Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:11]1=[O:26])=[O:4].O[Li].O>C1COCC1.CO.O>[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[S:6][C:5]=3[C:3]([OH:4])=[O:2])[C:11](=[O:26])[C@@H:12]([CH2:22][C@H:23]([OH:25])[CH3:24])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](C[C@@H](C)O)OC[C@H]1C1CCCCC1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)C[C@H]1OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of 3-[(2R,5R)-5-cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (650 mg, 1.41 mmol, 1.0 equiv) in THF (10 mL), MeOH (5 mL) and water (5 mL) was added LiOH.H2O (177 mg, 4.22 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for 2 hours. The volatile solvent was removed under vacuum and to the residue was added water (15 mL). The mixture was cooled to 0° C. and acidified by addition of 3.0 N HCl aqueous solution until pH=1. The precipitate was isolated by filtration to give product (586 mg, 93%) as white solid. MS: 448.3 [M−H+]. 1H NMR (400 MHz, CD3OD): 1.09-1.31 (m, 8H) 1.32 (s, 9H) 1.45-1.85 (m, 5H) 1.89-2.10 (m, 3H) 3.56-3.61 (m, 1H) 3.93-4.00 (m, 1H) 4.00-4.10 (m, 1H) 4.12-4.22 (m, 2H) 6.99 (s, 1H).
Reaction SMILES: [OH2:1].[OH-].[Li+].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[O:9][CH2:8]2>O1CCCC1.CO.O>[Br:4][C:5]1[CH:14]=[CH:13][C:12]([CH2:10][OH:11])=[C:7]([CH:6]=1)[C:8]([OH:1])=[O:9]
Reactant: O
Reactant: O=C1OCc2cc(Br)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (11.80 g, 281.6 mmol) was added at room temperature over several minutes to a solution of 5-bromophthalide (20.0 g, 93.88 mmol) in a 2:1:1 solution of tetrahydrofuran/methanol/water (570 mL) and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and azeotropically dried with benzene to give 5-Bromo-2-hydroxymethyl-benzoic acid as a white solid. The material was used without further purification: 1H NMR (300 MHz, CDCl3+CD3OD) δ 7.89 (d, J=8.3 Hz, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.50 (dd, J=8.3, 1.9 Hz, 1H), 3.99 (s, 2H); ESI MS (negative mode) m/z 229 [C8H7BrO3−H]−. Sodium hyride (15.0 g, 375 mmol, 60% dispersion in mineral oil) was added in small portions over the course of 0.5 h at room temperature to a solution of 5-Bromo-2-hydroxymethyl-benzoic acid in tetrahydrofuran (235 mL) containing bromoacetic acid (14.35 g, 103.2 mmol) and sodium iodide (1.41 g, 9.4 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and poured into water and then extracted with diethyl ether. The aqueous phase was acidified with 10% hydrochloric acid to pH 3–4 and extracted several times with ethyl acetate. The combined ethyl acetate phases were washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield -Bromo-2-carboxymethoxymethyl-benzoic acid as a white solid. The material was used without further purification: 1H NMR (300 MHz, CD3OD) δ 7.93–7.86 (m, 2H), 7.55–7.50 (m, 1H), 4.98 (s, 2H), 4.23 (s, 2H); ESI MS (negative mode) m/z 287 [C10H9BrO5−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][S:21]([CH3:20])(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: COC(=O)c1cc(OCCCO)ccc1NC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(OCCCOS(C)(=O)=O)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-acetylamino-5-(3-hydroxypropoxy)benzoic acid methyl ester (689 mg, 2.6 mmol) in dichloromethane (25 mL) cooled to 0° C. were added methanesulfonyl chloride (1 mL, 12.9 mmol) and triethylamine (3.6 mL, 25.8 mmol). The mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with ethyl acetate (100 mL) and washed with 1 N HCl (aq.) (1×50 mL), sat. NaHCO3 (aq.) (1×50 mL) and brine (1×50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Crude 2-acetylamino-5-(3-methanesulfonyloxypropoxy)benzoic acid methyl ester thus obtained was used without further purification in the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCCC1.CO>[C:9]([N:8]=[CH:7][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1)#[N:15]
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CN=CNCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
500 mg of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 400 mg of ethyl N2-cyanocarboxyimidate were dissolved in a solvent mixture of tetrahydrofuran (5 ml) with methanol (5 ml) and stirred at 40° C. for 1.5 hours. Then the reaction mixture was distributed into an aqueous solution of potassium carbonate and ethyl acetate. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) and recrystallized from methanol/ethyl acetate. Thus, 170 mg of the title compound was obtained as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][OH:14])[O:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:14][CH2:13][C@@H:10]2[O:9][C:8]3[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[O:12][CH2:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CO)CO2
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])cc3O2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 5 L three necked flask equipped with a mechanical stirrer and thermocouple is changed with [(2S)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (210.4 g, 0.996 mol) and anhydrous pyridine (600 mL). The flask is immersed in an ice/brine bath to achieve an internal temperature of 0-1° C. To this is added a solution of p-toluenesulfonyl chloride (220.0 g, 1.15 mol) is dissolved in pyridine (200 mL) over 30 min. The bath is allowed to expire, and the mixture is stirred for 18 h at room temperature. Water (1600 mL) is added at a constant rate over 45 min. The resulting suspension is stirred for 1 h, and then the precipitate is collected by vacuum filtration onto a medium porosity fritted funnel. The filter cake is washed with water (1600 mL) and suction dried under nitrogen to give [(2R)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (356.8 g, 98%) as a tan powder; m.p. 138° C. LCMS (Standard Method): 2.78 min, 388 (M+Na)+. 1H NMR (300 MHz, DMSO-d6) δ7.79-7.72 (m, 3H), 7.49-7.42 (m, 3H), 7.06 (d, J=8.8 Hz, 1H), 4.59-4.55 (m, 1H), 4.41 (dd, J=2.6, 11.6 Hz, 2H), 4.22 (dd, J=6.3, 11.5 Hz, 1H), 4.12 (dd, J=6.8, 11.7 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=[CH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].O.[Br:18][C:19](Br)=[N:20][OH:21]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:21][N:20]=[C:19]([Br:18])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: ON=C(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CC(Br)=NO1

Procedure:
To a solution of N-tert-butoxycarbonyl allyl amine, 20 gm, in 700 ml of ethyl acetate and containing 65 gm of NaHCO3 and 50 ml of water, was added portion-wise 80 gm of dibromoformaldoxime at room temperature with vigorous stirring. After completion of the reaction, the organic portion was washed with water (2×100 ml), 100 ml each of 5% NaHCO3, brine and dried over anh. MgSO4 and concentrated to give an oil. Purification by chromatography on silica gel gave the desired product as an oil which solidified on standing. IR(KBr): 3322, 2988, 1680, 1529 cm-1. 1H NMR (80 MHz, CDCl3): delta 1.45 (s, 9H, t-butyl), 2.8-3.5 (m, 4H, CH2CHO, CH2N), 4.6-5.1 (broad s, superimposed on a multiplet, 2H, NH, CHO).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([CH2:16][CH3:17])[C:6]=2[N:7]=1.[NH:26]1[CH2:34][CH2:33][CH:29]([C:30]([OH:32])=[O:31])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C.O>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:5]2[C:4]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=3)=[N:3][C:2]([N:26]3[CH2:34][CH2:33][CH:29]([C:30]([OH:32])=[O:31])[CH2:28][CH2:27]3)=[N:7][C:6]=2[C:8]([CH2:16][CH3:17])=[N:9]1)[CH3:15]
Reactant: O=C(O)C1CCNCC1
Reactant: CCOCCn1nc(CC)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCCn1nc(CC)c2nc(N3CCC(C(=O)O)CC3)nc(Nc3cc(C)ccn3)c21
Temperature: 125 °C
Reaction time: 20 h
Yield: 7.3 %

Procedure:
A mixture of N-[5-chloro-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-methylpyridin-2-ylamine from step 5 (5.42 g, 166 mmol), isonipecotic acid (85.9 g, 665 mmol), cesium carbonate (162 g, 498 mmol), and DMSO (55 mL) was heated, with stirring, at 125° C. After 20 h, the mixture was cooled to 20° C. and water (165 mL) was added. The mixture was stirred for 15 min and was then treated with ethyl acetate (55 mL). The layers were separated and the aqueous was treated with another portion of ethyl acetate (55 mL). The layers were separated again and the aqueous layer was taken to pH ˜5 using 6 M HCl. After stirring for 1 hour, the resulting solid was filtered, washed with water (20 mL) and dried in vacuuo, to give 5.5 g of the title compound. 1H NMR (400 MHz, DMSO-d6): 1.10 (t, 3 H), 1.30 (t, 3 H), 1.49-1.60 (m, 2 H), 1.84-1.95 (m, 2 H), 2.32-2.36 (m, 3 H), 2.52-2.57 (m, 1 H), 2.78 (q, 2 H), 2.99-3.08 (m, 2 H), 3.52 (q, 2 H), 3.78 (t, 2 H), 4.45-4.53 (m, 2 H), 4.56-4.64 (m, 2 H), 6.91 (d, 1 H), 8.05 (s, 1 H), 8.18 (d, 1 H), 9.63 (s, 1 H), 12.18 (s, 1 H). LCMS m/z 454.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:31]=[CH:30][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd]>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:1][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:26][CH:25]=1)(=[O:23])[C:21]1[CH:30]=[CH:31][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: O=C(c1ccccc1)c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1
Yield: 58 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo-[1,2-a]pyridin-3-yl)pyrimidine and 4-bromobenzophenone following the general method of Example 1 using cesium carbonate as the base and tris(dibenzylideneacetone)dipalladium (0) as the palladium source. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 95:5, as the eluent affording 0.14 g (58% yield) of the title compound as a yellow solid: mp (decomp.) 249-255° C.; MS (TSP) m/z 392 (M+1 ), 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1 H), 10.35 (d, J=6.8 Hz, 1 H), 9.03 (s, 1 H), 8.67 (d, J=5.4 Hz, 1 H), 8.01 (d, J=8.7 Hz, 2 H), 7.98 (m, 1 H), 7.87 (m, 1 H), 7.83 (d, J=8.7 Hz, 2 H), 7.76 (d, J=7.0 Hz; 2 H), 7.69 (m, 1 H), 7.59 (m, 3 H), 7.47 (m, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][C:4]([CH3:11])=[N:3]1.CCCCCCC.[C:19](OCC)(=[O:21])C>ClC(OC(Cl)(Cl)Cl)=O>[CH3:1][N:2]1[C:6]([C:7]2[O:8][C:19](=[O:21])[NH:10][N:9]=2)=[CH:5][C:4]([CH3:11])=[N:3]1
Reactant: Cc1cc(C(=O)NN)n(C)n1
Reactant: CCOC(C)=O
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: Cc1cc(-c2n[nH]c(=O)o2)n(C)n1

Procedure:
After suspending 2,5-dimethyl-2H-pyrazole-3-carboxylic acid hydrazide (CAS 89187-40-6) (1.15 g) in ethyl acetate (10 ml), trichloromethyl chloroformate (0.90 ml) was added dropwise while stirring on ice. Upon completion of the dropwise addition, the mixture was heated to reflux overnight. It was then allowed to cool, n-heptane (10 ml) was added to the reaction mixture, and the precipitate was collected by filtration to obtain the title compound (1.58 g).
Reaction SMILES: [CH2:1]([C:3](=[CH:8][CH3:9])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:2].ClCCl.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:13][N:14]([CH3:19])[S:15]([NH:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])(=[O:17])=[O:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC=C(C=CCN)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C(C=CCNS(=O)(=O)N(C)C)CC
Reaction time: 0.5 h

Procedure:
A mixture of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide (3.0 g), hydrazine monohydrate (0.88 g), and ethanol (30 ml) was refluxed for 40 minutes under nitrogen atmosphere. After cooling, the precipitate was filtered and washed with ethanol. Evaporation of the filtrate gave a crystalline residue which was dissolved in 1N sodium hydroxide solution and extracted with dichloromethane. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to give 4-ethyl-2,4-hexadien-1-ylamine as an oil. To a mixture of crude 4-ethyl-2,4-hexadien-1-ylamine, triethylamine 1.79 g), and dichloromethane (30 ml) at 0° C. was added dropwise dimethylsulfamoyl chloride (2.03 g) during 10 minutes. After 30 minutes, triethylamine (0.6 g) and dimethylsulfamoyl chloride (0.85 g) were added to the reaction mixture. After 1 hour at 0° C., the reaction mixture was washed with water and aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (dichloromethane-hexane, 7:3) to give N,N-dimethyl-N'-(4-ethyl-2,4-hexadien-1-yl)-sulfamide (924 mg) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.Cl[CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[O:25][CH:26]=1>>[CH3:35][C:32]1[CH:31]=[CH:30][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:23]=2)=[CH:34][CH:33]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: Cc1ccc(/C=C/c2nc(CCl)co2)cc1
Product: Cc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)cc1
Yield: 72.4 %

Procedure:
Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (260 mg) and (E)-4-chloromethyl-2-[2-(4-methylphenyl)ethenyl]oxazole(257 mg), the same reaction as Example 1 was carried out to yield the titled compound (331 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23](O)=[O:24])=[CH:15][CH:14]=1.[CH3:26][Si:27]([CH3:39])([CH3:38])[CH2:28][CH2:29][O:30][CH2:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[NH2:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[CH3:26][Si:27]([CH3:39])([CH3:38])[CH2:28][CH2:29][O:30][CH2:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[NH:37][C:23]([C:16]1[C:17]2[N:18]=[CH:19][CH:20]=[N:21][C:22]=2[C:13]([C:3]2[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:24]
Reactant: C[Si](C)(C)CCOCn1ccnc1N
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3nccnc23)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nccn3COCC[Si](C)(C)C)c3nccnc23)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 1.1) (0.400 g, 1.06 mmol), 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-ylamine (Step 14.2) (0.270 g, 1.27 mmol, 1.2 equiv), TBTU (408 mg, 1.27 mmol, 1.2 equiv), DIEA (0.74 mL, 4.23 mmol, 4.0 equiv) in DMF (5 mL) was stirred for 2 h at rt, diluted with EtOAc and H2O, and extracted with EtOAc.washed with a saturated aqueous solution of NaHCO3, H2O, and brine. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH, 95:5) to afford 0.518 g of the title compound as a yellow foam: ES-MS: 573.8/575.8 [M+H]+; tR=5.03 min (System 1); Rf=0.19 (DCM2/MeOH, 95:5).
Reaction SMILES: [OH:1]O.[CH2:3]([N:10]1[CH2:22][CH2:21][C:13]2[NH:14][C:15](=S)[N:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O>[CH2:3]([N:10]1[CH2:22][CH2:21][C:13]2[NH:14][C:15](=[O:1])[N:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cn1c(=S)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.2 1 of 30% hydrogen peroxide were added dropwise at 0° C. over a period of 51/2 h, with stirring, to a suspension of 210 g of 6-benzyl-3-methyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrido[4,3-d]pyrimidin-4-one from b) in a solution of 78 g of NaOH in 4 1 of water. After subsequent stirring for 1/2 hour at 0° C., the pH of 9.7 was adjusted to 7.4 with conc. hydrochloric acid and the precipitate was filtered off, washed with water and dried. The above preparation was repeated and the precipitates were combined (396 g). These were purified by suspension in I 1 of water and dissolution with 33% sodium hydroxide solution (pH 13.5). Activated charcoal was added, with stirring, the mixture was filtered and the filtrate was adjusted to pH 10. The precipitate formed was filtered off with suction, washed with water and dried under reduced pressure to give 192 g of 6-benzyl-3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione, which was debenzylated by hydrogenolysis in d).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccccc1F
Product: Cc1ccccc1OC1CCN(Cc2ccccc2)CC1

Procedure:
By following the manipulative procedure described in Example 1(a), 21.0 g of 1-benzyl-4-piperidinol and 24.0 g of o-fluorotoluene produces a yellow oil fraction which boils at 161°-163° C., 0.09 mm. This oil solidifies slowly upon standing and is recrystallized from petroleum ether (b.p. 30°-60°) to give white crystals of 1-benzyl-4-(o-tolyloxy) piperidine.
Reaction SMILES: FC1CCCN(C([O-])=O)C1.O=P(Cl)(Cl)[Cl:13].[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C@@H:29]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[C:42]=2[N+:41]([O-])=[CH:40][CH:39]=[CH:38]3)[C@H:28]([F:44])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C.C1(C)C=CC=CC=1.CN(C=O)C>[Cl:13][C:40]1[CH:39]=[CH:38][C:37]2[C:42](=[C:33]([O:32][C@@H:29]3[CH2:30][CH2:31][N:26]([C:24]([O:23][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:25])[CH2:27][C@H:28]3[F:44])[CH:34]=[CH:35][CH:36]=2)[N:41]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc[n+]([O-])c23)[C@H](F)C1
Agent: O=C([O-])N1CCCC(F)C1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc(Cl)nc23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
Preparation of (trans)-benzyl 4-f2-chloroquinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate: To a 0° C. solution of 4 mL 1:1 DMF:toluene was added neat POCl3 (0.360 ml, 3.94 mmol). The reaction mixture was warmed to ambient temperature, stirred 10 minutes, and then cooled to 0° C. A solution of 8-((trans)-1-(benzyloxycarbonyl)-3-fluoropiperidin-4-yloxy)quinoline 1-oxide (1.04 g, 2.62 mmol) in 1.2 mL 1:1 DMF:toluene was added dropwise by syringe to the reaction mixture, and the reaction mixture was heated in a 110° C. sand bath and stirred for 1 hours. The reaction mixture was cooled to ambient temperature and added dropwise to a stirring ice/saturated NaHCO3 mixture. The mixture was stirred 20 minutes, then extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (Biotage 40S, loaded with 12:1hexanes:ethyl acetate, flushed 300 mL, then gradient to 5:1 hexanes:ethyl acetate) to give (trans)-benzyl 4-(2-chloroquinolin-8-yloxy)-3-fluoropiperidine-l-carboxylate (0.563 g, 1.36 mmol, 51.7% yield) as a syrup. MS APCI (+) m/z 415 (M+1) detected.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[N+:20]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[C:14]=1[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
A mixture of tert-butyl (3-aminopropyl)carbamate (4.20 g, 24.1 mmol), 2-chloro-1,3-dinitrobenzene (4.07 g, 20.1 mmol) and triethylamine (5.60 mL, 40.2 mmol) in tetrahydrofuran (200 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 30% ethyl acetate/n-hexane mixture to give a yellow solid (6.79 g, 20.0 mmol, 99.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[C:18]1([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:28]4[N:24]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:25]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccccc1
Product: Fc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccccc4)cc32)cc1

Procedure:
The title compound, light brown solid (26 mg, 21%), MS (ISP) m/z=355.2 [(M+H)+], mp 194° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (100 mg, 344 μmol) and commercially available 1-phenyl-1H-pyrazol-5-ylboronic acid [CAS No. 1238702-56-1] (83.9 mg, 447 μmol).