Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[CH:26][N:25]=1>C1(C)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:28][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: Cc1ccc(-c2cnc(Cl)nc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1

Procedure:
Following the same procedure as outlined in Example 12, 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.19 g, 7.5 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-(4-methylphenyl)pyrimidine (1.03 g, 5 mmol) in toluene (50 mL, anhydrous) and DBU (0.9 mL) were reacted to yield the product as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[O:20][CH3:21].O>C(OCC)C>[C:16]([C:14]1[CH:13]=[CH:12][C:11]([O:20][CH3:21])=[C:10]([CH2:9][OH:8])[CH:15]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cc(C(C)(C)C)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C(C)(C)C)cc1CO
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 96.4 %

Procedure:
A solution of 1.0M lithium aluminium hydride in diethyl ether (27.0 ml, 27.0 mmol) was added dropwise over 10 min to a solution of 5-tert-butyl-2-methoxybenzoic acid methyl ester (5.00 g, 22.4 mmol) in diethyl ether (90 ml) under nitrogen, maintaining temperature between 0° C. and 5° C. When addition was complete, the reaction was stirred at 20° C. for 3.5 h, then again cooled to 0° C. Addition of water (5 ml) destroyed any excess reagent and filtration of the resulting mixture through dicalite removed the unwanted inorganic residue. After drying the resulting filtrate with magnesium sulfate, evaporation under reduced pressure afforded (5-tert-butyl-2-methoxyphenyl)methanol as a pale yellow gum (4.20 g, 21.6 mmol, 96%).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][CH:16]([F:35])[C:17]1[N:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:33][CH3:34])=[CH:25][CH:24]=2)[C:19]([SH:22])=[N:20][N:21]=1>ClCCl>[F:35][CH:16]([F:15])[C:17]1[N:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:33][CH3:34])=[CH:25][CH:24]=2)[C:19]([S:22][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:20][N:21]=1
Reactant: CCc1ccc(-n2c(S)nnc2C(F)F)c2ccccc12
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSc1nnc(C(F)F)n1-c1ccc(CC)c2ccccc12
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Triethylamine (0.11 mL, 0.786 mmol) and ethyl 2-bromoacetate (80 μL, 0.72 mmol) were added to a stirred solution of 5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.655 mmol) in dichloromethane (2.6 mL). The resulting mixture was stirred for 2 h. The crude reaction mixture was purified by SGC (0-50% EtOAc/Hexanes) to afford ethyl 2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as an off-white solid (0.246 g, 96%).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCl.[C-:12]#[N:13].[Na+].[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[N:8](=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]#[N:13])[OH:9]
Reactant: ON=Cc1ccccc1
Reactant: [C-]#N
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 9.07 g (75 mmol) of benzaldoxime in 25 ml of carbon tetrachloride is added dropwise, at 5°, a solution of 45 ml of carbon tetrachloride saturated with 5.6 g (79 mmol) of chlorine gas. The mixture is stirred for 1 hour in an ice bath and then excess HCl is removed by vacuum. A saturated solution of 7.35 g (150 mmol) of sodium cyanide in water is added dropwise, at 0°. The mixture is stirred for 2 hours as it is allowed to warm to RT. An excess of aqueous sodium hydroxide is added and then the carbon tetrachloride layer is discarded. The aqueous layer is acidified and filtered, and the resulting solid is washed with water and dried to give α-oximinophenylacetonitrile, m.p.=120°-125°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:44]/[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=4)[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2cc(/C=C/c3ccccn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.4 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (0.70 g), [(2-pyridyl)methyl]triphenylphosphonium chloride (0.82 g), potassium carbonate (0.29 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethenyl)pyridine as colorless crystals (0.65 g, yield 74%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([O:11][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:2]([CH3:1])[CH:7]=1)(=[O:9])[CH3:10]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(C)=O)cc1C
Reaction time: 66 h

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (5 g), methyl bromoacetate (3.70 ml) and anhydrous potassium carbonate (5.52 g) in acetone (100 ml) was stirred for 66 hours. The mixture was filtered and the filtrate evaporated to give an oil which crystallised on standing giving methyl 4-acetyl-2-methylphenoxyacetate, 7.2 g: m.p. 51°-53° C.; NMR (d6DMSO) δ 7.79 (1H, s), 7.77 (1H, d), 6.94(1H,d), 4.93 (2H, s), 3.71 (3H, s), 2.50 (3H, s+DMSO), 2.24 (3H, s).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:21])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[N:41]1([C:3]2[N:8]=[C:7]([NH:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=3)[C:6]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:21])=[CH:5][N:4]=2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: C1CNCCN1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)OCc2ccccn2)cc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Product: COc1ccc(CNc2nc(N3CCNCC3)ncc2C(=O)OCc2ccccn2)cc1Cl

Procedure:
2-Methylthio-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylmethoxycarbonyl]pyrimidine (prepared in Example 81) 0.1500 g is treated with m-chloroperbenzoic acid (80%) 78.9 mg at 0° C. for 15 minutes. Piperazine 0.2398 g is added thereto. The reaction mixture is treated in the same manner as Example 82-(1). The resulting residue is purified with silica gel chromatography (solvent; ethyl acetate sole—ethyl acetate:methanol=1:1) and recrystallized from ethyl acetate: isopropyl ether (1:1) to give 2-(1-pyperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylmethoxycarbonyl)pyrimidine as a colorless powder, 75.1 mg. mp 101–103° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C@@H:6]1[C@@H:12]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22](=[O:24])[CH3:23])[C:16]=2[CH3:25])[CH2:11]OC(C)(C)[O:8][CH2:7]1)(=[O:4])=[O:3].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:5][C@H:6]([C@@H:12]1[CH2:11][O:26][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22](=[O:24])[CH3:23])[C:16]=2[CH3:25])=[N:13]1)[CH2:7][OH:8])(=[O:3])=[O:4]
Reactant: CC(=O)Oc1cccc(C(=O)N[C@H]2COC(C)(C)OC[C@@H]2OS(C)(=O)=O)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(C2=N[C@H]([C@H](CO)OS(C)(=O)=O)CO2)c1C
Temperature: 25 °C

Procedure:
(5R, 6S)-N-(5-Methanesulfonyloxy-2,2-dimethyl-1,3-dioxepan-6-yl)-3-acetoxy-2-methylbenzamide (compound [9], 34.2 g, 82.3 mmol) was dissolved in dichloromethane (340 ml) and boron trifluoride-diethyl ether complex (30.4 ml, 247 mmol) was added over 5 minutes with stirring at room temperature. The mixture was stirred for 40 hours at room temperature. Triethylamine (34.5 ml, 247 mmol) was added at not more than 15° C. and the solvent was distilled away under reduced pressure to 1/5 volume. The residue was diluted with ethyl acetate (340 ml) and washed successively with 10% brine (340 ml), 10% brine (340 ml) containing citric acid (17 g), and saturated brine (340 ml). After drying over magnesium sulfate, the solution was concentrated to 36 g to give a crude product of (2R)-2-methanesulfonyloxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)ethanol (compound [10]).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([O:16][CH3:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]2[C:12](=[C:11]([O:16][CH3:17])[CH:10]=1)[NH:13][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]2=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OCc2ccccc2)ccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2c(OC)cc(OCc3ccccc3)cc2c1=O
Yield: 79.3 %

Procedure:
4-Benzyloxy-2-methoxyaniline (2.9 g) and diethyl ethoxymethylenemalonate (2.7 g) were reacted in the same manner as in Experimental Example 1 to obtain 6-benzyloxy-3-ethoxycarbonyl-8-methoxy-4(1H)-quinolone (3.5 g). The compound (2.0 g) was subjected to hydrolysis and decarboxylation in the same manner as in Experimental Example 8 to obtain 6-benzyloxy-8-methoxy-4(1H)-quinolone (compound 26, 1.0 g).
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>O>[CH3:19][CH2:18][O:17][C:12]([C:13]1([CH3:15])[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6]1)=[O:16]
Reactant: CCOC(=O)C(C)=O
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C1(C)NC(C(=O)O)CS1
Temperature: 40 °C
Reaction time: 4 h
Yield: 19.4 %

Procedure:
L-cysteine hydrochloride monohydrate (50 g, 285 mmol) was dissolved in water (100 ml), and the pH of the solution was adjusted to 5.15 with 6N aqueous sodium hydroxide. The reaction mixture was heated to 40° C., ethyl pyruvate (38 ml, 342 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 4 hr. Water was added, and the mixture was cooled to room temperature to precipitate the crystals and the crystals were collected by filtration. The obtained crystals were washed with water, and dried under reduced pressure at 50° C. to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (trans form:cis form=88:12, 12.1 g, yield 19%). The synthesized 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (5 g, 22.8 mmol) was dissolved in ethyl acetate (40 ml), and triethylamine (6.4 ml, 45.9 mmol) was added under argon. Acetyl chloride (2.4 ml, 33.8 mmol) was slowly added dropwise, and the mixture was stirred at room temperature overnight. After completion of the reaction, water (15 ml) was added thereto, and the pH of the mixture was adjusted to 1.0 with HCl. The aqueous layer was separated, and the organic layer was washed with water (10 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution was concentrated to precipitate crystals. The crystals were collected by filtration, washed with heptane/ethyl acetate=1/1 (10 ml), and dried under reduced pressure at 50° C. to give (2S,4R)-N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester as crystals (3.3 g, yield 55%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[CH3:19][SiH:20]([CH3:24])[O:21][CH2:22][CH3:23]>C(O)C>[NH2:4][CH2:1][CH2:2][CH2:3][Si:20]([CH3:24])([CH3:19])[O:21][CH2:22][CH3:23]
Reactant: C=CCN
Reactant: CCO[SiH](C)C
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCO
Product: CCO[Si](C)(C)CCCN
Yield: 55 %

Procedure:
Into the same reactor as used in Example 1, 54.7 parts of allylamine, 1.0 part of phenothiazine and 0.0005 part as platinum atom of the same platinum complex as in Example 1 were charged, 100 parts of dimethylethoxysilane were added at 50° C. through the dropping funnel over 20 minutes, and the reaction was completed by elevating the temperature to 125° C. over 4 hours. After cooling, 5.5 parts of ethanol were added, and distillation was carried out to give 87.8 parts of γ-aminopropyldimethylethoxysilane boiling at 75° to 77° C./18 Torr. This corresponded to 55% yield based on the theoretical amount.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:5][CH:4]=1.C[Si]([Br:25])(C)C>C(Cl)Cl>[Br:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)Br
Reactant: CN(C)C(=O)Nc1ccccc1-c1ccc(CO)cc1
Solvent: ClCCl
Product: CN(C)C(=O)Nc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the intermediate obtained in Step B in 4 mL of methylene chloride was treated with 0.16 mL (1.21 mmol) of trimethylsilylbromide. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with methylene chloride then washed with aqueous saturated sodium chloride (2×). The organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum to yield 133 mg of crude product. 1H NMR (400 Hz, CDCl3): 2.78 (s, 6H), 4.5 (s, 2H), 6.4 (br s, 1H), 7.08 (t, 1H), 7.16 (dd, 1H), 7.34 (m, 4H), 7.49 (d, 1H), 8.10 (d, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH:17][C:18](=O)[CH2:19][CH2:20][CH3:21]>C(O)C>[CH2:2]([O:4][N:5]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:18]1[CH2:19][CH2:20][CH3:21])[CH3:3]
Reactant: CCON
Reactant: CCCC(=O)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1OCC
Temperature: 25 °C
Yield: 93.8 %

Procedure:
Ethoxyamine hydrochloride (2.34 g, 2.0 eq) was added to a solution of N-(4-chloroquinolin-3-yl)butyramide (3.0 g, 1.0 eq) in ethanol (75 mL). The reaction mixture was heated at reflux for 3 hours, cooled to ambient temperature, and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 2.89 g of 1-ethoxy-2-propyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([CH2:18][C:19]([OH:21])=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.[ClH:26].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:49][O:50][CH2:51][CH2:52][NH2:53]>ClCCl>[ClH:1].[ClH:26].[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([CH2:18][C:19]([NH:53][CH2:52][CH2:51][O:50][CH3:49])=[O:21])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: O=C(O)CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COCCNC(=O)CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 22.5 %

Procedure:
A mixture of 33 mg (0.088 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1H-1,4-benzodiazepine-1-acetic acid, 30 mg (0.157 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 16 mg (0.105 mmol) of 1-hydroxybenzotriazole hydrate and 14 mg (0.187 mmol) of 2-methoxyethylamine was stirred in 3 ml of dichloromethane for 3 hours. The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was chromatographed three times on silica gel using dichloromethane/methanol (94:6), dichloromethane/methanol 92:8) and ethyl acetate/methanol (9:1) for the elutions. The product was dissolved in a solution of hydrogen chloride in ethyl acetate, evaporated to dryness and the residue triturated with diethyl ether. There was obtained 5 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-N-(2-methoxyethyl)-1H-1,4-benzodiazepin-1-acetamide dihydrochloride as a red solid. MS: m/e 431.9 [M+H]+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[O:12]1[CH:18]2[CH:13]1[CH:14]=[CH:15][CH2:16][CH2:17]2>[Pd].O1CCCC1>[OH:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][CH:14]1[N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C1=CC2OC2CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1C=CCCC1O

Procedure:
If 19.11 g (0.13 mol) of phthalimide are reacted with 0.6 mol % of the palladium(0) catalyst prepared in situ as described above and one equivalent of 3,4-epoxycyclohexene in tetrahydrofuran first at 0° C. and then for 4 hours at the reflux temperature, 1.45 g (4.6% of theory) of [(1RS,2SR)-2-hydroxy-1-phthalimido-cyclohex-5-ene of melting point 112° to 114° C. are obtained after purification by chromatography over silica gel using ethyl acetate/cyclohexane 3/2. 1H NMR (270 MHz, d6 -DMSO); δ[ppm]: 7.83 (m, 4H), 5.90 (m, 1H), 5.63 (m, 1H), 4.84 (d, 1H), 4.75 (m, 1H), 3.90 (m, 1H), 2.27 (m, 1H), 2.1-1.65 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(OC(C)C)(OC(C)C)[O:25]C(C)C.C([Li])(C)(C)C.OO>C(OCC)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: OO
Agent: [Li]C(C)(C)C
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
A stirred solution of 5.40 g (14.1 mmol) (4R,9aR)-7-bromo-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 350 mL diethyl ether was cooled to −100 deg C. and 6.30 mL (5.13 g, 27.7 mmol) triisopropyl borate was added. To this solution, 11.3 mL (16.9 mmol) tert-butyllithium (1.5 M in n-pentane) was added dropwise and the reaction was stirred at this temperature for another 15 min. The reaction was warmed to −75 deg C., stirred for another 15 min., warmed to 0 deg C., stirred again for 15 min. and then 6.85 mL acetic acid (50% in water) and 0.12 g 35% hydrogen peroxide solution were added successively. The cooling bath was removed and the reaction was stirred for 1 h at room temperature. The reaction mixture was extracted with 10% aqueous thiosulfate solution, the organic layer was washed with brine, dried over magnesium sulfate and filtered. The solvent was removed at a rotary evaporator and the residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant to give the compound as a light yellow solid (75.4%).
Reaction SMILES: [P:1]([O:19][C:20]([C:23]1[N:28]=[CH:27][C:26]([C:29]2[C:43]([F:44])=[C:42]([C@H:45]3[CH2:49][CH2:48][CH2:47][O:46]3)[C:32]3[NH:33][C:34]([NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])=[N:35][C:31]=3[CH:30]=2)=[CH:25][N:24]=1)([CH3:22])[CH3:21])([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].CCO.[OH-].[Na+:54]>[Pd].O>[P:1]([O-:11])([O-:3])([O:19][C:20]([C:23]1[N:28]=[CH:27][C:26]([C:29]2[C:43]([F:44])=[C:42]([C@H:45]3[CH2:49][CH2:48][CH2:47][O:46]3)[C:32]3[NH:33][C:34]([NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])=[N:35][C:31]=3[CH:30]=2)=[CH:25][N:24]=1)([CH3:21])[CH3:22])=[O:2].[Na+:54].[Na+:54]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)(OCc4ccccc4)OCc4ccccc4)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)OP(=O)([O-])[O-])nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
A 1 L round bottom flask was charged with (R)-dibenzyl 2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate (24) (9.37 g, 13.61 mmol), EtOH (300 mL), water (150 mL), Pd/C (10 wt % dry basis, wet, Degussa type, 3 g) and 1 M aqueous NaOH (27.22 mL, 27.22 mmol). The suspension was evacuated for 3 min (needle to pump) then placed under an atmosphere of hydrogen gas (balloon). After stirring 2.5 h at 23° C., the reaction was filtered through a 0.22 μm PES membrane (disposable Corning filter system, 1 L, polystyrene, #431098) to remove catalyst and washed with EtOH (50 mL). The resulting solution was concentrated, the residue dissolved in water (80 mL), treated with MeCN (80 mL), then frozen and lyophilized to give disodium (R)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate (W) (7.10 g, 12.81 mmol, 94.12%) as a white solid. ESMS (M+1)=509.3; 1H NMR (300 MHz, D2O) δ 8.58 (s, 2H), 6.92 (d, J=6.3 Hz, 1H), 5.13 (t, J=7.5 Hz, 1H), 3.98-3.81 (m, 2H), 3.04 (q, J=7.2 Hz, 2H), 2.26 (t, J=5.7 Hz, 1H), 1.97-1.92 (m, 2H), 1.67 (s, 6H) and 1.01 (t, J7.2 Hz, 3H) ppm.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9][CH:10]1[N:13]([CH2:14][C:15]([OH:17])=O)[C:12](=[O:18])[CH2:11]1.ClC(OCC)=O.[CH2:25]([O:32][NH2:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:25]([O:32][NH:33][C:15](=[O:17])[CH2:14][N:13]1[CH:10]([S:9][CH3:8])[CH2:11][C:12]1=[O:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NOCc1ccccc1
Reactant: CSC1CC(=O)N1CC(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSC1CC(=O)N1CC(=O)NOCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
Triethylamine (2 ml) was added to a solution of (4-methylthio-2-oxo-azetidin-1-yl)acetic acid (1.67 g) in dry chloroform (15 ml) cooled to -10° C. After 5 mins ethyl chloroformate (1.6 ml) was added, then after a further 5 mins a solution of O-benzylhydroxylamine free base (1.67 g) in chloroform was added. The solution was allowed to warm to room temperature and stirred for 16 hours then washed with brine, dried (MgSO4) and evaporated. Chromatography of the residue on silica gel (petroleun ether/ethyl acetate) gave N-benzyloxy-(4-methylthio-2-oxo-azetidin-1-yl)acetamide as a clear gum (22% yield).