Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([SH:26])[NH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl[CH2:28][CH2:29]Br.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]3[C:13]([S:26][CH2:28][CH2:29]3)=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: ClCCBr
Reactant: CC(=O)Nc1ccc(-c2nc(S)[nH]c2-c2ccc(NC(C)=O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(NC(C)=O)cc2)CCS3)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 10.0 g. (0.027 mole) of 4,5-bis-(p-acetamidophenyl)-2-mercaptoimidazole and 4.9 g. (0.034 mole) of 2-chloroethyl bromide in 80 ml. of sieve dried dimethylformamide was refluxed with stirring under nitrogen for 75 minutes. Potassium carbonate (3.8 g., 0.027 mole) was added and the suspension was refluxed for 2 hours, then allowed to cool to room temperature and poured into 650 ml. of water. The gum which formed was filtered off and crystallized from 50 ml. of hot methanol. The crystals were washed with cold methanol and ether and air dried to give 5,6-bis(p-acetamidophenyl)-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 285°-290° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:3]
Reactant: BrBr
Reactant: COC(=O)c1cc(C(C)=O)ccc1OC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(=O)CBr)ccc1OC
Yield: 75.4 %

Procedure:
To a solution of 52.0 g (0.25 mole) of this ketone in 400 ml of chloroform is added a solution of 40.0 g (0.25 mole) of bromine in 200 ml of chloroform at such a rate as reaction mixture decolorizes (50 minutes after a 25 minute initiation period). Solvent is evaporated and the residue recrystallized from methanol to give 54.1 g (75%) of methyl 5-(2-bromoacetyl)-2-methoxybenzoate, m.p. 149°-153° C. A second crop of 10.4 g is obtained from the mother liquor.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16]>C(O)C>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[N:16]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11]
Reactant: Nc1c(F)cccc1F
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2c(F)cccc2F)C1=O
Yield: 46 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 2,6-difluoroaniline (0.575 g; 4.36 mmol) in ethanol (3 mL). 1-(2,6-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.161 g (46%) was obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9](=[N:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.C(O[C:26](=[O:30])[CH2:27][C:28]#[N:29])C.C([O-])(=O)C.[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:10]([CH3:11])=[C:27]([C:28]#[N:29])[C:26](=[O:30])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(NN=C(Sc2ccc(Cl)cc2)C(C)=O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(-n2nc(Sc3ccc(Cl)cc3)c(C)c(C#N)c2=O)cc1
Temperature: 160 °C

Procedure:
A flask equipped with a claisen distillation head and magnetic stirring was charged with an intimate mixture of 32.6 g (0.097 mole) 1[(4-chlorophenyl)thio]-1-[(4-methoxyphenyl) hydrazono]-2-propanone, 24.8 ml of ethylcyanoacetate and 12.2 g of ammonium acetate. The mixture was heated under a nitrogen atmosphere at 160° C. for 30 min. The reaction mixture was cooled and dissolved in methylene chloride. The organic layer was washed successively with saturated aqueous sodium bicarbonate and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to yield semi pure product. The residue was recrystallized from 1900 ml of ethanol to yield 6-[(4-chlorophenyl)thio]-2,3-dihydro-2-(4-methoxyphenyl)-5-methyl-3-oxo-4-pyridazinecarbonitrile, mp 146-148° C. (EtOH).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8](C(O)=O)[C:7](=[O:13])[NH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2].C>C(O)(C)C>[C:1]([C:4]1[CH:12]=[CH:8][C:7](=[O:13])[NH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)c(=O)[nH]c1C
Solvent: CC(C)O
Product: CC(=O)c1ccc(=O)[nH]c1C
Temperature: 25 °C

Procedure:
A 10 g portion of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid was heated neat in a bath of a boiling mixture of diphenyl and diphenyl ether for 40 minutes and the mixture allowed to cool to room temperature. The reaction mixture was dissolved in hot isopropyl alcohol, treated with decolorizing charcoal and filtered, and the filtrate allowed to stand at room temperature for several hours. The separated product was collected and dried at 90°-95° C. to yield 4.3 g of 5-acetyl-6-methyl-2-(1H)-pyridinone, m.p. 193°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[S:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>>[S:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][N:23]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])=[CH:20][CH:21]=1)(=[O:15])(=[O:14])[NH2:13]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccc(Cl)cc2Cl)cc1
Yield: 59 %

Procedure:
A solution of 2,4-dichlorobenzaldehyde (5 mmol) and 4-sulfamylphenylhydrazine hydrochloride was subjected to the General Procedure. The title compound, melting point 219–221° C., was obtained in 59% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([NH:14][CH3:15])=[O:13])=[C:7]([OH:16])[CH:6]=[CH:5]2.[CH3:17]OS(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([NH:14][CH3:15])=[O:13])=[C:7]([O:16][CH3:17])[CH:6]=[CH:5]2
Reactant: COS(=O)(=O)OC
Reactant: CNC(=O)c1c(O)ccc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(OC)ccc2cc(Br)ccc12
Temperature: 60 °C

Procedure:
A mixture of 6-Bromo-2-hydroxy-N-methyl-1-naphthamide (1.20 g), dimethylsulfate (0.49 mL), and powdered K2CO3 (1.18 g) in anhydrous DMF (10 mL) was heated at 60° C. for 30 min. After dilution with 1N HCl, the resulting mixture was extracted with Ethyl acetate. The combined organic layers were washed with water and brine followed by drying over MgSO4. After removal of the solvent in vacuo, the residue was washed with hexane-AcOEt (1:1) to give the title compound (1.21 g) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH2:25][O:26][CH2:27][CH2:28]O)[CH:3]=1.[C:30]([O:33][C@H:34]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C:38](=[O:44])[NH:37][C:35]1=[O:36])(=[O:32])[CH3:31]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH:3]=1)[CH2:25][O:26][CH2:27][CH2:28][N:37]1[C:38](=[O:44])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]([O:33][C:30](=[O:32])[CH3:31])[C:35]1=[O:36]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Reactant: CC(=O)O[C@@H]1C(=O)NC(=O)[C@@H]1OC(C)=O
Product: CC(=O)O[C@@H]1C(=O)N(CCOCc2cc(Br)ccc2Nc2ccc(C(=O)c3ccccc3C)c(Cl)c2)C(=O)[C@@H]1OC(C)=O

Procedure:
Compound 158 (67 mg, 0.1 mmol) and 2,3-cis-diacetoxysuccinimide (30 mg, 0.14 mmol) were treated as described in the preparation of compound 219. Purification was done by flash chromatography (CH2Cl2/ethyl acetate 1:20) to provide the title compound as yellow oil.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:19][CH:2]([F:1])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][N:20]=4)=[CH:31][N:30]=3)=[O:18])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)Cc1ccc(-c2ccnc(C(F)F)c2)cc1
Reactant: Nc1ccc(-c2cnccn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccnc(C(F)F)c2)cc1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetic acid 203-5 (70 mg, 0.27 mmol), 5-(pyrazin-2-yl)pyridin-2-amine (55 mg, 0.32 mmol), N,N-diisopropylethylamine (139 μL, 0.80 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (152 mg, 0.40 mmol) in DMF (2 mL) was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 203. MS m/z 418.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.99(d, 1H), 8.90(dd, 1H), 8.70(d, 1H), 8.63(dd, 1H), 8.53(d, 1H), 8.40-8.33(m, 2H), 8.30(s, 1H), 7.84(s, 1H), 7.70-7.68(m, 2H), 7.62-7.60(m, 1H), 7.50-7.49(m, 2H), 6.70(t, 1H), 3.87(s, 2H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6](=[O:12])[O:5][C:4]1=[O:13].I[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[O:13]=[C:4]1[N:3]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6](=[O:12])[O:5]1
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Reactant: CCOC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)oc(=O)c2sccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (851 mg, 60% dispersion in oil) in dry N,N-dimethylformamide (DMF) (15 ml) was cooled under argon in an ice bath. A solution of 1H-thieno[3,2-d][1,3]oxazine-2,4-dione (3 g) in DMF (10 ml) was added over ca 20 min. The reaction mixture was stirred for 30 min at room temperature, then recooled in an ice bath. Ethyl iodoacetate (4.55 g) was added and the mixture stirred at room temperature for ca 2 h. The solution was concentrated to about half volume and cooled in an ice bath. Water was added (ca 200 ml). After 10 min the precipitate was filtered off and washed with water and hexane and dried at 40° C. in vacuo overnight. The title compound was obtained as a white solid (3.62 g, 80%). 1H-NMR (CDCl3) δ 1.30 (3H, t), 4.28 (2H, q), 4.71 (2H, s), 6.77 (1H, d), 7.87 (1H, d). (APCI+) Found (M+1)=256, C10H9NO5S requires 255.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[N:19]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[C:13]1([S:10]([C:7]2[CH:6]=[C:3]3[C:2](=[CH:9][CH:8]=2)[NH:1][N:5]=[C:4]3[NH2:19])(=[O:12])=[O:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=N[O-]
Reactant: N#Cc1cc(S(=O)(=O)c2ccccc2)ccc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2ccc(S(=O)(=O)c3ccccc3)cc12
Temperature: 4 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
2-Amino-5-benzenesulfonyl-benzonitrile (0.81 g, 3.15 mmol) in 37% HCl (5 mL) was treated dropwise at 4° C. with NaNO2 (261 mg, 3.78 mmol) in 5 mL of water. After 1.75 hours the suspension was added dropwise to a solution of SnCl2 (4.88 g, 25.21 mmol) in 5 mL of 37% HCl. After stirring at 4° C. for 3 hours the solid was filtered, taken up with water (30 mL) and boiled for 1.5 hours. The hot mixture was filtered and washed thoroughly with boiling water. The filtrate was cooled to 4° C. and treated under stirring with 17% NaOH (approximately 5 mL) dropwise. After overnight cooling in a fridge the solid was filtered and washed with water to neutral pH affording 0.348 g of title compound (40% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=3)[S:10][C:3]=12.C(Cl)(=O)C(Cl)=O.[CH3:25][NH2:26]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([NH:26][CH3:25])=[O:18])[N:15]=3)[S:10][C:3]=12
Reactant: CN
Reactant: O=C(O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazole-4-carboxylic acid 43a (0.123 g, 0.41 mmole) in CH2Cl2 cooled at 0° C. was added 2.0 M oxalyl chloride in CH2Cl2 (0.520 ml, 1.04 mmole) and DMF (2 drops). The reaction mixture was stirred at room temperature for 1 h, concentrated and dried. The residue was taken into CH2Cl2 (10 ml), and 2.0 M methylamine in CH2Cl2 (0.250 ml, 0.492 mmole) was added. The reaction mixture was stirred at room temperature for 1 h, and then partitioned between H2O (100 ml) and CH2Cl2 (2×100 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 2–8% CH3OH in CH2Cl2 to give yellow solid (0.116 g, 91%). 1H NMR (300 MHz, CDCl3) δ 8.62 (1H, d, J=5.1 Hz), 8.19 (1H, s), 7.96 (1H, s), 7.33 (1H, d, J=5.1 Hz), 3.06 (3H, d, J=4.9 Hz); ESIMS (MH+): 309.95.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1)[CH3:9]
Reactant: CCN
Reactant: ClCc1cscn1
Solvent: C1CCOC1
Product: CCNCc1cscn1

Procedure:
prepared by reaction of the commercially available 4-chloromethyl-thiazole with 2M ethylamine in THF.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3nccs3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3nccs3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 20 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-thiazol-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (28 mg, 0.071 mmol), β-alanine (844 mg, 9.5 mmol) and NaOMe solution (14 mL, 7.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 6.4 mg of the title compound. MS: (+) m/z 451.18 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-:8].[O-:19][CH2:20][CH3:21].[Na+].[Na]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH3:21])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-:8]
Reactant: Cc1cccc(-c2cc([N+](=O)[O-])cc(C)[n+]2[O-])n1
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOc1cc(C)[n+]([O-])c(-c2cccc(C)n2)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
6,6'-Dimethyl-4-nitro-2,2'-bipyridine-N-oxide (17) (1.0 g, 4.1 mmoles) was added to sodium ethoxide solution made from (0.19 g, 0.0083 g-atoms) sodium and 25 ml ethanol. The mixture was stirred at 70° C. for 30 minutes. After neutralization with concentrated hydrochloric acid the reaction mixture was filtered and evaporated to dryness. The product was purified by means of flash chromatography (silica, 0%-50% methanol/chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:43])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:43][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C@@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8]
Reactant: O[C@H]1CCCCC[C@@H]1c1ccccc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Yield: 28.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 350 mg, 0.786 mmol), (1S*,2R*)-2-phenylcycloheptanol (150 mg, 0.788 mmol), sodium hydride (63%; 60 mg, 1.58 mol) and DMSO (4.0 mL), to yield the title compound (140 mg, 29%) as a colorless oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]1(B2OC(C)(C)C(C)(C)O2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1>>[NH2:30][C:29]1[S:28][C:27]([C:39]2=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: CC1(C)OB(C2=CCCCCC2)OC1(C)C
Product: Cn1ncc(NC(=O)c2nc(C3=CCCCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 28 %

Procedure:
Following the procedure for Example 337 starting with tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 1-cycloheptenylboronic acid pinacol ester gave 266 as a pale brown solid (25 mg, 28%). 1H NMR (400 MHz, d6-DMSO) δ 8.64 (s, 1H), 7.43 (s, 1H), 7.29 (s, 2H), 6.38 (t, J=6.7 Hz, 1H), 3.64 (s, 3H), 3.08-2.94 (m, 4H), 2.78 (d, J=8.2 Hz, 2H), 2.47 (d, J=6.2 Hz, 2H), 2.35-2.20 (m, 2H), 1.82-1.72 (m, 4H), 1.56-1.49 (m, 4H), 1.33-1.11 (m, 3H). LCMS (ES+) m/z 430 (M+1).
Reaction SMILES: Cl.[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=O>>[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][N:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:18][CH2:19]1
Reactant: O=C(C1CCc2ccccc2O1)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: c1ccc(CN2CCN(CC3CCc4ccccc4O3)CC2)cc1
Yield: 93 %

Procedure:
By carrying out the preparation in the same way as in Example 1, but starting with the hydrochloride of 1-[(chroman-2-yl)carbonyl]-4-benzylpiperazine obtained in Stage A, the title compound is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[CH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[H][H]>C(O)C.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(CCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1

Procedure:
A mixture of 0.75 g (2.07 mmol) of (4-(4-(2-quinolinylmethyloxy)styryl)benzonitrile and 0.08 g of 10% Pd on carbon in 75 ml of ethanol is shaken for 1.5 hours under 30 PSI of hydrogen. The mixture is filtered through a bed of celite and the filtrateconcentrated in vacuo. Trituration with ether gives a precipitate which is filtered off and recrystalized from methylene chloride-ether to give 4-(4-(2-quinolinylmethyloxy)phenethyl)benzonitrile. (M.P. 156° C.-158° C.)
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=O>O1CCOCC1>[Cl:1][CH2:2][C:3](=[O:4])/[CH:5]=[CH:26]/[C:25]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCl
Reactant: CCOC(=O)C=O
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/C(=O)CCl
Reaction time: 1.5 h
Yield: 47.8 %

Procedure:
The mixture of 1-chloro-3-(triphenylphosphoranylidene)acetone (6.6 g) and ethyl glyoxylate (50% in toluene, 4.6 g) in dioxane (66 mL) was stirred at 80′ for 1.5 hour. The solvent was removed by concentration. The residue was purified by column chromatography on silica gel using a mixture of chloroform and hexane (1:1 v/v) as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-5-chloro-4-oxo-2-pentenoate (1.58 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[NH:13]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: NN
Reactant: Clc1cnc2ccccc2n1
Solvent: O
Solvent: CCO
Product: NNc1cnc2ccccc2n1
Temperature: 0 °C

Procedure:
15.0 g (91.1 mmol) of 2-chloroquinoxaline are initially charged in 150 ml of ethanol. 45.6 g (911.3 mmol) of hydrazine hydrate are added, and the mixture is stirred under reflux for 16 h. The mixture is then cooled to 0° C., and the solid formed is filtered off, washed with ethanol and dried under high vacuum.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH:9][C:10](=O)OC(C)(C)C)=O.C(OC=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[N:9]1[C:4]2[C:3](=[CH:8][CH:7]=[N:6][CH:5]=2)[CH:1]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=1
Reactant: CCOC=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc2cnccc2c1

Procedure:
A mixture of tert-butyl 4-formylpyridin-3-ylcarbamate (1.7 g, 7.65 mmol), ethyl 3-ethoxyacrylate (1.27 g, 8.8 mmol) and TFA (5.9 mL, 76.5 mmol) in CHCl3 (30 mL) is heated at reflux for 4 hr. The mixture is cooled and the solvent is removed in vacuo. The residue is dissolved in EtOAc (30 mL) and washed with saturated NaHCO3 solution (20 mL). The organic layer is dried and evaporated. Purification of the residue with flash column with hexane/EtOAc (2:1) gives the title compound as a white solid. MS (M+1): 203.1.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[NH2:1][C:4]1[C:5]([N:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:12][CH2:13][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ncccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccnc1N(CCCN1C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
2-[3-[(3-Nitro-2-pyridinyl)phenylamino]propyl]-1H-isoindole-1,3(2H)dione is reduced with hydrogen and palladium-on-carbon catalyst in ethanol-ethyl acetate mixtures to give the title compound.