Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]4=[N:14][N:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:23][S:24]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]4=[N:14][N:13]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:3][CH2:2]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: C1CCCn2c(nnc2C2(C3CCNCC3)CCCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(C2(c3nnc4n3CCCCCC4)CCCC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(1-Piperidin-4-ylcyclopentyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (302 mg) was dissolved in methylene chloride (5 ml) and then methanesulfonyl chloride (0.09 ml) and pyridine (0.24 ml) were added thereto, followed by stirring at room temperature for 6 hours. Furthermore, methanesulfonyl chloride (0.09 ml) and pyridine (0.57 ml) were added thereto, followed by stirring at room temperature for 16 hours. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=1:9) and then the resulting solid washed with ethyl acetate to obtain 117 mg of 3-{1-[1-(methylsulfonyl)-4-piperidinyl]cyclopentyl}-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (white solid).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:15])[C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCc1nc2ccc(Cl)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2ccc(Cl)nc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 3.00 g of 5-chloro-2-hydroxymethyl-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 43), 0.71 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 1.1 ml of methyl iodide and 70 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 1.60 g of the title compound, melting at 204°-210° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=O)=[CH:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:4]5[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[CH:3]=5)=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1cn(C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cn(C)cc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 28.5 %

Procedure:
In the same manner as in Example 18-4 and using 1,4-dimethyl-1H-pyrrole-3-carboxylic acid (270 mg, 1.94 mmol), tetrahydrofuran (7 mL), oxalyl chloride (203 μL, 2.32 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (79.2 mg, 28%) was obtained as a white solid.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH:18]=[CH2:19].[C:21](#[N:25])[CH2:22][C:23]#[N:24]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:17]([N:20]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:22]([C:23]#[N:24])=[C:21]1[NH2:25])[CH:18]=[CH2:19]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: C=CCN
Reactant: N#CCC#N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCn1c(N)c(C#N)c(-c2ccccc2)c1-c1ccccc1

Procedure:
A solution of benzoin (6.81 g, 32.1 mmol), allylamine (2 g, 35 mmol) and p-toulenesulfonic acid monohydrate (20 mg, cat.) in toluene (100 mL) was heated to 80° C. for 5 minutes. Malononitrile (2.12 g, 32.1 mmol) was then added and the reaction mixture was heated to reflux for 3 hours using a reflux condenser fitted with a Dean-Stark trap. The solution was then cooled, diluted with ethyl acetate (100 mL), extracted with sodium bicarbonate (conc., aq., 50 mL), hydrochloric acid (0.5 N, aq., 50 mL) and water (50 mL), dried, filtered and the filtrate was concentrated under reduced pressure. Chromatography (SiO2, ethyl acetate:hexane 1:2) afforded the title compound as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH2:24][O:25][CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:27]([C:31]1[N:32]=[N:33][C:34]([C:37]([O:39][CH3:40])=[O:38])=NN=1)([O:29][CH3:30])=[O:28].N1C=NN=CN=1.CCOC(C)=O.C(Cl)Cl>C1(C)C=C(C)C=C(C)C=1>[CH3:22][O:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:13]([C:12]2[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:31]([C:27]([O:29][CH3:30])=[O:28])[N:32]=[N:33][C:34]=2[C:37]([O:39][CH3:40])=[O:38])=[C:14]([O:23][CH2:24][O:25][CH3:26])[CH:15]=1
Reactant: COC(=O)c1nnc(C(=O)OC)nn1
Reactant: COCOc1cc(OC)c(OC)cc1C#Cc1ccc(OC)c(OC)c1
Agent: c1nncnn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)cc(C)c1
Product: COCOc1cc(OC)c(OC)cc1-c1c(C(=O)OC)nnc(C(=O)OC)c1-c1ccc(OC)c(OC)c1
Temperature: 140 °C
Yield: 91.8 %

Procedure:
A solution of 6 (1.10 g, 3.07 mmol, 1.0 equiv) and 3,6-dicarbomethoxy-1,2,4,5-tetrazine (2,13 0.91 g, 4.60 mmol, 1.5 equiv) in mesitylene (15.4 mL) was warmed at 140° C. under Ar for 24 h. Additional 2 (0.91 g, 4.60 mmol, 1.5 equiv) was added, and the mixture was maintained at 140° C. for an additional 24 h before the reaction mixture was cooled to 25° C. and the solvent was evaporated. Chromatography (SiO2, 4.5 (20 cm, 30% EtOAc/CH2Cl2) provided 7 (1.49 g, 92% yield) as an orange oil. An analytically pure sample was prepared by recrystallization from EtOAc-hexanes: mp 131-133° C.; FABHRMS (NBA/NaI) m/z 551.1663 (M+Na+, C26H28N2O10 requires 551.1642).
Reaction SMILES: [C:1]([C@@:3]1([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:33][C@H:7]([CH:8]([C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[OH:9])[C@@H:5]([OH:6])[CH2:4]1)#[N:2].[C:43]([Si:47]([CH3:50])([CH3:49])Cl)([CH3:46])([CH3:45])[CH3:44].N1C=CN=C1>N1C=CC=CC=1>[C:1]([C@@:3]1([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:33][C@H:7]([CH:8]([C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[OH:9])[C@@:5]([Si:47]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:50])[CH3:49])([OH:6])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2O[C@@](C#N)(n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2O[C@@](C#N)(n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1'-Cyano-5'-(4,4'-dimethoxytrityl)thymidine in anhydrous pyridine is added to a stirred solution of t-butyldimethylchlorosilane (1.5 equivalents) and imidazole (3.0 equivalents) in anhydrous pyridine at 0° C. The resulting reaction mixture is stirred at room temperature overnight. Pyridine is evaporated and the residue dissolved in ethyl acetate, washed with brine. The crude product is directly used for the next reaction.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([CH2:17]Br)[C:13]=2[CH:19]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[C:13]=2[CH:19]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc2onc(CBr)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc2onc(Cn3ccnc3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 276.6 g, 6.92 moles) is added in portions to a solution of imidazole (471 g, 6.92 moles) in dimethylformamide (4 L) over a period of 1 hour. After the addition is complete, the resulting suspension is stirred for 1 hour at ambient temperature. A solution of 5-chloro-3-bromomethyl-1,2-benzisoxazole (1.57 kg, 6.37 moles) in dimethylformamide (3 L) is then added over a period of 30 minutes, during which time there is an exotherm from 24° C. to 68° C. On completion of this addition, the reaction mixture is stirred and heated at 90° C. for 2 hours. The solvent is then removed in vacuo and the residue is taken up in methylene chloride (4 L). The resulting suspension is washed with water (2×2 L), which dissolves the solid material, and the organic solution is then dried over anhydrous sodium sulfate (1 kg), filtered and evaporated to give 5-chloro-3-[(1H-imidazol-1-yl)methyl]-1,2-benzisoxazole, m.p. 100-102° C.; hydrochloride salt, m.p. 201-203° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][C:13]([OH:15])=O.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C=O)C.C(Cl)Cl>[F:7][C:8]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:9]=1[O:10][CH2:11][CH2:12][C:13]2=[O:15]
Reactant: O=C(O)CCOc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCOc2c(F)cccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Oxalyl chloride (8.79 mL) and 1 drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0° C. for 2 hours, then aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, then dried, evaporated, and purified by column chromatography (eluting with 20% EtOAc/Hex) to give of the title compound (8.20 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:34][CH3:35])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13](COCC[Si](C)(C)C)[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([Cl:33])[CH:27]=1)[N:5]=2.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:3]([CH2:34][CH3:35])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([Cl:33])[CH:27]=1)[N:5]=2
Reactant: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(-c3ccc(O)c(Cl)c3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(N)c(-c2ncc[nH]2)c(=O)c2ccc(-c3ccc(O)c(Cl)c3)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.5 %

Procedure:
400 mg (0.59 mmol) of impure 2-amino-7-(3-chloro-4-hydroxy-phenyl)-1-ethyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-[1,8]naphthyridin-4-one was dissolved in 20 ml DCM. At 0° C., 3.39 g of TFA were added and the mixture was stirred at room temperature for 24 hours. The solution is neutralized by adding an excess of aqueous NaHCO3 solution. The mixture was then extracted three times with DCM. The combined organic phases were dried over MgSO4 and the solvents were evaporated off under reduced pressure. The so-gained raw material was purified on silica gel (DCM:MeOH:NH4OH=4:10.1) yielding 0.035 g of the unprotected title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:21]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:19](=[O:20])[C:18]2[N:16]([CH3:17])[CH:15]=[N:14][C:13]=2[N:11]([CH3:12])[C:9]1=[O:10].[BrH:23].O.C(=O)(O)[O-].[Na+].[C:30]([OH:33])(=O)[CH3:31]>>[C:30]([O:1][CH:2]([CH2:21][Br:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:19](=[O:20])[C:18]2[N:16]([CH3:17])[CH:15]=[N:14][C:13]=2[N:11]([CH3:12])[C:9]1=[O:10])(=[O:33])[CH3:31]
Reactant: Br
Reactant: CC(=O)O
Reactant: Cn1cnc2c1c(=O)n(CCCCCC(O)CO)c(=O)n2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(CBr)CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
1-(6,7-Dihydroxyheptyl)-theobromine (4.00 g, 12.9 mmol) was stirred with hydrogen bromide (12.53 g of a 30% solution in acetic acid, 38.7 mmol) for 2 hours. The mixture was then added over 10 minutes to water (50 mL), ice (50 g) and sodium bicarbonate (30 g) and stirred for 30 minutes. The reaction mixture was extracted with dichloromethane (3×100 mL). A combined organic phase was dried over magnesium sulfate and the solvent was evaporated to obtain a residue (4.90 g, 91% yield) of 1-(6-acetoxy-7-bromoheptyl)-3,7-dimethylxanthine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:15]=[C:14]([C:16]([O:18]CCCC)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>O1CCOCC1>[CH2:1]([O:5][C:6]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1cc(OCCCC)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCOc1cc(C(=O)O)c2ccccc2n1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of 2.67 g (8.86 mmols) of Compound b, 1.77 g of sodium hydroxide, 60 ml of water and 60 ml of dioxane was stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform/methanol=5/1) to give 1.91 g (yield 90%) of Compound a.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:19]=[CH:18][O:17][C:16]=1[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.[Cu]>[C:27]1([NH:33][C:34]([O:1][CH:2]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1ccoc1[Si](CC)(CC)CC
Agent: [Cu]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(OC(=O)Nc1ccccc1)c1ccoc1[Si](CC)(CC)CC

Procedure:
3-(1-Hydroxytridecyl)-2-triethylsilylfuran (Compound 20) is reacted with phenyl isocyanate and copper (2) chloride in dimethylformamide to give 3-(1-phenylcarbamoyloxytridecyl)-2-triethylsilylfuran (Compound 21). Oxidizing the intermediate with singlet oxygen, under similar conditions as in Example 1, and thereafter reduction with sodium borohydride gives 3-(1-phenylcarbamoyloxytridecyl)-2(5H)-furanone (Compound 8).
Reaction SMILES: [I:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.Br[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:4]2[C:5]([CH3:7])=[CH:6][C:2]([I:1])=[N:3]2)=[CH:12][CH:13]=1
Reactant: Cc1cc(I)n[nH]1
Reactant: Fc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(I)nn1CCc1ccc(F)cc1
Temperature: 95 °C

Procedure:
A solution of 3-iodo-5-methyl-1H-pyrazole (1.45 g, 6.97 mmol) in dimethyl sulfoxide (10 mL) was treated with 1-(2-bromo-ethyl)-4-fluoro-benzene (1.41 g, 6.97 mmol) and potassium carbonate (2.89 g, 20.91 mmol), and the reaction mixture was heated to 95° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (hexanes:ethyl acetate, 1:1) to provide 1-[2-(4-fluoro-phenyl)-ethyl]-3-iodo-5-methyl-1H-pyrazole as a yellow oil. MS (M+H)+=331.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][NH2:20].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:20][O:19][CH3:18])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 21 mmol) and O-methylhydroxylamine hydrochloride (2.7 g, 32.8 mmol) in chloroform (100 ml) containing triethyl-amine (5.5 g, 55 mmol). The reaction mixture was then stirred at ambient temperature over-night, prior to removal of solvent. The resultant crude reaction mixture was dissolved in ethyl acetate (150 ml) and washed rapidly with 1N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.3 g, 94%) was isolated as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2O)=[CH:7][C:6]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:26].[CH3:31][NH:32][CH3:33]>ClCCl.C(OCC)C.ClCCl>[ClH:26].[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[N:32]([CH3:33])[CH3:31])=[CH:7][C:6]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CNC
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)C(O)CC2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C)C1CCc2cc(NS(C)(=O)=O)c(Oc3ccc(F)cc3F)cc21
Product: Cl
Reaction time: 2 h
Yield: 72 %

Procedure:
2.84 g of N-[6-(2,4-difluorophenoxy)-1-hydroxy-5-indanyl]methanesulfonamide and 1.83 g of phosphorus pentachloride are stirred in 50 ml of dichloromethane-diethyl ether (1:1) for 45 minutes at 0° C. At 0° C., a solution of 7 g of dimethylamine in 25 ml of dichloromethane is added to the reaction mixture. After 2 hours at 20° C. and 20 minutes of boiling, the mixture is concentrated and the residue is recrystallized from aqueous hydrochloric acid, yielding 2.41 g of N-[6-(2,4-difluorophenoxy)-1-dimethylamino-5-indanyl]methanesulfonamide, hydrochloride, mp 195° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[F:15][C:16]([F:20])([F:19])[CH2:17][NH2:18].C(N(CC)C(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[N+:8]([C:7]1[C:2]([NH:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: NCC(F)(F)F
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 79.4 %

Procedure:
A mixture of 2-chloro-3-nitro-5-trifluoromethylpyridine (2.60 g), 2,2,2-trifluoroethylamine (0.79 g), N,N-diisopropylethylamine (1.04 g) and N-methyl-2-pyrrolidone (5 ml) was stirred at room temperature for 10 hours. To the reaction mixture was poured aqueous 10% citric acid solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give (3-nitro-5-trifluoromethylpyridin-2-yl)-(2,2,2-trifluoroethyl)amine (1.83 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH:22][CH2:23][CH3:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]([CH2:23][CH3:24])[CH3:21])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CCNC
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCN(C)C(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
The compound from Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of N-methylethanamine (379 mg, 6.41 mmol) in CH2Cl2. Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 50% EtOAc/hexane giving a yellow oil (1.03 g, 100%).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH2:17][CH:18]([CH3:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH:18]([CH3:28])[CH2:17][O:16][CH2:14][CH3:15])=[CH:27][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CCOCC(C)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCC(C)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 3 h
Yield: 38.5 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 2.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 3.0 g of 4-(2-ethoxy-1-methylethoxy)-benzyl bromide, and then 1.9 g of anhydrous potassium carbonate was added thereto. The mixture was heated under stirring on an oil bath at 80° to 90° C. for 3 hours. Then, procedures similar to those in Preparation Example 2 were carried out to obtain 1.5 g of the aimed product, m.p. 72.3°~73.1° C.
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:24][NH:25][CH3:26]>CS(C)=O.O>[CH3:24][N:25]([CH3:26])[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Reactant: CNC
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1N(C)C
Temperature: 60 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
A solution of rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 32.0 mg, 0.103 mmol) and dimethylamine (2.0M in THF; 0.155 mL, 0.309 mmol) in DMSO (0.8 mL) was stirred under argon in a sealed microwave flask at 25° C. for 10 min, then at 60° C. for 18 h. Additional dimethylamine (2.0M in THF; 0.155 mL, 0.309 mmol) was added, and the resulting mixture was stirred under argon in a sealed microwave flask at 60° C. for 4.5 h. The reaction was cooled to 25° C. and diluted with water (10 mL). The precipitated solid was collected by vacuum filtration, washed with water (2×5 mL), and dried in vacuo to provide rac-2-(3-(dimethylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (22.7 mg, 0.068 mmol, 66% yield) as a yellow-orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, br. s.), 7.96 (1H, dd, J=7.5, 1.1 Hz), 7.66 (1H, dd, J=8.1, 0.9 Hz), 7.47 (1H, t, J=7.8 Hz), 7.08 (1H, d, J=2.2 Hz), 6.99 (1H, br. s.), 3.40-3.49 (1H, m), 3.13-3.15 (6H, m), 3.06-3.18 (2H, m), 2.71 (3H, s), 1.30 (3H, d, J=6.5 Hz). m/z (ESI, +ve) 336.2 (M+H)+.