Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])[CH2:7][C@@H:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])[CH2:7][C@@H:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]=3[N:3]=2)=[CH:31][CH:30]=1
Reactant: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NCC1CCOCC1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(CN1C[C@@H]2COCCN2c2nc(-c3ccc(CO)cc3)ncc21)NCC1CCOCC1
Temperature: 120 °C
Yield: 32 %

Procedure:
A mixture of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x26, 50 mg, 0.131 mmol), 4-(hydroxymethyl)phenylboronic acid (29.8 mg, 0.196 mmol), tetrakis(triphenylphosphine)palladium(0) (15.13 mg, 0.013 mmol), and sodium carbonate (27.8 mg, 0.262 mmol) in 1,4-dioxane (0.5 mL) and water (0.25 mL) was heated to 120° C. for 1 hour in a microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica-NH, gradient 0-10% MeOH/CHCl3) to afford a white solid, which was recrystallized from EtOH/EtOAc to give the title compound as an off-white solid (19.0 mg, 32.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.21 (m, 2H), 1.48-1.71 (m, 3H), 2.91-3.02 (m, 3H), 3.12-3.32 (m, 5H), 3.50-3.67 (m, 2H), 3.73-4.08 (m, 6H), 4.49-4.61 (m, 3H), 5.19 (t, J=5.68 Hz, 1H), 7.34 (d, J=8.59 Hz, 2H), 7.47-7.51 (m, 1H), 8.08 (t, J=5.94 Hz, 1H), 8.16 (d, J=8.34 Hz, 2H); ESI-MS m/z [M+H]+ calc'd for C24H31N5O4, 454.24. found 454.4.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C:21]2([CH:28]3[CH2:30][CH2:29]3)[NH:26][C:25](=O)[CH2:24][O:23][CH2:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCCC1.C(OCC)(=O)C>[C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C:21]2([CH:28]3[CH2:30][CH2:29]3)[NH:26][C:25](=[S:41])[CH2:24][O:23][CH2:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COCC(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)(C2CC2)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(N=C(c2ccccc2)c2ccccc2)cc1C1(C2CC2)COCC(=S)N1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of (RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholin-3-one (2.10 g, 5.07 mmol) and Lawesson's reagent (0.926 mg, 2.3 mmol) in tetrahydrofuran (15 mL) was stirred at 70° C. for 3 hours. For the workup, the reaction mixture was diluted with ethyl acetate and extracted with a saturated solution of sodium hydrogen-carbonate. The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of hexane/ethyl acetate as the eluent. The (RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholine-3-thione was obtained as a yellow foam (1.42 g, 65% of theory). Mass (calculated) C26H23FN2OS [430.545]; (found) [M+H]+=431.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>C(#N)C>[Br-:29].[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:30][C:31](=[O:32])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O[C@H]1CN2CCC1CC2
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.9 %

Procedure:
To a solution of (S)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (260 mg, 0.67 mmol) in dry acetonitrile (10 ml), was added portionwise 2-bromo-1-phenylethanone (126 mg, 0.63 mmol). The reaction was stirred at RT for 3 hours. The solvent was evaporated, and the residue was purified by flash chromatography (DCM/MeOH=85/15), and the recovered product was triturated with i-PrOH to obtain (R)-3-((S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)-propanoyloxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (74 mg, 18.8% yield).
Reaction SMILES: [Cl:1][C:2]([Cl:41])([Cl:40])[CH2:3][O:4][C:5]([C:7]1[N:12]2[C:13](=[O:24])[C@@H:14]([C:15](=[O:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:11]2[S:10](=O)[CH:9]([NH2:26])[C:8]=1[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([O:38][CH3:39])=[CH:30][CH:29]=1)=[O:6].C1S(=O)(=O)CCC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(Cl)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:40][C:2]([Cl:1])([Cl:41])[CH2:3][O:4][C:5]([C:7]1[N:12]2[C:13](=[O:24])[C@@H:14]([C:15](=[O:23])[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:11]2[S:10][CH:9]([NH2:26])[C:8]=1[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([O:38][CH3:39])=[CH:30][CH:29]=1)=[O:6]
Reactant: COc1ccc(CC2=C(C(=O)OCC(Cl)(Cl)Cl)N3C(=O)[C@@H](C(=O)Cc4ccccc4)[C@H]3S(=O)C2N)c2ccccc12
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CC(=O)Cl
Solvent: CC#N
Product: COc1ccc(CC2=C(C(=O)OCC(Cl)(Cl)Cl)N3C(=O)[C@@H](C(=O)Cc4ccccc4)[C@H]3SC2N)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 0.317 g of 3-(4-methoxy-1-naphthylmethyl)-7β-phenylacetyl-amino-ceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester 1-oxide in 10 ml of a 9:1-mixture of tetramethylenesulphone and acetonitrile is treated with 0.250 g of sodium dithionite. The mixture is cooled to 0° and agitated in an ultrasonics bath, then treated with 0.275 g of acetic acid chloride. The mixture is allowed to react for 30 minutes and an equal amount of acetic acid chloride is again added. After a further 30 minutes, the reaction mixture is poured out onto a 5% aqueous sodium hydrogen carbonate solution. After extraction with diethyl ester, the combined organic extracts are washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on 10 g of silica gel, elution being carried out with methylene chloride and fractions of 50 ml being taken. Fractions 3 and 4 yield the 3-(4-methoxy-1-naphthylmethyl)-7β-phenylacetyl-amino-ceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester, which after crystallisation from a mixture of ethyl acetate and diethyl ether melts at 164°-165°; thin-layer chromatogram (silica gel): Rf = 0.73 (system: toluene/ethyl acetate 1:1) and Rf = 0.59 (system: toluene/acetone 4:1); infrared absorption spectrum (in mineral oil): characteristic bands at 2,99μ, 5,63μ, 5,75μ, 5,99μ, 6,12μ, 6,29μ and 6,53μ.
Reaction SMILES: [C:1](Cl)(=[O:3])C.C([O-])=O.[Na+].[NH2:9][C@H:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1.C([O-])(O)=O.[Na+]>C(OCC)C.C(Cl)Cl>[NH:9]([CH:1]=[O:3])[C@H:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:13]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])O
Agent: O=C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 101.7 %

Procedure:
To a solution of acetyl chloride (22.6 ml, 299 mmol) in diethyl ether (11), sodium formate (30.6 g, 450 mmol) was added under cooling with ice and stirred at room temperature for 23 hours. The reaction mixture was filtered and evaporated to remove the solvent. The thus obtained residue was added dropwise to a solution of H-Tyr(3-tBu)-OMe (22.2 g, 83.8 mmol) in methylene chloride (500 ml) under cooling with ice, mixed with TEA (46.7 ml, 335 mmol) and stirred at room temperature for 2 hours. The reaction mixture was mixed with saturated aqueous NaHCO3 and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=1:1), giving N-formyl-Tyr(3-tBu)-OMe (23.8 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Br:16]Br>C(Cl)(Cl)Cl.CN(C=O)C>[NH2:1][C:2]1[C:11]([Br:16])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: BrBr
Reactant: COC(=O)c1c(N)ccc2ccccc12
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(N)c(Br)cc2c1CCCC2
Yield: 101.2 %

Procedure:
Methyl 2-amino-1-naphthoate (0.5 g, 2.4 mmol) in chloroform (5 mL) and DMF (1 mL) was treated with bromine (0.125 mL, 2.4 mmol) for 30 minutes, concentrated, and dissolved in ethyl acetate. The organic layer was washed with NaHCO3 (3×), brine (3×) and water (3×), dried (Na2SO4), filtered, and concentrated to provide the desired product (0.69 g). MS (DCI) m/e 284, 286 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[F:12][C:13](I)([F:18])[C:14]([F:17])([F:16])[F:15]>CN(C)C=O.[Cu]>[F:12][C:13]([F:18])([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11])[C:14]([F:17])([F:16])[F:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1I
Reactant: FC(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F
Temperature: -60 °C
Reaction time: 16 h

Procedure:
A mixture of 2.36 g of 1-iodo-2-methyl-4-nitro-benzene and 2.2 g of powdered copper (Org. Synthesis Coll., Vol. II (1948), page 445 washed with water, acetone and dried under reduced pressure) in 10 ml of dimethylformamide under nitrogen in a sealed vessel was cooled to -60° C. and 11 5 g of pentafluoroethyl iodide were added. The mixture was stirred at 160° C. at a pressure of 3.5 bars for 16 hours and then cooled in ice and returned to room temperature. The mixture was poured into ice and was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica (eluant-pentane containing 2 to 3% of dichloromethane) to obtain 1.5 g of 1-pentafluoroethyl-2-methyl-4-nitro-benzene which was hydrogenated in the presence of palladized active carbon to obtain the desired product.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](C3CC(=O)N(O)C3=O)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][CH:2]([C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=3)[CH2:3][C:4]([OH:6])=[O:5])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Reactant: NC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
A cold (0°) solution of 3-amino-3-(4-nitrophenyl)propanoic acid (3.2 g, 15 mmol) in 10% aqueous sodium carbonate (60 ml) and 1,4-dioxan (30 ml) was treated portion-wise with 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (5.6 g, 17 mmol) in 1,4-dioxan (15 ml) and the mixture stirred at room temperature for 12 h. The mixture was poured into water (300 ml) and the aqueous phase washed 3 times with ether. The aqueous layer was then acidified with solid citric acid and extracted into ether. The combined organic layers were dried (MgSO4) and evaporated to a yellow oil then triturated from hexane and EtOAc to afford the title compound as a yellow solid (2.83 g); m/z (ES+, 70V) 432 (MH+).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C(Br)(=O)C.[CH3:8][N:9]([C:13]([NH2:15])=[NH:14])[CH2:10][CH2:11][OH:12].[C:16](O)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[C:16]([O:12][CH2:11][CH2:10][N:9]([CH3:8])[C:13]([NH2:15])=[NH:14])(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CN(CCO)C(=N)N
Agent: CC(=O)Br
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCCN(C)C(=N)N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 12.73 mL (150 mmol) of acetyl bromide and 35 mL of dry DCM. The flask is charged with 35.14 g (300 mmol) of Creatinol and 150 mL of dry DCM, and cooled with an ice-water bath to about 0° C., under a nitrogen atmosphere. The acetyl bromide solution is then added slowly with stirring, over a period of 10 minutes, to the Creatinol solution. The solution is stirred for another 15 minutes, after which 23.84 g (70 mmol) of Docosanoic acid is added in one portion and the reaction is slowly heated to about 65° C. for about 12 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 1/3) to yield pure 2-(1-methylguanidino)ethyl docosanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18](C)[CH:17]=[CH:16]2.[NH3:22]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:5][CH2:4][CH2:3][CH:8]([CH3:7])[O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH2:22])[CH:17]=[CH:16]2
Reactant: N
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: COc1ccccc1O
Product: COc1ccccc1OCCCC(C)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 86 substituting 2-methoxyphenol for 8-hydroxyquinaldine. 1H NMR (500 MHz, CDCl3) δ ppm 7.94 (d, 1H), 7.28 (t, 1H), 7.15 (m, 1H), 7.14 (d, 1H), 7.02 (d, 1H), 6.86 (m, 4H), 4.74 (m, 1H), 4.06 (m, 2H), 3.80 (m, 3H), 2.21 (m, 1H), 2.02 (m, 3H), 1.45 (d, 3H); MS (DCI/NH3) m/z 353 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:25])[C:14]1[S:18][C:17]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:16]=2[CH:15]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>ClC1C=CC=CC=1>[N:26]1([CH2:2][C:3]2[CH:11]=[CH:10][C:6]([C:7]([C:15]3[C:16]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=4[S:18][C:14]=3[N:13]([CH3:25])[CH3:12])=[O:8])=[CH:5][CH:4]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc2cc(N(C)C)sc2c1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: C1CCNC1
Solvent: Clc1ccccc1
Product: COc1ccc2c(C(=O)c3ccc(CN4CCCC4)cc3)c(N(C)C)sc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
4-(Chloromethyl)benzoyl chloride (105 mg, 0.558 mmol) was added to a stirred solution of 2-dimethylamino-6-methoxybenzo[b]thiophene (105 mg, 0.507 mmol) in chlorobenzene (1 mL) under nitrogen. The resultant mixture was heated in an oil bath at 110° C. for 2.5 h. The mixture was cooled to 0° C., treated with pyrrolidine (5 mL), then allowed to stir at room temperature for 2 h. After dilution with THF (20 mL), the mixture was washed with saturated aqueous NaHCO3 (5 mL). The organic layer was dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 20-40% EtOAc in hexanes, then 0-10% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to give 148 mg (74%) of the ketone as a foam.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][C:4]1[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[C:7]([C:9]([O:11]CC)=[O:10])[N:8]=1.[OH-].[Na+]>C1COCC1.O>[F:23][C:2]([F:1])([F:22])[CH2:3][C:4]1[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[N:8]=1
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c(CC(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-(2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (2.41 mmol, 850 mg) was dissolved in THF (30 ml) and H2O (20 ml). NaOH (4.82 mmol, 200 mg) was added and the mixture was stirred at RT for 48 h. The reaction mixture was concentrated and acidified to pH 2 using 1 N HCl. The mixture was extracted with DCM and the organic layer was concentrated. Yield 310 mg. LC-MS: [M+1]=325.01.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:18][C:19]1[N:20]=[C:21](Cl)[C:22]2[O:27][CH:26]=[CH:25][C:23]=2[N:24]=1.O.CCOC(C)=O>O1CCOCC1>[Cl:18][C:19]1[N:20]=[C:21]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)[C:22]2[O:27][CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Clc1nc(Cl)c2occc2n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3nc(Cl)nc4ccoc34)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (0.83 g, 3.4 mmol, Alfa Aesar), 2,4-dichlorofuro[3,2-d]pyrimidine (0.65 g, 3.4 mmol, ArkPharm) and TEA (0.96 mL, 6.9 mmol) in 1,4-dioxane (35 mL) was stirred at about 25° C. for about 12 h. Water (4 mL) and EtOAc (25 mL) were added and the layers were separated. The organic layer was concentrated under reduced pressure to give tert-butyl 8-(2-chlorofuro[3,2-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1.25 g, 55%): LC/MS (Table 2, Method f) Rt=2.12 min; MS m/z: 393 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].[C:22]([C:30](O)=[O:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:30](=[O:31])[C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)C(=O)c2ccccc2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 67 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol) and benzoylformic acid (45 mg, 0.30 mmol) were suspended in DMF (3 mL). The suspension was subjected to the same operation as in Example (138a) to obtain 86.2 mg of the title compound as a colorless amorphous solid (67%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4][N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17](Cl)(=[O:21])[C:18](Cl)=O.C(N(CC)CC)C.[C:30]1(=O)[CH2:35][CH2:34]CC[C:31]1=[O:36]>ClCCl.CN(C)C=O.CC(C)(O)C#N>[O:1]=[C:2]1[C:7]([C:8]([CH:18]2[C:17](=[O:21])[CH2:34][CH2:35][CH2:30][C:31]2=[O:36])=[O:10])=[CH:6][CH:5]=[N:4][N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1CCCCC1=O
Reactant: O=C(O)c1ccnn(-c2ccccc2)c1=O
Agent: CC(C)(O)C#N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCC(=O)C1C(=O)c1ccnn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Oxo-2-phenyl-2,3-dihydropyridazine-4-carboxylic acid (0.52 g, 2.42 mmol) was stirred in anhydrous dichloromethane (13 ml) and 1 drop of anhydrous dimethylformamide was added. Oxalyl chloride (0.25 mL, 2.90 mmol) was added dropwise to the suspension resulting in a brown solution. After 1.5 h the reaction was concentrated in vacuo. The residue obtained was dissolved in dichloromethane (20 ml). To the brown solution anhydrous triethylamine (1 ml), then cyclohexanedione (0.33 g, 2.90 mmol) was added, producing a reddish coloured solution. A further 0.33 ml of anhydrous triethylamine was added. The reaction mixture was stirred at room temperature for 2 h (reaction monitored by LCMS), then acetone cyanohydrin (1 drop) and anhydrous triethylamine (0.67 ml) was added and the reaction mixture was stirred overnight. LCMS indicated the desired product had been formed. The reaction mixture was concentrated in vacuo. The residue obtained was purified using column chromatography (SiO2, Toluene/Triethylamine/Dioxane/EtOH/Water 100:40:20:20:5 by volume), and then further purified by column chromatography (SiO2, hexane/ethyl acetate/acetic acid 2:1:0.02 to 0:100:2) to afford the title compound as an orange oil (25 mg, 3% yield). 1H NMR (CDCl3) 2.04 (m, 2H), 2.61 (br s, 4H), 7.18 (d, 1H) 7.46 (m, 2H), 7.59 (m, 3H) 7.96 (d, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[Cl:26][C:27]1[CH:38]=[C:31]2[C:32](OC(=O)[NH:36][C:30]2=[CH:29][CH:28]=1)=[O:33]>O1CCCC1>[NH2:36][C:30]1[CH:29]=[CH:28][C:27]([Cl:26])=[CH:38][C:31]=1[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:33]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: Nc1ccc(Cl)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of 2-amino-5-chloropyridine (328 mg, 2.55 mmol) in tetrahydrofuran (5 ml) was 0.5M potassium bis(trimethylsilyl)amide in toluene (10 ml, 5.05 mmol) dropwise at −78° C. After stirred for additional 0.5 hr at −78° C., the mixture was added 5-chloroisatoic anhydride (0.5 g, 2.55 mmol) at −78° C. The mixture was warmed up to r.t gradually and stirred overnight. After quenched by saturated ammonium chloride solution, the mixture was extracted by ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide (0.71 g, 100%). MS found for C12H9Cl2N3O M+=282, (M+2)+=284.