Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][N:5]=[CH:6][CH:7]=1.Br[CH:9]([C:11]1[CH:12]=[C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[C:18]2=[O:28])[CH:14]=[N:15][CH:16]=1)[CH3:10]>CN(C=O)C>[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:28])[N:17]([C:13]1[CH:14]=[N:15][CH:16]=[C:11]([CH:9]([N:4]3[N:5]=[CH:6][CH:7]=[N:3]3)[CH3:10])[CH:12]=1)[CH2:26][CH2:25]2
Reactant: c1cn[nH]n1
Reactant: CC(Br)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1)n1nccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
NaH (30 mg, 0.12 mmol) was added to a solution of 2H-[1,2,3]triazole (8.3 mg, 0.12 mmol) in DMF (5 mL) at 0° C. and the resulting reaction mixture was stirred for 10 min before 2-[5-(1-bromo-ethyl)-pyridin-3-yl]-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (36.5 mg, 0.1 mmol) was added. After additional stirring at RT for 1 hour, it was poured into ice-water (5 mL) and extracted with EtOAc (2×10 mL). The organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (7.5 mg, 21%) as a white solid. MS: 354.2 (M+H+).
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@H:6]2[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH3:10])[C@H:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[N+:66]([C:69]1[CH:82]=[CH:81][C:72]([CH2:73][O:74][C:75]([NH:77][CH2:78][CH2:79][SH:80])=[O:76])=[CH:71][CH:70]=1)([O-:68])=[O:67]>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:25][C:9]([C@@H:6]1[C:5](=[O:26])[N:4]2[C@@H:7]1[CH2:8][C:2]([S:80][CH2:79][CH2:78][NH:77][C:75]([O:74][CH2:73][C:72]1[CH:81]=[CH:82][C:69]([N+:66]([O-:68])=[O:67])=[CH:70][CH:71]=1)=[O:76])=[C:3]2[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])([O:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:10]
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (602 mg) and 4-(N,N-dimethylamino)pyridine (13.6 ml) in acetonitrile (30 ml) was added a solution of diisopropylethylamine (0.232 ml) in acetonitrile (2.08 ml) at 0° C. To the mixture was further added a solution of diphenyl chlorophosphate (0.242 ml) in acetonitrile (2.18 ml). After stirring at 0° C. for an hour, the mixture was cooled to -15° C. To the mixture was added a solution of diisopropylethylamine (0.775 ml) in acetonitrile (6.97 ml) and N-(4-nitrobenzyloxycarbonyl)cysteamine (299 mg) were added. After standing overnight at -15° C., the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed in turn with water and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (18 g) eluting with a mixture of benzene and acetone (20:1 to 6:1) to give 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (716 mg) as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].P(Cl)(Cl)(Cl)(Cl)[Cl:15].C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(C(=O)Cl)c1

Procedure:
The reaction of 36.2 g of 5-methyl-2-nitrobenzoic acid and 41.6 g of phosphorus pentachloride in 150 ml of toluene gave a crude product which was treated with methylene chloride to give 5-methyl-2-nitrobenzoyl chloride as an oil. When 30 g of this acid chloride in 50 ml of tetrahydrofuran was added to a warm solution of 30.9 g of 5-aminotetrazole monohydrate in 600 ml of tetrahydrofuran and 30 ml of water, a precipitate formed quickly. This was allowed to stand for 1 hour, the white solid was separated by filtration, washed with water and air dried to give 5-methyl-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 278°-279° C.
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:5][CH2:4][CH2:3]1.Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:2]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: [Zn+]C1CCC1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C2CCC2)cc1C
Temperature: 65 °C
Yield: 88.4 %

Procedure:
Cyclobutylzinc(II) bromide (50 mL, 0.5 M in THF, 25.0 mmol) was added to a mixture of methyl 4-bromo-2-methylbenzoate (compound 6.1, 5.2 g, 22.7 mmol) and PdCl2(dppf).CH2Cl2 (1.85 g, 2.27 mmol). The mixture was degassed and the flask was filled with argon through a balloon. The mixture was heated at 65° C. under argon for 24 hours, then cooled to 0° C. and carefully quenched with water (10 mL). The mixture was diluted with EtOAc (200 mL) and washed with water then brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (hexanes:EtOAc 30:1 to 20:1) to yield the title compound as a clear oil (4.1 g, 89%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, 1H), 7.12-7.02 (m, 2H), 3.88 (s, 3H), 3.59-3.48 (m, 1H), 2.59 (s, 3H), 2.35 (m, 2H), 2.22-1.96 (m, 3H), 1.86-1.84 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10]C)=[O:9])=[CH:5][C:4]2[CH2:12][O:13][C:14]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:3]1=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][C:4]2[CH2:12][O:13][C:14]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:3]1=2
Reactant: COC(=O)Cc1cc2c(n1C)C(=O)c1ccc(C)cc1OC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)OCc1cc(CC(=O)O)n(C)c1C2=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To an ice-cooled suspension of 1.74 g (0.006 m) of methyl 4,10-dihydro-1,7-dimethyl-10-oxo-1H[1]-benzoxepino[4,3-b]pyrrole-2-acetate in a mixture of methanol (50 ml) and water (5 ml) under a nitrogen atmosphere was added 2.5 N sodium hydroxide solution (2.6 cc, 0.0066 m) over 1 minute. After 30 minutes the ice-bath was removed, and the mixture stirred at ambient temperatures for five hours. The mixture was diluted to ca. 150 ml with water, aged, filtered, and the filtrate acidified dropwise with 2.0 N hydrochloric acid. After filtration, washing and drying, 1.5 g of product was obtained which upon recrystallization from i-propanol-water yielded pure 4,10-dihydro-1,7-dimethyl-10-oxo-1H[1]-benzoxepino[4,3-b]-pyrrole-2-acetic acid, m.p. 196°-197° C.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])([O-])=O.[Na+].[Na+].[CH:28]1(O)[CH2:32]CC[CH2:29]1>>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH:7]1[CH2:32][CH2:28][CH2:29][CH2:8]1)=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Reactant: OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CC(C(=O)OC1CCCC1)=C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 82 %

Procedure:
83.1 g (0.3 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 100 ml of cyclopentanol and 6 g of Na2CO3 were reacted with one another at 145° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 3 h, the reaction mixture was filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with petroleum ether and dried, giving 78.1 g (82%) of cyclopentyl 2-cyano-3,3-diphenylacrylate as a colorless solid. [λmax 300 nm; E11 (MeOH) 395]
Reaction SMILES: [CH3:1][C@:2]([OH:7])([CH2:5]Cl)[CH2:3][OH:4].[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([O:18][CH3:19])=[C:12]([CH3:20])[C:11]=1[CH3:21].[H-].[Na+].O>O1CCOCC1>[CH3:1][C@:2]([OH:7])([CH2:5][CH2:17][C:14]1[C:15]([CH3:16])=[C:10]([O:9][CH3:8])[C:11]([CH3:21])=[C:12]([CH3:20])[C:13]=1[O:18][CH3:19])[CH2:3][OH:4]
Reactant: C[C@@](O)(CO)CCl
Reactant: COc1c(C)c(C)c(OC)c(C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
2.4 g (19.6 mmol) of (2R)-2-methyl-3-chloropropane-1,2-diol and 4.28 g (22 mmol) of 2,5-dimethoxy-1,3,4,6-tetramethylbenzene were dissolved in 20 ml of dioxane and heated to reflux temperature within 1 hour with 1.27 g (66 mmol) of sodium hydride (80% in mineral oil) and 0.1 ml of polyethylene glycol 400 (as the phase transfer catalyst) and stirred at this temperature for 16 hours. The mixture was then treated with 50 ml of water, filtered and washed with water. The residue was recrystallized from ether/hexane and there were obtained 4.91 g of (2S)-2-methyl-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1,2-butanediol in the form of white crystals with a melting point of 82°-84° C. and [α]D20 =+2.86° (c=1.5% in CHCl3).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:3])C.[CH2:19](SC1C=CC(B(O)O)=CC=1)[CH2:20][CH2:21][CH2:22]CC>>[CH2:1]([S:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=2)=[CH:9][CH:10]=1)[CH2:3][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(C)Sc1ccc(-c2csc(C(=O)O)c2)cc1
Reactant: CCCCCCSc1ccc(B(O)O)cc1
Product: CCCCCCSc1ccc(-c2csc(C(=O)O)c2)cc1

Procedure:
The title compound was prepared in a similar manner as described in the preparation of 4-(4-(isopropylthio)phenyl)thiophene-2-carboxylic acid (compound 73, example 12), except 4-(hexylthio)phenylboronic acid (Chemical Communications 2003, 1, 138-139) was used in the place of 4-(isopropylthio)phenylboronic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[C:4]([C:15]([F:18])([F:17])[F:16])=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH2:9][C:10]#N)[CH:8]=1.C(O)C.C(O)(=O)C>[C].[Pd].O>[CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16])[NH:12][CH:10]=[CH:9]2
Reactant: CN(C)c1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CN(C)c1cc2cc[nH]c2cc1C(F)(F)F
Temperature: 35 °C
Reaction time: 16 h
Yield: 119.7 %

Procedure:
To a solution of (5-dimethylamino-2-nitro-4-trifluoromethylphenyl)acetonitrile (0.058 g) in a mixed solvent of ethanol (1 mL), acetic acid (0.1 mL) and water (0.1 mL) was added palladium-carbon powder (0.0058 g), and this mixture was stirred at 35° C. for 16 hours. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (0.058 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:17][O:18][C:2]([CH3:7])([CH3:3])[CH3:1])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](CO)NC(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 234010.09 %

Procedure:
130 L of methylene chloride was added; 20.5 g of (R)-methyl 2-(benzyloxycarbonylamino)-3-hydroxypropanate to a reactor; then stirred for 30 minutes; and then 0.4 kg of sulfuric acid was added. Isobutylene gas was bubbled for 24 hours while its temperature was maintained at 20-25° C. After completing the reaction, 18 L of saturated sodium hydrogen carbonate aqueous solution was slowly added, stirred for 1 hour, and then an organic layer was isolated. 5 kg of sodium sulfate was added to the organic layer, stirred for 1 hour, filtered, washed, and then the filtrate was concentrated under reduced pressure to obtain 29.3 kg of a title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11]O)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[CH2:24]([N:26]([CH2:34][CH3:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:25]>C(#N)C>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][N+:26]([CH2:24][CH3:25])([CH2:34][CH3:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:4][CH:3]=1
Reactant: OC/C=C\Cc1ccc(Cl)cc1
Reactant: CCCCCCCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: CCCCCCC[N+](CC)(CC)C/C=C\Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mix 5.40 g (0.016 mole) of (Z)-4-(4-chlorophenyl)but-2-en-1-ol 4-methylbenzenesulfonate and 10.96 g (0.064 mole) of N,N-diethylheptanamine in 200 ml of acetonitrile. Stir the mixture at room temperature for 2 hours. Evaporate and recrystallize from ethyl acetate to yield the title compound, m.p. 79°-80° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:29]([O:31]CC)=O)[CH:17]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C([NH2:39])=O>>[NH2:39][C:29]([C:18]1[CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:14]=2)[N:20]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[N:19]=1)=[O:31]
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)n(-c2ccc(OC)cc2)n1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-n2nc(C(N)=O)cc2-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 5-(4-{[(tert-butoxycarbonyl)amino]-methyl}phenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (500 mg) and sodium methoxide (239 mg) in formamide 5 ml was stirred at 70° C. for 2 hours. The mixture was cooled to ambient temperature and partitioned between AcOEt and brine. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give tert-butyl {4-[3-(aminocarbonyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamate (512 mg) as an oil.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:22])[CH:20]=[CH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:22])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.8 %

Procedure:
A mixture of 0.097 g (0.33 mmol) of the product from Step 7 (23) and 0.02 g of Palladium on activated carbon was stirred in 5 mL of ethyl acetate. The flask was equipped with a balloon containing hydrogen gas and the reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was then filtered through celite and washed with ethyl acetate. The resulting organic mixture was concentrated yielding 0.084 g (0.28 mmol, 85%) of 3-benzyl-2-(1-hydroxypropyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (24) as a clear oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(S)[CH2:12][S:13]([O-])(=O)=O.[Na+]>CS(C)=O.[Cu]I>[CH3:12][S:13][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: Ic1n[nH]c2cnccc12
Reactant: O=S(=O)([O-])CCS
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1n[nH]c2cnccc12
Temperature: 150 °C
Yield: 49.9 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-c]pyridine 3 (9.5 g, 38.8 mmol) in DMSO (20 mL) was added aq. MeSNa (wt. 20%, 40 mL, 116 mmol), followed by CuI (270 mg, 1.94 mmol). The mixture was degassed and refilled with nitrogen. The reaction was heated at 150° C. overnight. After cooled to RT, the volatiles were removed and the residue was purified by column (PE/EtOAc=2/1 to 1/1) to give 3-(methylthio)-1H-pyrazolo[3,4-c]pyridine (3.2 g, yield: 50%) as a yellow solid. MS obsd. (ESI+) [(M+H)+] 166.0.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=[O:15].Cl>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(O)c(C(=O)O)cnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
Ethyl 4-hydroxy-7-methoxy-3-quinolinecarboxylate (24.7 g, 0.1 mol) was hydrolysed with 2N aqueous solution of sodium hydroxide (250 ml) through boiling for 2 hours. The reaction mixture was allowed to cool to room temperature and adjusted with 2N hydrochloric acid to pH 5. The resulting precipitates were collected by filtration and washed with water. The precipitates were dried at 100°-120° C. for 3 hours in an oven and further dried under reduced pressure overnight over calcium chloride to obtain 21.4 g (98%) of 4-hydroxy-7-methoxy-3-quinolinecarboxylic acid.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C@@H:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10](=[O:12])N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH2:27]>CN(C)C=O>[CH2:19]([N:14]1[C@@H:13]([CH2:17][SH:16])[C@H:9]([C:10]([OH:12])=[O:27])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:15]1=[O:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NC(=O)[C@H](NCc1ccccc1)[C@@H]1CSC(=O)N1Cc1ccccc1
Reactant: O
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)[C@H]1[C@H](CS)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
In 200 ml of N,N-dimethylformamide was dissolved 100 g of (4R)-4-[(1R)-1-(N-benzylamino)-1-carbamoylmethyl]-3-benzylthiazolidin-2-one, and under nitrogen atmosphere, the solution was stirred at 85° C. for 5 hours. At 90° C. to 95° C., 200 ml of 35% hydrochloric acid was added dropwise to the solution, and the mixture was stirred for 1 hour and 15 minutes. Moreover, 100 ml of 35% hydrochloric acid was added dropwise, and the mixture was stirred for 2 hours. Then, 200 ml of water was added dropwise to the mixture at 85° C. The solution was ice-cooled, and precipitated crystal was collected by filtration, washed with water and then dried at 50° C. for 17 hours to give 93.1 g of (4R,5R)-1,3-dibenzyl-2-oxo-5-(mercaptomethyl)-imidazolidin-4-carboxylic acid as colorless crystal.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH:10](OCC)(OCC)OCC>>[Br:1][C:2]1[C:3]2[NH:9][CH:10]=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cncc(Br)c1N
Product: Brc1cncc2nc[nH]c12
Yield: 75 %

Procedure:
To a solution of 5-bromopyridine-3,4-diamine (12 g, 63 mmol) in (EtO)3CH (150 mL) was added camphorsulfuric acid (0.5 g). The reaction mixture was heated at reflux for 2 h then the EtOH was distilled to afford a solid. The solid was filtered to afford 9.5 g (75%) 7-bromo-1H-imidazo[4,5-c]pyridine as a white solid; MS (ESI) m/z: 199.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH:9](Br)[CH2:10][C:11](Cl)([Cl:13])[Cl:12])[CH2:3][C:4]([O:6]CC)=[O:5].CC(C)(C(Cl)CC(Cl)(Cl)Cl)CC(OCC)=O>>[CH3:1][C:2]1([CH3:16])[CH:9]([CH:10]=[C:11]([Cl:13])[Cl:12])[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(C)C(Br)CC(Cl)(Cl)Cl
Agent: CCOC(=O)CC(C)(C)C(Cl)CC(Cl)(Cl)Cl
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl
Yield: 90 %

Procedure:
The procedure of Reference Example 1 was repeated except that 35.4 parts of ethyl 3,3-dimethyl-4-bromo-6,6,6-trichlorohexanoate was used in lieu of ethyl 3,3-dimethyl-4,6,6,6-tetrachlorohexanoate. By this procedure was obtained 19.0 parts of 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide (yield 90%).
Reaction SMILES: C([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][C@@H:11]1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[Si:17]([O:16][C@H:13]1[CH2:14][CH2:15][C@H:10]([OH:9])[C@@H:11]([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[CH2:12]1)([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:18])[CH3:19]
Reactant: Cn1nccc1[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cn1nccc1[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1O
Yield: 68 %

Procedure:
A solution of the (1S*,2R*,4S*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (367 mg, 0.885 mmol) prepared in Example 162e and potassium carbonate (245 mg, 1.77 mmol) in methanol (5.0 mL) was stirred at room temperature for 3 hours. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (100 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=3:2) to yield the title compound (187 mg, 68%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11](CC1C=CC(OC)=CC=1)[C:12](=[O:29])[N:13]2[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:29])[N:13]2[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc([N+](=O)[O-])cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(-c3ccccc3Cl)cc([N+](=O)[O-])cc2N1c1c(Cl)cccc1Cl

Procedure:
A solution of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-nitro-3,4-dihydroquinazolin-2(1H)-one (32 mg, 0.56 mmol) in 1 mL trifluoroacetic acid was stirred at 95° C. for 1.25 h. The solvent was removed under reduced pressure and the product was purified by preparative thin-layer chromatography, eluting with 93:7 CH2Cl2-methanol to yield 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-nitro-3,4-dihydroquinazolin-2(1H)-one. Mass spectrum (ESI) 448 (M+1). 1H NMR (500 MHz, CDCl3): δ 3.35 (½ ABq, J=15.5 Hz, 1H); 3.52 (½ ABq, J=15.5 Hz. 1H); 7.00 (s, 1H); 7.32 (d, J=2.1 Hz, 1H); 7.46 (m, 3H); 7.58 (m, 3H); 7.81 (s, 1H).