grey solid was obtained. LC/ESI-MS: m/z=266 [M+H]+; m/z=264 [M−H]−; Rt=2.54 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][CH:10]([CH2:19][CH3:20])[CH2:11][CH2:12][CH2:13][C:14](OCC)=[O:15])[CH3:8]>O1CCCC1>[CH2:7]([O:9][CH:10]([CH2:19][CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH3:8]
Reactant: CCOC(=O)CCCC(CC)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(CC)CCCCO
Temperature: 25 °C

Procedure:
A solution of tetrahydrofuran (2000 ml) and lithium aluminum hydride (46 g, 1.21 moles) is cooled in a -60° C. dry ice/ethanol bath. Ethyl 5-ethoxyheptanoate (302 g ,1.49 moles) is diluted in tetrahydrofuran (300 ml) and added dropwise to the stirring reaction. After the addition is complete the reaction is warmed to room temperature and stirred for an additional hour. The solution is cooled in a -78° C. dry ice/ethanol bath and the excess hydride is destroyed by adding dropwise the following: water (46 ml), 15% sodium hydroxide solution (46 ml), and water (136 ml). The reaction is filtered and the solids washed several times with tetrahydrofuran (3×500 ml). The volume of the filtrate is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The remaining solvent is then removed leaving a clear, colorless oil of 5-ethoxyheptanol suitably pure for the next reaction (238 g, 1.49 moles).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[CH3:17].Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][N:21]=1.COC(=O)C(=CC1C=CC(F)=CC=1)CC(O)=O>>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:27])=[O:28])=[CH:22][N:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[CH3:17]
Reactant: CCS(=O)(=O)c1ccc(Br)nc1
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1C
Agent: COC(=O)C(=Cc1ccc(F)cc1)CC(=O)O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)c(C)c3ccc(F)cc23)nc1
Yield: 74.5 %

Procedure:
Starting with (6-fluoro-4-hydroxy-1-methyl-naphthalen-2-yl)acetic acid methyl ester (18 mg, 0.073 mmol) and 2-bromo-5-ethanesulfonyl-pyridine (27 mg, 0.109 mmol), using a method analogous to the one described for the methyl ester of example 1-1, [4-(5-ethanesulfonyl-pyridin-2-yloxy)-6-fluoro-1-methyl-naphthalen-2-yl]-acetic acid methyl ester (22.7 mg, 75%) was obtained as a light yellow solid.
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])=O)C.Cl.[C:21]([NH2:24])(=[NH:23])[CH3:22].C(O[K])(C)(C)C.Cl>C(O)C.O>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:23]=[C:21]([CH3:22])[NH:24][C:4](=[O:19])[CH:5]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)c1ccccc1OCCOC
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COCCOc1ccccc1-c1cc(=O)[nH]c(C)n1
Yield: 66.6 %

Procedure:
To a solution of 3-[2-(2-methoxy-ethoxy)-phenyl]-3-oxo-propionic acid ethyl ester (0.26 g, 0.98 mmol) in absolute ethanol (10 mL) was added acetamidine hydrochloride (0.3 g, 3.19 mmol) and tBuOK (0.5 g, 4.46 mmol). The reaction mixture refluxed 12 h. After cooling, a mixture poured into water (10 mL), adjusted to pH 3 with 10% HCl and extracted with CHCl3 (3×20 mL). Organic layers were combined, washed with water (10 mL), then dried over anhydrous sodium sulfate, concentrated and triturated with hexane to obtained 0.17 g (67%) 6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-3H-pyrimidin-4-one as a white powder.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[C:9](=[N:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[C:24]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[O:30])[CH:25]=[CH:26][CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[C:24]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=4)=[O:30])[CH:25]=[CH:26][CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)cn2CC(N)=O)cc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
A mixture of N-(3-{[1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]imino}-1,6-dihydropyridin-3-yl]oxy}phenyl)-6-methylpyridine-2-carboxamide (14.6 g, 27.5 mmol), trifluoroacetic anhydride (31 mL) and tetrahydrofuran (300 mL) was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (200 mL) and 4M aqueous sodium hydroxide solution (80 mL) were added to the residue, and the mixture was stirred at 60° C. for 24 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane) to give the title compound (2.22 g, 22%) as a pale-brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)=[CH:11][C:3]=12.[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:45][CH3:46])=[C:40](B(O)O)[CH:41]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O.O>[Cl:8][C:7]1[C:2]([C:38]2[CH:37]=[C:36]([F:35])[CH:41]=[CH:40][C:39]=2[O:45][CH3:46])=[C:3]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH:13]=3)[N:9]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:4]2=[N:5][CH:6]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)c(Cl)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1-c1c(Cl)cnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccc(C)cc1
Temperature: 110 °C

Procedure:
A mixture of Example 229C (0.16 g, 0.306 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (0.062 g, 0.368 mmol) and sodium hydrogencarbonate (0.103 g, 1.225 mmol) in degassed N,N-dimethylformamide (2.55 mL) and water (0.851 mL) was treated with 1,1′-bis(di-t-butylphosphino)ferrocenepalladium dichloride (TCI, 0.014 g, 0.021 mmol) under nitrogen and the mixture was heated at 110° C. for 10 minutes in a Biotage Initiator microwave reactor. Water and ethyl acetate was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel (AnaLogix IntelliFlash 280) eluting with a gradient of 0-45% ethyl acetate in heptanes afforded the title compound. MS (ESI+) m/z 612.2 (M+H)+.