Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])C.C([O-])(=O)C.[NH4+:17].C(OCC)(=O)C.O>C(N(CC)CC)C>[N+:10]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[NH2:17])([O-:12])=[O:11]
Reactant: [NH4+]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccncc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 74.9 %

Procedure:
A 25 ml round bottom flask was fitted with a reflux condenser and magnetic stirrer and placed in an oil bath. The flask was charged with 1.0 g (5.95 mmol) of 4-ethoxy-3-nitropyridine and 5.0 g (65 mmol) of ammonium acetate. The reaction mixture was heated at 120° C. to provide a homogeneous liquid. The progress of the reaction was followed by thin layer chromotography employing a 10:1 ethyl acetate:triethylamine solvent system. After 21/2 hours the reaction mixture was cooled and poured into water. The yellow precipitate was collected by filtration, washed with water and dried in vacuo at 60° C. over phosphorus pentoxide. A total of 620 mg of 3-nitro-4-aminopyridine was obtained and chromatographically verified by comparison to an authentic reference standard. Yield 75%.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=O.C([O:33]CC)C>>[C:27]1([CH3:30])[CH:28]=[CH:29][C:24]([O:23][CH:20]2[CH2:21][CH2:22][N:17]([CH:15]([NH:1][C:2]3[CH:12]=[CH:11][C:5]4[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=4[CH:3]=3)[CH:14]=[O:33])[CH2:18][CH2:19]2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(OC2CCN(C(=O)CCl)CC2)cc1
Reactant: CCOCC
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Product: Cc1ccc(OC2CCN(C(C=O)Nc3ccc4c(c3)OCC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from 7-amino-4H-benzo[1,4]oxazin-3-one and 2-chloro-1-(4-p-tolyloxy-piperidin-1-yl) ethanone (Example 208a) according to the method described in Example 206. Melting Point: 223-224° C. (diethylether)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8].C(O)(=O)C.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C.[Zn]>[Br:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CNc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-bromo-N-methyl-2-nitroaniline (1-1) (12.4 g, 53.7 mmol) in 1,4 Dioxane (100 mL) at 0° C. was added powdered zinc (17.6 g, 269 mmol), followed by dropwise addition of glacial acetic acid (15.0 mL, 262 mmol). The reaction mixture was then permitted to warm to room temperature, sonicated for a few minutes, then permitted to stir at room temperature overnight, then heated to 90° C. in a hot oil bath for four hours. The crude reaction mixture was then cooled to room temperature, then suspended in ethyl acetate, cooled to 0° C. and neutralized with 6N NaOH while stirring until slightly basic. Crude mixture was then filtered. Filtrate organics were separated, then washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated to give 4-bromo-N2-methylbenzene-1,2-diamine (1-2) as a black oil. MS (M)+: observed=200.9, calculated=201.06.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:50][C@H:51]([C:61]([O:63][CH3:64])=[O:62])[CH2:52][CH2:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57].Cl>CN(C=O)C.C(Cl)CCl>[CH3:64][O:63][C:61](=[O:62])[C@@H:51]([NH:50][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)=[O:30])[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=1)=[O:28])[CH2:52][CH2:53][C:54]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:60]
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
To a solution of 1.1 g 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 20 ml DMF were added 1 ml DIPEA, 0.41 g HOBt, 0.51 g EDC and 0.68 g H-Glu(OtBu)-OMe hydrochloride. After stirring for 24 h the solution was concentrated, taken up with dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product was purified by flash chromatography on silica using an ethyl acetate/heptane 50:50 to 100:0 gradient.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1>C(OCC)(=O)C.[Pd]>[NH2:21][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc([N+](=O)[O-])cc2F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N)cc2F)C1

Procedure:
3-Fluoro-4-(3(S)-(t-butoxycarbonyl)aminopyrrolidin-1-yl)nitrobenzene (33.5 g, 0.103 M) was dissolved in ethyl acetate (500 ml) treated with palladium catalyst (10% on carbon, 5 g) and hydrogenated at atmospheric pressure until the theoretical uptake of gas. After filtration through celite and evaporation, the required product was obtained as a red gum of sufficient quality for use without purification (30.4 g).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[S:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:21][C:20]3=[O:33])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.C[OH:35].C(Cl)Cl>CO.O>[O:35]=[S:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[O:21][C:20]3=[O:33])=[CH:17][CH:18]=2)[CH2:9][CH2:8]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3CCSCC3)cc2)C(=O)O1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3CCS(=O)CC3)cc2)C(=O)O1
Temperature: 4 °C
Reaction time: 20 h

Procedure:
Sodium periodate (1.7 g, 8.0 mmol) is added to a suspension of the product from Step 3 (3.0 g, 7.6 mmol) in 125 mL of 2:1 methanol:H2O. The mixture is stirred for 20 h at 4° C. in a cold room and then filtered to remove solids. The solids are washed with CHCl3 and the combined filtrate concentrated to give an aqueous solution that is diluted with H2O. This aqueous solution is extracted with five portions of CHCl3 and the combined organic extracts are dried (Na2SO4), filtered and concentrated to provide the crude product. Column chromatography (0-5% MeOH-DCM) provides the title compound as a foam. Step 5. Preparation of [[(5S)-3-[4-[2,3-dihydro-6-(trifluoroacetyl)-4H-1,4-thiazin-4-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]carbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[H-].[Na+].COC1C=C2C(=CC=1OC)N=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43](NC(NC2CCNCC2)=O)=[CH:42][CH:41]=1.[C:56](=O)([O-])[OH:57].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:32][CH2:31][CH2:30][O:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=2[O:57][CH3:56])=[CH:20][CH:21]=1
Reactant: O=C([O-])O
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Reactant: COc1cc2nccc(Oc3ccc(O)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(OCCCOc4ccccc4OC)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenol (100 mg) was dissolved in dimethylformamide (2 ml) to prepare a solution. Sodium hydride (16 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. A solution of the compound (1) (91 mg) in dimethylformamide was added thereto, and the mixture was further stirred at room temperature for 6 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing three times with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (116 mg, yield 75%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[C:15]([Cl:25])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)[CH2:23][CH2:24]3)=[C:15]([Cl:25])[CH:14]=2)=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(Cl)c2)c1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(Cl)c2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-2-chloro-phenyl]-piperazin-1-yl}-benzoic acid was synthesized by the coupling of N-(3-tert-Butyl-phenyl)-3-chloro-4-piperazin-1-yl-benzamide and 4-bromo benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H30ClN3O3 (m/e) 491, obsd 490 (M−H)
Reaction SMILES: [CH2:1]([S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([S:16]([NH:19][C@H:20]([CH3:24])[C:21](O)=[O:22])(=[O:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C([Cl:28])=O.CN(C=O)C>ClCCl>[CH2:1]([S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([S:16]([NH:19][C@H:20]([CH3:24])[C:21]([Cl:28])=[O:22])(=[O:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCSc1nc2ccc(S(=O)(=O)N[C@H](C)C(=O)O)cc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCSc1nc2ccc(S(=O)(=O)N[C@H](C)C(=O)Cl)cc2s1
Temperature: 0 °C

Procedure:
(2R)-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl) amino]propionic acid (190 mg, 0.49 mmol) prepared in Example 29 was dissolved in dichloromethane (2 mL) and cooled down to 0° C. Oxalylchloride (0.17 mL, 4 equi.) and DMF of catalytic amount were added and the reaction solution was refluxed for 3 hours at RT. Then, the solution was distilled under reduced pressure to remove the solvent and dried under reduced pressure to give (2R)-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl)amino]propionic chloride. And then, the compound was dissolved in THF (2 mL) to obtain acid chloride THF solution. Hydroxyamine hydrochloride salt (0.34 g, 10 equi.) and NaHCO3 (0.49 g, 12 equi.) was dissolved in THF/H2O (1 mL/1 mL) and cooled down to 0° C. Acid chloride THF solution was slowly added to hydroxyamine solution at 0° C., and the solvent was removed after 1 hour. Then, the product was extracted with ethylacetate (5 mL), washed with H2O and 0.1N HCl, dried over MgSO4, distilled and vacuum-dried to prepare the titled compound, (2R)-N-hydroxy-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl)amino] propion amide (190 mg, 97%).
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[CH2:8][C:7]3([CH3:15])[CH2:13][NH:14][C:5]([C:6]=23)=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.O>C1COCC1.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:7]12[CH2:13][NH:14][C:5]3[C:6]1=[C:11]([C:2]([CH3:16])=[CH:3][CH:4]=3)[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: O=C([O-])[O-]
Reactant: CC12CNc3ccc(Br)c(c31)NC(=O)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccc2c3c1NC(=O)CC3(C)CN2

Procedure:
A mixture of (±)-6-bromo-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one from Step B (48 mg, 0.18 mmol), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol), potassium carbonate (75 mg, 0.54 mmol), and trimethylboroxine (0.126 mL of a 50 wt. % solution in THF, 0.50 mmol) in 1,4-dioxane (0.9 mL) and H2O (0.1 mL) was heated at 120° C. in a microwave reactor for 40 min. The cooled reaction mixture was quenched with H2O (5 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=203 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+].[OH2:20]>>[C:1]1([C:7]2[CH:8]=[N:9][C:10]([C:13]([OH:15])=[O:20])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: Cc1ccc(-c2ccccc2)cn1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C

Procedure:
A suspension of 3-phenyl-6-methyl pyridine (1.99 g, 11.78 mmol) and potassium permanganate (7.65, 48.6 mmol), in water (50 mL) was heated at reflux for 16 hours. The reaction was allowed to cool to ambient temperature and filtered through celite to remove the solids. Acetic acid (2 mL) was added to the colourless filtrate and the product was collected as a white solid by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[NH:8][CH:9]=[CH:10][O:11][C:5]=2[CH:4]=1.[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:8]1[C:7](=[O:12])[C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:11][CH:10]=[CH:9]1
Reactant: BrCCCCCBr
Reactant: COc1ccc2c(c1)OC=CNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC=CN(CCCCCBr)C2=O
Reaction time: 0.5 h

Procedure:
350 mg of 4,5-dihydro-8-methoxy1,4-benzoxazepin-5-one was dissolved in 5 ml of dimethylformamide, then 88 mg (1.2 equivalents) of 60% sodium hydride was added. This was agitated for 30 minutes, then 0.60 ml (2.4 equivalents) of 1,5-dibromopentane was added and the resultant mixture was agitated at room temperature for 6 hours.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:6]([OH:15])=[CH:5][CH:4]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][CH:18]=[C:17]2[O:15][C:6]1[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(O)c(-c2cccnc2)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(SC)nc3-c3cccnc3)c2cc1OC
Temperature: 140 °C
Reaction time: 4 h
Yield: 103.5 %

Procedure:
6-Methylsulfanyl-[2,3′]bipyridin-3-ol (13 mg), 4-chloro-6,7-dimethoxyquinoline (46 mg), and 4-dimethylaminopyridine (29 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (25 mg, yield 91%).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH2:6][CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:15]1[CH:16]=[N:17][C:12]2[C:13]=1[NH:14][C:9]([CH:7]1[CH2:6][CH:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:4][CH:3]([CH3:2])[CH2:8]1)=[N:10][CH:11]=2)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccccc2)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2cnc(C3CC(C)NC(c4ccccc4)C3)[nH]c1-2
Temperature: 110 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
A mixture of 2-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyridine (Example 35) (50 mg, 0.17 mmol), acetic anhydride (Aldrich Chemical Company) (168 mg, 1.64 mmol, 9.7 eq), K2CO3 (227 mg, 1.64 mmol, 9.7 eq) and 4—N,N-dimethylaminopyridine (2.6 mg, 0.021 mmol, 0.12 eq) in anhydrous DMF (2.0 mL) was stirred under N2 at 110° C. overnight. After cooling to the room temperature, the reaction was quenched by the addition of saturated NaHCO3 (5 mL) and extracted with CHCl3 (3×30 mL). The organic layers were washed with saturated NaCl, dried over Na2SO4 and concentrated with a rotary evaporator. The crude material was purified by flash chromatography on silica gel with a gradient eluant of EtOAc(0-25%):hexanes(100-75%) to afford 13 mg (22%) of the title compound as an off-white solid. Mp: 188-190° C. 1H NMR (CDCl3; 400 MHz): δ 11.43 (s, 1), 7.61 (d, 2, J=7.4), 7.43 (t, 2, J=7.4), 7.37 (t, 1, J=7.4), 4.88 (br s, 2), 4.06 (br s, 2), 2.58 (s, 3), 2.11 (s, 3), 1.73 (br s, 6). MS m/z: 335 (M+1), 333 (M−1). HRMS (NBA-NaI) m/z Calcd for M+H, C20H22N4O: 335.1888. Found: 335.1872.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=C[CH:16]=[CH:15][CH:14]=1.O1CCC[CH2:20]1>>[ClH:1].[C:6]([O:5][CH2:2][CH2:16][CH2:15][CH2:14][NH:13][CH3:18])(=[O:12])[CH3:20]
Reactant: C1CCOC1
Reactant: c1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CNCCCCOC(C)=O
Product: Cl

Procedure:
To a solution (20 mL) of bis(trichloromethyl)carbonate (0.59 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.49 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 30 min., 4-(methylamino)butyl acetate hydrochloride (1.08 g) obtained in Reference Example 37 was added. A solution (1 mL) of triethylamine (0.84 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 3 hrs. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The layer was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.02 g), triethylamine (0.77 mL) and 4-dimethylaminopyridine (catalytic amount) were added, and the mixture was stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give the title compound (0.93 g) as a yellow amorphous solid.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:4]=1.[OH2:17].[CH3:18]O>>[CH3:18][O:17][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:4]=1
Reactant: Cc1ccc(-c2nc(C)cc(Cl)n2)cc1
Reactant: CO
Reactant: O
Agent: [Na]
Product: COc1cc(C)nc(-c2ccc(C)cc2)n1
Yield: 97 %

Procedure:
A solution of 11.5 g of sodium in 100 ml of methanol is added to a suspension of 76.5 g of 4-chloro-6-methyl-2-p-tolylpyrimidine in 200 ml of methanol. The reaction mixture is refluxed for 2 hours and poured into water. The precipitate is filtered with suction, washed with water and dried, affording 72.9 g (97% of theory) of 4-methoxy-6-methyl-2-p-tolylpyrimidine with a melting point of 66°-67° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=[O:18])C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)[N+]([O-])=Cc1ccc(C#N)cc1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of 4-cyanobenzaldehyde (392.9 mg, 3.00 mmol) and t-butylamine (227.3 mg, 3.10 mmol) in 1,2-dichloroethane (12 ml) was added sodium triacetoxyborohydride (0.8567 g, 4.04 mmol) and stirred for 3 hours. Acetic acid (0.17 ml, 2.95 mmol) was added to the mixture and stirred for 2.5 hours. The mixture was added to sat. NaHCO3 aqueous solution, extracted three times with ethyl acetate and dried over MgSO4. The solvent was evaporated to give the crude title compound (595.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[C:31](=[O:36])N(OC)C)=[O:24])([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+]>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[C:31]([C:10]1[O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:12][CH:11]=1)=[O:36])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1ccc(-c2ccco2)cc1
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1ccc(-c2ccc(F)cc2)o1
Yield: 86.6 %

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-furan (1.8 g, 11.1 mmol) in THF (100 ml) at −35° C. was added n-butyl lithium (2.5M in THF) (4.54 ml, 11.4 mmol) over 3 min. The resultant mixture was stirred for 10 min. at −35° C. and then (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)piperidine (3.09 g, 11.4 mmol) in THF (10 ml) was added over 1 min. The resultant solution was stirred for 15 min. at −35° C. and then poured into saturated ammonium chloride (120 ml) and extracted with ethyl acetate (3×50 ml). The combined organics were washed with saturated aqueous sodium hydrogen carbonate (50 ml) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to give the title compound as a golden oil (3.59 g, 85%).