Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:32][OH:33].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:33][NH:32][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.2 %

Procedure:
To a solution of compound 12j (125 mg, 0.281 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (194 mg, 2.80 mmol) and a freshly prepared solution of sodium methoxide in methanol (96 mg, 4.20 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13j (9 mg, yield 7.2%). HPLC: 97.51% (Rt=14.61 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([C:7]1[C:8](=[O:15])[NH:9][C:10]([CH2:13][CH3:14])=[CH:11][CH:12]=1)=[O:6].C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClC(Cl)C.CN(C)C1C=CN=CC=1>[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([O:15][C:8]2[C:7]([C:5](=[O:6])[C:4]3[CH:16]=[CH:17][CH:18]=[C:2]([Cl:1])[CH:3]=3)=[CH:12][CH:11]=[C:10]([CH2:13][CH3:14])[N:9]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ccc(C(=O)c2cccc(Cl)c2)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCc1ccc(C(=O)c2cccc(Cl)c2)c(OS(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
3-(3-Chlorobenzoyl)-6-ethyl-2-pyridone (95.8 g, 366 mmol) was dissolved in 1,000 ml of dichloroethane, 56.4 ml (403 mmol) of triethylamine, 4.52 g (366 mmol) of 4-dimethylaminopyridine and 76.7 g (403 mmol) of p-toluenesulfonyl chloride were added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was washed with water, 1 N hydrochloric acid-brine and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration and then the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was recrystallized from ethyl acetate-hexane to give 139.90 g of 3-(3-chlorobenzoyl)-6-ethyl-2-pyridyl p-toluenesulfonate in the form of crystals. The yield was 91.9%.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].CC(O)C.[Br:11][C:12]1[CH:13]=[C:14]([Cl:19])[C:15](Cl)=[N:16][CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([Cl:19])[C:15]([O:4][CH:2]([CH3:3])[CH3:1])=[N:16][CH:17]=1
Reactant: CC(C)(C)[O-]
Reactant: Clc1cc(Br)cnc1Cl
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)Oc1ncc(Br)cc1Cl
Temperature: 95 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
Potassium tert-butoxide (25.7 g, 229 mmol) was added to 2-propanol (100 mL, 57.3 mmol) and the solution was stirred at 95° C. for 3 h, then 5-bromo-2,3-dichloropyridine (13 g, 57.3 mmol) was added. This reaction was refluxed overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with water and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude product 5-bromo-3-chloro-2-[(1-methylethyl)oxy]pyridine (D107) (14.5 g), which was used directly without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([Cl:21])=[O:12])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c[nH]c2ccccc12
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
Next, a solution of indole-3-carbonyl chloride was prepared. A well-stirred suspension of indole-3-carboxylic acid (67.7 mg, 0.42 mmol) in dry DCM (2 ml) containing a small amount of dimethylformamide (DMF) (20 μL) was treated with oxalyl chloride (0.84 mmol, 107 mg, 72 μL) at 0° C. Following addition to the oxalyl chloride, the mixture was stirred for 20 minutes at 23° C., producing a clear, slightly yellow solution. This solution was evaporated to dryness in vacuo at 0.1 Torr to ensure removal of excess oxalyl chloride, and was subsequently re-dissolved in 2 ml of dry DCM.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=[CH:15][CH:16]=3)[NH:11][C:10](=[O:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>O>[O:22]=[C:10]1[CH2:9][CH:8]([C:4]2[CH:3]=[C:2]([NH:1][C:23](=[O:25])[CH3:24])[CH:7]=[CH:6][CH:5]=2)[C:17]2[C:12](=[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]3=[CH:15][CH:16]=2)[NH:11]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(3-Amino-phenyl)-3,4-dihydro-1H-benzo[h]quinolin-2-one (0.25 g, 0.87 mmol), acetic anhydride (1 ml) and anhydrous pyridine (1 ml) was stirred at ambient temperature overnight. Water was added and the precipitate was separated by filtration. Crystallization from methanol-acetonitrile afforded the title compound (0.06 g, 0.18 mmol).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:27]=[N:26][C:8]2[N:9]([CH3:25])[C:10](=[O:24])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12](=[O:13])[C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[CH:39][CH:38]=1>C1COCC1>[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]([OH:42])[C:6]2[C:7]3[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:10](=[O:24])[N:9]([CH3:25])[C:8]=3[N:26]=[CH:27][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[CH:39][CH:38]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)Oc1cnc2c(c1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1cnc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (87 mg, 0.23 mmol) in THF (5 mL) cooled to −78° C. was added LDA (2.0 M in THF, 0.6 mL, 1.15 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-chlorobenzaldehyde (64.8 mg, 0.46 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h, quenched with aq. NH4Cl (5 mL), diluted with water (25 mL) then extracted with EA (3×25 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:2) to give 5-((4-chlorophenyl)(hydroxy)methyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (64 mg, 53.6% yield) as a white solid. LCMS: [M+-THP-OH] 416 and TR=3.210 min. Used without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([O:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][CH2:55]O)=[CH:50][CH:49]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH2:40]([O:47][C:48]1[CH:49]=[CH:50][C:51]([CH2:54][CH2:55][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][C:4]3[C:5]4[C:10](=[N:9][CH:8]=[CH:7][N:6]=4)[N:1]=[CH:2][N:3]=3)=[CH:15][CH:16]=2)=[CH:52][CH:53]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(CCOc3ccc(CCNc4ncnc5nccnc45)cc3)cc2)cc1
Reaction time: 18 h
Yield: 7.3 %

Procedure:
4-[2-(Pteridin-4-ylamino)-ethyl]-phenol (300 mg, 10.1 mmol), triphenylphosphine (790 mg, 3.0 mmol) and 2-(4-benzyloxyphenyl)ethanol (700 mg, 3.0 mmol) were combined in 10 mL anh. dioxane, treated with diisopropylazodicarboxylate (590 μL, 610 mg, 3.0 mmol) and stirred for 18 h. The volatiles were removed in vacuo and the residue was chromatographed on SiO2 with EtOAc (10% to 40%) in CH2Cl2 to obtain (2-{4-[2-(4-benzyloxyphenyl)-ethoxy]-phenyl}-ethyl)-pteridin-4-ylamine (105 mg; 20%) as a white solid: mp 120-122° C.; ESIMS m/z 478 ([M+H]+); 1H NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 6.8-7.5 (m, 13H), 4.1 (m, 2H), 3.90 (m, 2H), 3.01 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)OCCCOc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCOc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 17.1 g. of ethyl p-aminobenzoate, 14.6 g. of 3-(4-chlorophenoxy)-1-propanol O-methanesulfonate and 100 ml. of hexamethylphosphoramide is heated at 110°-115° C. for 16 hours. The solution is diluted with 100 ml. of water, allowed to cool and is filtered to give 12.5 g. of solid. Recrystallization from cyclohexane gives 7.8 g. of yellow needles. Chromatography over silica gel gives 6.8 g. of product as white crystals, m.p. 87°-88° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCOC(C)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:7]([S:9]([N:25]2[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: Cc1ccc(C)c(Oc2ccc(C#N)cc2S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(Oc2ccc(C#N)cc2S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 42 %

Procedure:
A solution of sulfonyl chloride 32 (0.160 g, 0.50 mmol), tert-butyl piperazine-1-carboxylate (0.121 g, 0.65 mmol), and TEA (0.066 g, 0.65 mmol) in DCM (5 mL) was stirred overnight at room temperature. The reaction was monitored with TLC (25% EtOAc in hexanes). The reaction mixture was concentrated in vacuo and the residual was redissolved with a minimal amount of DCM and chromatographed on normal-phase silica to produce compound 33 as a white powder (0.099 g, 42.0% yield, 100.0% pure). 1H NMR (500 MHz, DMSO-d6): δ 8.24 (d, J=2 Hz, 1H), 8.00 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 6.98 (s, 1H), 6.78 (d, J=8 Hz, 1H), 3.39 (m, 4H), 3.22 (m, 4H), 2.29 (s, 3H), 2.07 (s, 3H), 1.37 (s, 9H); MS (ESI, EI+): m/z=372 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][N+:6]([O-:8])=[O:7].[CH3:13][N:14]([CH3:18])[C:15](=[S:17])[S-:16].C[NH2+]C>C(=S)=S>[CH3:13][N:14]([CH3:18])[C:15](=[S:16])[S:17][CH:4]([CH2:5][N+:6]([O-:8])=[O:7])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1ccccc1Cl
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccccc1Cl

Procedure:
As in Example 17, reaction of o-chloro-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave o-chloro-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 102° - 103.5° C. when recrystallized without heating from acetone-methanol solution.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:36](=[O:45])[C:37]2=[CH:44][CH:43]=[CH:42][CH:41]=[C:38]2[C:39]1=[O:40])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(Br)CCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 25.8 %

Procedure:
In 100 ml of acetonitrile are dissolved 2.8 g of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate and 7.6 g of ethyl 2-bromo-8-phthalimidooctanoate, and 1.3 g of triethylamine is added to the solution. After heating at 80° C. for 3 days, the reaction solution is concentrated under reduced pressure, diluted with 200 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (10 ml) and oxalic acid (2.8 g) are added to the residue, and 200 ml of petroleum ether is added to the solution. After shaking, the resulting solution is allowed to stand. The supernatant is removed by decantation and 150 ml of water and 200 ml of ethyl acetate are added to the precipitate. The mixture is neutralized with sodium bicarbonate and the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily product is separated and purified by silica gel column chromatography to give 1.5 g of tert-butyl 3(S)-[1(R)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate from the first fraction.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[S:14][CH:15]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:32][C:33]2([CH3:37])[CH2:36][O:35][CH2:34]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:32][C:33]1([CH2:37][N:10]2[C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:8]([C:11]3[CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[S:14][CH:15]=3)=[N:9]2)[CH2:36][O:35][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Reactant: NC(=O)c1cc(-c2n[nH]c3cc[nH]c(=O)c23)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(Cn2nc(-c3csc(C(N)=O)c3)c3c(=O)[nH]ccc32)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (60.0 mg) in DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 23.0 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (148 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (2.3 mg).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Reactant: NNc1cccc(F)c1
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1cccc(F)c1
Yield: 62 %

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and (3-fluoro-phenyl)-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for Example 91 in 62% yield. MS: M=399.1 (M+H)+
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)=[CH2:12]>N1C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:11]=[CH2:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)nc1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=Cc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 5-isopropylpyridin-2-amine (400 mg, 2.94 mmol) in pyridine (5 mL), stirred at room temperature, was added 4-vinylbenzene-1-sulfonyl chloride (760 mg, 3.75 mmol). The reaction mixture was stirred for 30 minutes then stood overnight. The solvent was evaporated in vacuo and the crude sample purified by normal phase chromatography on silica (Si) (0-50% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title product, 670 mg, as an off-white solid. LCMS (2 min, formic) Rt 0.98 min, m/z (ES+) 303 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[C:21]2[C:12](=[CH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)[CH:11]=[CH:10][CH:9]=1)=[O:7].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>O1CCCC1>[CH2:29]([N:31]([CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[C:21]2[C:12](=[CH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:30]
Reactant: CCNCC
Reactant: O=C(CCCCCl)c1cccc2cc3c(C(=O)CCCCCl)cccc3cc12
Solvent: C1CCOC1
Product: CCN(CC)CCCCC(=O)c1cccc2cc3c(C(=O)CCCCN(CC)CC)cccc3cc12
Temperature: 110 °C

Procedure:
In each of four Carius tubes is placed 10 g of 1,5-bis(5-chlorovaleryl)anthracene (0.024 mole), 80 ml of diethylamine and 40 ml of tetrahydrofuran. The tubes are heated to 110° C. for 30 hours, cooled and their contents combined. The volatile components are evaporated in vacuo and the residue is slurried with 400 ml of chloroform. The organic phase is extracted twice with 100 ml portions of water, and two additional times with 100 ml portions of 10% HCl solution. The combined acid extracts are neutrallized using a cold 50% sodium hydroxide solution and reextracted with two 100 ml portions of chloroform. The combined chloroform extracts are dried over magnesium sulfate, filtered, evaporated to dryness and the residue is crystallized from n-heptane to give 36 g of 1,5-bis(5-diethylaminovaleryl)anthracene having a m.p. of 65°-7° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:28][CH2:27][C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:12][CH2:13][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]3)[CH2:27][CH2:28]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (495.9 mg, 2.7 mmol) in ethanol (20 mL) were added tert-butyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate (1.08 g, 4.0 mmol) and Et3N (413.6 mg, 4.1 mmol). The mixture was stirred at room temperature for 12 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/7) to give the product as a light yellow solid (387.1 mg, 34.5%).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[CH2:10][C:11](OCC)=[O:12].Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[O:2]1[C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4][CH2:10][C:11]1=[O:12]
Reactant: Oc1ccccc1O
Reactant: CCOC(=O)CCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Product: O=C1COc2ccccc2O1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a stirred solution of 120 grams of catechol and 10 grams of Aliquat® 336 (brand of tricaprylmethylammonium chloride, of General Mills Chemical Company of Minneapolis, Minnesota) at 80° C. is added ethyl chloroacetate (87 grams, 1 mole) over a one hour period. The reaction mass is stirred for one hour and then cooled. 1000 ml of dilute (5%) hydrochloric acid is added with stirring. The aqueous layer is discarded. The organic layer is washed twice with a minimum amount of water. The toluene is distilled off under reduced pressure to afford 119 grams of crude product. Recrystallization from ethanol afforded 92 grams of 1,4-benzodioxan-2-one.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+]>C(O)CCCCC>[ClH:1].[NH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[O:11]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCO
Product: NC1CCCCNC1=O
Yield: 74.9 %

Procedure:
A stirred mixture of L-lysine hydrochloride 1 (55 g, 300 mmol) and NaOH (12 g, 300 mmol) in hexanol (1.2 L) is heated to reflux with a Dean-Stark trap used to remove H2O. The suspension is refluxed for 8 hours until all starting material is consumed (which maybe determined by 1H NMR). The suspension is then cooled and filtered to remove byproduct NaCl. The filtrate is concentrated and the resulting crude α-amino-ε-caprolactam 2 is dissolved in water. After acidification to pH 6 with addition of concentrated HCl and partial concentration, crystals maybe formed at room temperature to afford α-amino-ε-caprolactam hydrochloride (37 g) in 75% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1COCCC)[C:7]([O-:9])=[O:8])([O-:3])=[O:2].[Li+].[OH-].[CH2:20]1C[O:23][CH2:22][CH2:21]1>CCO.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:23][CH2:22][CH2:21][CH3:20])[C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: CCCOCc1ccc(C(=O)[O-])cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a stirred solution of 3-nitro-4-propoxymethylbenzoate (0.35 g, 1.46 mmol) in a mixture of THF and EtOH (3 ml:1 ml) the solution of LiOH (0.345 g; 15 mmol) in H2O (1 ml) was added and the mixture was stirred for 4 h at room temperature. The solvent was distilled off and the residue was treated with 1 M HCl and extracted with EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.32 g, 97%), as creamy solid. 1H NMR (CDCl3) 8.53 (d, 1H, J=1.65 Hz); 8.21 (dd, 1H, J=8.79, 1.62 Hz); 7.12 (d, 1H, J=8.82 Hz); 4.14 (t, 2H, J=6.39 Hz); 1.94-1.82 (m, 2H); 1.07 (t, 3H, J=7.35 Hz).