Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]#[C:8][NH2:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[C:15]2/[CH:22]=[C:23]1/[C:24](=[O:30])[N:25]=[C:26](SC)[S:27]/1.O>C(O)(C)(C)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[C:15]2/[CH:22]=[C:23]1/[C:24](=[O:30])[N:25]=[C:26]([NH:9][C:8]#[N:7])[S:27]/1
Reactant: N#CN
Reactant: COc1ccc2[nH]c(C)c(/C=C3\SC(SC)=NC3=O)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc2[nH]c(C)c(/C=C3\SC(NC#N)=NC3=O)c2c1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
To a room temperature suspension of potassium t-butoxide (73 mg, .65 mmols) and cyanamide (96 mg, 2.27 mmols) in 10 mL of t-butanol is added (Z)-5-[(5-methoxy-2-methyl-1H-indol-3-yl)methylene]-2-(methylthio)- 4(5H)-thiazolone (146 mg, 0.46 mmols). The mixture is heated at reflux for 5 minutes, then cooled to room temperature. The mixture is poured into 50 mL of water and the orange solution is washed with diethyl ether. The layers are separated and the aqueous layer is acidified with 10% aqueous hydrochloric acid. The orange solid is collected by filtration, washing with water to give 106 mg (74%) of (Z)- [4,5-dihydro-5-[(5-methoxy-2-methyl-1H-indol-3-yl)methylene]-4-oxo-2-thiazolyl]cyanamide; mp >300.
Reaction SMILES: [NH2:1][C:2]1[C:12]([I:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:14][CH3:15])[CH:3]=1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].Cl>C(Cl)Cl>[I:13][C:12]1[C:2]([N:1]([S:24]([CH3:23])(=[O:26])=[O:25])[S:24]([CH3:23])(=[O:26])=[O:25])=[CH:3][C:4]([S:14][CH3:15])=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(I)c(N)cc1SC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(I)c(N(S(C)(=O)=O)S(C)(=O)=O)cc1SC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-amino-5-iodo-2-(methylthio)benzoate (13.6 g, 40 mmol) in DCM (100 mL) was added Et3N (13.8 mL, 100 mmol), followed by MsCl (7.7 mL, 100 mmol) at 0° C. After addition the mixture was stirred at rt for 2 h. 1N HCl solution (50 mL) was added to the mixture and the aqueous phase was extracted with DCM (1×100 mL). The organic solution was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give ethyl 5-iodo-4-(N-(methylsulfonyl)methylsulfonamido)-2-(methylthio)benzoate.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:16]2[N:17](C(=O)C)[C:18](=[O:25])[C:19]([CH:22]([CH3:24])[CH3:23])([CH3:21])[N:20]=2)[N:7]=1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:16]2[NH:17][C:18](=[O:25])[C:19]([CH:22]([CH3:23])[CH3:24])([CH3:21])[N:20]=2)[N:7]=1
Reactant: COC(=O)c1ccc(COC(C)=O)nc1C1=NC(C)(C(C)C)C(=O)N1C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CO)nc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
A solution of 16.7 g of methyl 6-acetoxymethyl-2-(1-acetyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate in 125 mL methanol containing 0.7 g of sodium methoxide is stirred at room temperature for 16 hours. The solution is adjusted to pH 5 with acetic acid and concentrated in vacuo. The residue is chromatographed on silica gel using ether-methanol as eluant to give the desired product as a solid. Recrystallization from methylene chloride-hexane gives analytically pure material, mp 115°-118° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[CH:18]=1)([O-])=O.C(O)C.Cl>[Pd].O>[N:11]1[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[CH:18][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=12
Reactant: O=[N+]([O-])c1ccccc1-c1cn2ccccc2n1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1-c1cn2c(n1)CCCC2
Reaction time: 120 h

Procedure:
In a dry flask was charged 2-(2-Nitro-phenyl)-imidazo[1,2-a]pyridine (239 mg, 1 mmol), 10% Pd/C (15 mg), Ethanol (25 ml), water (1.5 ml) and 4M HCl (0.5 ml). The atmosphere was flushed with nitrogen and stirred over 1 atm. hydrogen over 5 days with an additional charge of Pd/C catalyst (15 mg) and 4 N HCl (4.5 ml) until reaction completion was obtained. The reaction mixture was filtered through Celite, and neutralized to pH=6 with a saturated NaHCO3 solution. The solution was roto-evaporated to remove the ethanol, the aqueous layer was extracted with CH2Cl2 (2×5 ml), and the combined organic layer dried over Na2SO4 and concentrated to obtain the product as an oil in quantitative yield (205 mg). (MS, M++H=214.1)
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[CH:12]([Sn](C=C)(C=C)C=C)=[CH2:13]>CN(C=O)C.CCOC(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH:12]=[CH2:13])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1
Reactant: C=C[Sn](C=C)(C=C)C=C
Reactant: OCc1cc(I)c(O)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cc(CO)nc(Cl)c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
2-Chloro-6-(hydroxymethyl)-4-iodopyridin-3-ol (5.7 g, 20 mmol) is combined with bis (triphenylphosphine) palladium dichloride (1.12 g, 1.6 mmol) in 50 ml DMF under nitrogen. The mixture is treated with tetravinyl tin, is warmed to 60° C. for 6 h followed by 50° C. for 18 h, and at rt for 72 h. The mixture is diluted with 250 ml EtOAc and is extracted with 4×100 ml 2:1:1 water/saturated NaCl/saturated NaHCO3. The organic layer is dried (MgSO4) and is concentrated in vacuo to a yellow oil. The crude material is chromatographed over 200 g SiO2 (230-400 mesh) eluting with 37% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.45 g (39%) of 2-chloro-6-(hydroxymethyl)-4-vinylpyridin-3-ol as a pale yellow solid. MS for C8H8ClNO2 (EI) m/z: 185 (M)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:10]([CH3:17])=[N:11][N:12]([CH2:15][CH3:16])[C:13]=2[OH:14])=[O:8])=[C:5]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]#N>O>[S:20]([C:32]1[CH:33]=[CH:2][C:3]([CH3:19])=[CH:4][CH:5]=1)([O:14][C:13]1[N:12]([CH2:15][CH3:16])[N:11]=[C:10]([CH3:17])[C:9]=1[C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([C:2]([F:24])([F:1])[F:25])=[CH:4][C:5]=1[S:20]([CH3:23])(=[O:22])=[O:21])(=[O:22])=[O:21]
Reactant: CCn1nc(C)c(C(=O)c2ccc(C(F)(F)F)cc2S(C)(=O)=O)c1O
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCn1nc(C)c(C(=O)c2ccc(C(F)(F)F)cc2S(C)(=O)=O)c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.37 g (1 mmol) of 4-(4-Trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy-1-ethyl-3-methylpyrazole and 0.20 g (1.1 mmol) of p-Tos-Cl were dissolved in 20 ml of CH3CN. 0.26 g (1.8 mmol) of potassium carbonate was then added, and the mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The extract was dried with MgSO4 and concentrated. This gave 4-(4-Trifluoromethyl-2-methylsulfonylbenzoyl)-l-ethyl-3-methyl-5-pyrazolyl tosylate as a wax.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCCC2)cc1
Yield: 96.6 %

Procedure:
Add pyrrolidine (0.89 mL, 10.74 mmol) to a stirred solution of 4-bromomethyl-benzonitrile (1 g, 5.1 mmol) and triethylamine (1.5 mL, 10.74 mmol) in anhydrous THF (26 mL). Stir reaction overnight at room temperature. Partition the reaction mixture between EtOAc and water. Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over MgSO4, filter, and concentrate in vacuo to obtain the desired intermediate (918 mg, 97%) suitable for use without further purification. MS (APCI+) m/z: 187 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:35])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:23]4)=[C:17]([F:34])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.[OH-].[K+].C(O)(=O)C>C(O)C>[F:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23]2)=[C:17]([F:34])[C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:35])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccccc5)C4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccccc5)C4)c(F)c3nc21
Temperature: 75 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A suspension of (RS)-3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (2 g) in ethanol (25 cc) and N aqueous potassium hydroxide (15 cc) is heated with stirring to a temperature in the region of 75° C. for 2 hours. The solution obtained, at approximately 75° C., is treated with 10% strength aqueous acetic acid solution (9 g). The insoluble matter obtained is drained at a temperature in the region of 75° C. and washed with water (3×30 cc) at approximately 20° C. After 1 recrystallization in dimethylformamide (40 cc), (RS)-7,9-difluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.5 g) is obtained in the form of an orange-colored solid, m.p. 298° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:8]([C:10]([O:12]CC)=O)[CH3:9].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][CH2:6][N:7]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:8]([CH3:9])[C:10]1=[O:12])=[O:22]
Reactant: CCOC(=O)C(C)N(CCCC(=O)OC)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CCN(Cc2ccccc2)C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[benzyl-(1-ethoxycarbonyl-ethyl)-amino]-butyric acid methyl ester (1.5 g, 4.9 mmol), potassium tert-butoxide (906 mg, 8.9 mmol) and toluene (100 mL) is stirred at rt for 3 h. The mixture is then partitioned between DCM and saturated aqueous NH4Cl. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated. The crude residue is used without further purification. MS (ESI) m/z 262.2 (M+1).
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[C:17]1([C:23]2([CH2:26][NH2:27])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)CCC>O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:27][CH2:26][C:23]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCC1(c2ccccc2)CC1
Agent: I
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: N=C(NCC1(c2ccccc2)CC1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 7.80 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide and 4.37 of 1-phenylcyclopropanemethylamine in 100 ml. of n-butanol and 25 ml. of water is heated at reflux for 24 hours. The solution is cooled, diluted with water to a final volume of 2 liters and is allowed to stand. Filtration gives a tan solid which is dissolved in ethyl acetate and purified by silica gel column chromatography. Crystallization of the product from diethyl ether gives the desired final product as colorless crystals, m.p. 136.5°-138.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10][CH:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19]COCC>CCOCC.CO.[Si](C=[N+]=[N-])(C)(C)C>[CH2:12]1[C:11]2([CH2:14][CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)CC1C(=O)O
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C1CC2(CCN1C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 199.9 %

Procedure:
To an ice cooled solution of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid (racemic mixture) (D1) (500 mg, 0.78 mmol) in Et2O/MeOH (10/5 ml), TMSCHN2 2M sol in Et2O (1.5 ml, 2.94 mmol) was added and the resulting mixture was stirred 2 hrs at 0° C. then 18 hrs at RT. After solvent evaporation the crude residue was loaded onto SPE-Si cartridge (10 g) eluting with DCM. Collected fractions after solvent evaporation afforded the title compound (D4) (420 mg) as a clear oil.
Reaction SMILES: [CH2:1]=[O:2].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])([CH3:6])([CH3:5])[CH3:4].CC1C=CN=CC=1.[Sn](Cl)Cl>C1(C)C=CC=CC=1.C(OCC)C>[C:3]([C:7]1[C:8]([OH:13])=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:1]=[O:2])([CH3:6])([CH3:4])[CH3:5]
Reactant: C=O
Reactant: CC(C)(C)c1ccccc1O
Agent: Cl[Sn]Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: Cc1ccncc1
Product: CC(C)(C)c1cccc(C=O)c1O
Temperature: 95 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
9.0 g (300 mmol) of para-formaldehyde in 200 ml of toluene were introduced into a 500 ml three-necked flask fitted with magnetic stirrer, reflux condenser and nitrogen/vacuum connection, and 15.4 ml (100 mmol) of 2-tert-butylphenol (Aldrich), 3.9 ml (40 mmol) of 4-methylpyridine and 1.89 g (10 mmol) of tin(II) chloride were added. The batch was subsequently allowed to stir at 95° C. for six hours. The isolated product was taken up in diethyl ether, and the solution was washed with sodium chloride solution, dried over sodium sulfate and evaporated in a rotary evaporator, giving the product in a yield of 39.5%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([C:19]3[CH:20]=[CH:21][C:22]([O:24][Si](C(C)C)(C(C)C)C(C)C)=[CH:23][C:18]=3[O:17][CH2:16]2)[C:8]1=[O:35].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:24][C:22]1[CH:21]=[CH:20][C:19]2[C:9]3([CH2:16][O:17][C:18]=2[CH:23]=1)[C:10]1[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=1)[N:7]([CH2:6][C@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[C:8]3=[O:35]
Reactant: CC(C)[Si](Oc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To a solution of 1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6-{[tris(1-methylethyl)silyl]oxy}spiro[1-benzofuran-3,3′-indol]-2′(1H)-one (1.69 g, 3.43 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogen was added tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 10 mL, 10 mmol), and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated, and the residue was re-dissolved in ethyl acetate (25 mL), washed with water (2×20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography with 40% ethyl acetate in hexanes to afford 6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.00 g, 86%) as a colorless solid: mp 72-74° C.; 1H NMR (300 MHz, CDCl3) δ 7.29 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 7.18-7.01 (m, 3H), 6.80-6.67 (br, 1H), 6.44 (d, J=8.4 Hz, 1H), 6.24 (d, J=2.1 Hz, 1H), 6.17-6.09 (m, 1H), 4.96-4.90 (m, 1H), 4.69-4.63 (m, 1H), 4.36-4.24 (m, 1H), 4.00-3.71 (m, 4H), 2.12-1.61 (m, 4H); MS (ES+) m/z 338.1 (M+1).
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:17][C:16]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:11](=[O:25])[C:10]=2[C:9]=1[CH3:26])=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(OCC)OCC)C.[OH-].[Na+]>ClCCl.O>[CH3:26][C:9]1[C:10]2[C:11](=[O:25])[N:12]([CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:13][CH2:14][CH2:15][C:16]=2[NH:17][C:8]=1[CH:6]=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(OCC)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Temperature: -5 °C
Yield: 39.1 %

Procedure:
3-Methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 28b (3.562 g, 9.87 mmol) was dissolved in 50 ml of dichloromethane under stirring, and added with trifluoroacetic acid (19.7 ml, 260 mmol) to the solution at room temperature. Upon the completion of the addition, the mixture was heated to reflux for 30 minutes in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was cooled down to −5° C. in an ice-salt bath, added with triethoxy methane (2.96 ml, 14.8 mmol) in one portion, stirred at −5° C. for 5 minutes, for another 1 hour at room temperature. The reaction system was added with water (25 ml), adjusted to about pH 11 with dilute sodium hydroxide solution (2 mol/L) and extracted with dichloromethane (100 ml×3). The combined organic extracts were concentrated under reduced pressure to obtain a henna oil. The oil was purified by silica gel column chromatography to obtain the title compound 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c (1.116 g, yield 49%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH2:11])=[O:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1)=[O:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@H]1CCCC[C@H]1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H]1CCCC[C@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
The crude (1S,2R)-2-amino-cyclohexanecarboxylic acid methyl ester (4.97 mmol) was dissolved in methanol (15 mL) at 25° C. and 4-fluorobenzaldehyde (0.533 mL, 4.97 mmol), glacial acetic acid (1 mL) and sodium cyanoborohydride (0.781 g, 12.4 mmol) were added sequentially. The reaction mixture was stirred at 25° C. for 19 h, and then was partitioned between saturated sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, decanted, and were concentrated in vacuo to afford the crude product, (1S,2R)-2-(4-fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1)=[O:3].S1C=CC=C1.O(C(C)C)C(C)C.[H][H]>CO.[Pd].CN(C)C(=O)C>[CH:2]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1)=[O:3]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(C(=O)Cl)C1
Agent: [Pd]
Solvent: CC(C)OC(C)C
Solvent: c1ccsc1
Solvent: CO
Product: CCOC(=O)N1CCC(C=O)C1
Yield: 93 %

Procedure:
A mixture of 22 parts of ethyl 3-(chlorocarbonyl)-1-pyrrolidinecarboxylate, 36 parts of N,N-dimethylacetamide, 3 parts of a thiophene solution 4% in methanol and 210 parts of 2,2'-oxybispropane was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 17 parts (93%) of ethyl 3-formyl-1-pyrrolidinecarboxylate as a residue (int. 26).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O1CCOCC1>O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
A mixture of 1.00 g of ethyl 2-(tert-butoxycarbonyl)amino-1,3-thiazole-4-carboxylate, 0.46 g of lithium hydroxide monohydrate, 10 mL of water and 10 mL of 1,4-dioxane was stirred at room temperature for 6 hrs. After the reaction mixture was diluted with water, it was washed with ethyl acetate. The separated aqueous phase was acidified with an aqueous 2N-hydrochloric acid solution and the precipitated crude product was washed with water and dried to obtain 0.82 g of the aimed 2-(tert-butoxycarbonyl)amino-1,3-thiazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[C:21]12([NH2:31])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:21]12([NH:31][C:2]3[C:3](=[O:20])[N:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:7]=3)[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(NC23CC4CC(CC(C4)C2)C3)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 130 °C
Yield: 9.1 %

Procedure:
27 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one and 130 mg of 1-adamantylamine were dissolved in 10 ml of dimethylformamide. To the mixture was added 20 mg of sodium hydride, followed by stirring at 130° C. in nitrogen atmosphere. After the reaction solution was cooled to room temperature, a saturated aqueous solution of ammonium chloride and water were added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 3 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:20])[NH:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][CH:23]1[O:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][CH2:24]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[O:28]1[C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][CH2:24][CH:23]1[CH2:22][N:16]1[CH:17]=[CH:18][N:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[C:15]1=[O:20]
Reactant: ClCC1COc2ccccc2O1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccn(CC3COc4ccccc4O3)c2=O)CC1
Temperature: 120 °C

Procedure:
A mixture of 3-(4-tert-butoxycarbonyl-1-piperazinyl)-2(1H)-pyrazinone (4.00 g, 14.3 mmol; from Example 48, Step 1), 2-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (2.60 g, 14.3 mmol), DMF (10 g) and potassium carbonate (4.00 g, 28.9 mmol) was heated at 120° C. for 3 h. Water (100 g) and EtOAc (200 g) were added to the reaction mixture and the layers were separated. The organic layer was concentrated and the residue purified by chromatography on a MPLC column using a continuous gradient (0-100% EtOAc in heptane) as eluent. This provided 0.60 g (15%) of the title compound as an oil. 1H NMR analysis supports the stated structure.