Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[CH2:11]([O:13][CH2:14][CH2:15]Br)[CH3:12]>C(O)C>[CH2:11]([O:13][CH2:14][CH2:15][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:1][CH3:2])[CH3:12]
Reactant: CCNCc1ccccc1
Reactant: CCOCCBr
Solvent: CCO
Product: CCOCCN(CC)Cc1ccccc1
Yield: 61 %

Procedure:
The synthesis of FEA was carried out in a manner similar to that of BnEO (process 2) using N-ethylbenzylamine (15 mL, 0.101 mol), bromoethyl ethyl ether (17 mL, 0.101×1.5 mol), and ethanol (100 mL) as a solvent. BnEE (12.79 g, 61.69 mmol, yield 61%) was obtained as a pale yellow clear liquid.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25]Br>>[F:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)ccc2F)c1
Yield: 48.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (200 mg, yield: 48.5%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7](=[NH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)#[N:22]>C(#N)C>[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:20]=[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(CN=C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.1 %

Procedure:
270 g (2.0 mol) of anhydrous K2CO3 were added to a solution of 150 g (0.8 mol) of 97% pure benzophenone imine and 144.8 g (0.74 mol) of p-cyanobenzyl bromide in 450 ml of acetonitrile, and the mixture was left to stir at room temperature for 6 h. The inorganic salts were filtered off with suction and then most of the solvent was removed by distillation, 300 ml of water were added to the residue, and the mixture was extracted several times with ethyl acetate. The organic phase was washed 2× with water, dried over Na2SO4 and evaporated to dryness. Digestion with ether resulted in 180 g of white crystals, melting point 101-102° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>>[C:28]1([O:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH3:22])[CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1ccccc1
Reactant: COc1cc(F)ccc1-c1ccc(OC(C)=O)c(C(=O)O)c1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(F)ccc1-c1ccc(OC(C)=O)c(C(=O)Oc2ccccc2)c1

Procedure:
A mixture of 2-acetoxy-5-(4'-fluoro-2'-methoxyphenyl)-benzoic acid (0.1 mole), phosphorous oxychloride (0.1 mole), and phenol (0.12 mole), is heated at 75° C. until no more hydrogen chloride is evolved. The product, phenyl-2-acetoxy-5-(4'-fluoro-2'-methoxyphenyl)-benzoate, is isolated by partitioning the reaction mixture between benzene and dilute sodium bicarbonate solution, and subjecting the benzene solution to chromatography on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1>O1CCCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:20]([O:21][CH3:22])[CH3:19])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(-c2ccc(Br)cc2)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN1CCOCC1
Product: CON(C)C(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(4′-Bromobiphenyl-4-yl)acetic acid (12 g, 37 mmol) was dissolved in a mixed solvent of tetrahydrofuran (200 mL) and methanol (200 mL), and N,O-dimethylhydroxylamine hydrochloride (5.4 g, 56 mmol), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (15 g, 60 mmol) and N-methylmorpholine (6.1 mL, 56 mmol) were added, followed by stirring at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the organic layer was washed with water. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.45 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (12 g, 37 mmol) as a white solid (yield 100%).
Reaction SMILES: [C:1]([C:3]1[NH:17][C:16]2[C:18]3[C:4]=1[CH2:5][C@@H:6]1[C@@H:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:19][C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:8][N:7]1[CH3:27])#[CH:2].N1C2C(=CC=CC=2)C=CC=1>C(O)C.[Pd]>[CH3:27][N:7]1[C@H:6]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:18]=3[C:4]([CH2:5]2)=[C:3]([CH:1]=[CH2:2])[NH:17]4)[CH2:10][C@H:9]([NH:19][C:20](=[O:26])[N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:8]1
Reactant: C#Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Agent: [Pd]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: C=Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Yield: 14.9 %

Procedure:
200 mg of 3-(2-ethynyl-6-methyl-8α-ergolinyl)-1,1-diethylurea is hydrogenated at room temperature and under normal pressure in 35 ml of ethanol with 200 mg of palladium/calcium carbonate (2%) and 200 mg of quinoline. After the mixture has been filtered off from the catalyst, it is evaporated. The residue is chromatographed over silica gel with methylene chloride/ethanol 6:1, thus obtaining 30 mg of 3-(6-methyl-2-vinyl-8α-ergolinyl)-1,1-diethylurea after recrystallization from ethanol/hexane, mp 145°-150° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([CH2:18][C:19](=O)[CH3:20])[C:15]([CH3:17])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:20][C:19]1[N:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[C:15]([CH3:17])=[CH:14][CH:18]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 77.3 %

Procedure:
A mixture of 4-nitrobenzenesulfonamide (30.3 g, 0.15 mol), acetonylacetone (34.2 g, 0.30 mol) and 4-toluenesulfonic acid (3.0 g, catalyst) in 200 mL of toluene was heated at reflux under nitrogen using a Dean-Stark trap for 18 hours. The reaction was cooled and filtered through silica gel (700 g), eluting with mixtures of ethyl acetate and hexane. Removal of solvent in vacuo gave a crude brown solid. The crude product in ethyl acetate was treated with activated charcoal, and recrystallized from ethyl acetate and hexane to afford 4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]nitrobenzene (32.5 g, 77%) as a light yellow solid: mp (DSC): 101–103° C. Anal. Calc'd. for C12H12N2O4S: C, 51.42; H, 4.32; N, 9.99; S, 11.44. Found: C, 51.62; H, 4.18; N, 9.96; S, 11.31.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:14]([N:6]1[C:5]2=[C:4]([CH3:18])[N:3]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:2]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7]1=[O:13])[CH:15]([CH3:17])[CH3:16]
Reactant: COc1ccc(Cn2c(Cl)c3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Reactant: Nc1ccccc1
Product: COc1ccc(Cn2c(Nc3ccccc3)c3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Temperature: 150 °C

Procedure:
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (12 mg, 0.03 mmol) is placed in a Biotage microwave tube, and then aniline (0.22 mL) is added. The mixture was heated at 150° C. for 3 h., and then purified by a semi-preparative HPLC to give 4 mg of pure product. MS (ESI) m/z 447.3 [M+H]+.
Reaction SMILES: [CH2:1](Cl)[C:2]#[CH:3].[CH3:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1>CO>[CH3:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:3][C:2]#[CH:1]
Reactant: C#CCCl
Reactant: CC1CCCCN1
Solvent: CO
Product: C#CCN1CCCCC1C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A flask was charged with propargyl chloride (17.27 g, 0.232 mol, 70 wt % in toluene) in dry methanol (21 mL) under nitrogen atmosphere. (+/−)-2-Methyl-piperidine (55 mL, 0.46 mol) in dry methanol (43 mL) was added via drop-wise addition over 30 minutes. The material was stirred overnight. The mixture was placed on a rotovap and about half the volume of methanol was stripped, providing a precipitate. The solid precipitate was removed by filtration, rinsing through with ether (150 mL). The filtrite was placed on the rotovap and concentrated. Another small amount of precipitate was removed by filtration. The remaining oily product was purified by distillation providing 7.23 g (bp=180-185° C.) of (+/−)-2-methyl-1-prop-2-ynyl-piperidine as a clear mobile oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(=O)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a solution of 4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexan-1-one (450 mg, 1.41 mmol, 1.00 equiv) in DCM (10 mL) was added methanesulfonyl chloride (242 mg, 2.11 mmol, 1.50 equiv) and triethylamine (430 mg, 4.25 mmol, 3.00 equiv) via syringe under nitrogen. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was diluted with 50 mL of DCM, washed with brine, dried over anhydrous sodium sulfate and evaporated to give 500 mg (89%) of [(3S)-12-[(4-oxocyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][O:53][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][OH:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CC(=O)Cl
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 6k (2.32 g, 2.69 mmol) was dissolved in 12 mL methanol, followed by addition of acetyl chloride (16 μL, 0.40 mmol). The reaction mixture was stirred for 1.5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 6m (1.22 g, pale yellow grease), yield: 60.7%. 1H NMR (400 MHz, CD3OD): δ 7.54-7.52 (m, 2H), 7.41 (d, 1H), 7.32-7.22 (m, 13H), 7.18 (d, 2H), 7.08-7.04 (m, 4H), 4.91-4.85 (m, 3H), 4.75 (d, 1H), 4.52 (d, 1H), 4.17-4.09 (m, 3H), 4.00 (d, 1H), 3.94-3.83 (m, 3H), 3.75-3.69 (m, 2H), 3.09 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:21]1[CH2:22][CH2:23][NH:18][CH2:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: O=C1CCNCC1
Product: C1=C(c2c[nH]c3ccc(OCc4ccccc4)cc23)CCNC1

Procedure:
Starting with 5.0 gm (22 mMol) 5-benzyloxyindole and 6.88 gm (45 mMol) 4-piperidone.HCl.H2O, 6.53 gm (97.6%) of 5-benzyloxy-3-[1,2,5,6-tetrahydro-4-pyridinyl]-1H-indole were recovered as a light yellow solid by the procedure described in Preparation I. The material was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:20][CH2:21]Br)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26].C(OCC)(=O)C.C(OC(C)C)(C)C>O>[CH2:1]([O:8][N:9]([CH2:20][CH2:21][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)N(CCBr)OCc2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CCOP(=O)(CCN(OCc1ccccc1)S(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 160 °C
Reaction time: 10 h
Yield: 57 %

Procedure:
A mixture of N-benzyloxy-N-(2-bromoethyl)-p-toluenesulfonamide (16.2 g.) and triethyl phosphite (21.0 g.) was stirred at 160° C. for 10 hours and then cooled to ambient temperature. To the reaction mixture was added ethyl acetate and water. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an oily residue (20.5 g.). A small volume of isopropyl ether was added to the residue to give crystals, which was separated by filtration and dried to give crystalline diethyl 2-(N-benzyloxy-N-tosylamino)ethylphosphonate (10.6 g.). The object compound (2.1 g.) was also recovered from the mother liquor by subjecting to a column chromatography on silicagel (developing solvent: chloroform)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:29])([CH3:28])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8]CC.[OH-].[K+].CN1CCN(C)C1=O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:29])([CH3:28])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)c(Cl)c1
Temperature: 150 °C
Yield: 48.9 %

Procedure:
One hundred grams of 3-phenoxybenzyl 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl ether and 25 g of potassium hydroxide were added to 300 ml of 1,3-dimethyl-2-imidazolidinone (to be abbreviated as DMI hereinafter), and the mixture was stirred at 150° C. for hours. The reaction mixture was cooled to room temperature, poured into water, acidified with a concentrated hydrochloric acid, and extracted with benzene. The benzene solution was washed with water, and dried. Benzene was evaporated under reduced pressure. The resulting oily residue was purified by column chromatography (silica gel; eluent: benzene) to give 45.6 g 3-phenoxybenzyl 2-(3-chloro-4-hydroxyphenyl)-2-methylpropyl ether having a melting point of 68° to 69° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:29]=[CH:28][C:18]([CH:19]=[N:20][CH:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])=[CH:17][CH:16]=1.O>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:19]([NH:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])[C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:29][CH:28]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)CC(CO)N=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@@H](CO)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,4-dibromobenzene (11.4 g, 48.35 mmol) in ether (120 mL) at −30° C. was added n-butyllithium (24.2 mL, 2.0M cyclohexane solution) over 10 minutes. The reaction mixture was stirred for 45 minutes, whereupon a solution of (S) 2-[(4-fluorobenzylidene)-amino]-4-methylpentan-1-ol (maximum 2.16 g, 9.67 mmol from the previous step) in ether (30 mL) was added dropwise. After 2 hours, during which the reaction mixture was allowed to warm to 0° C., water (200 mL) was added. The product was extracted with ethyl acetate (150 mL), washed with brine (100 mL), dried over MgSO4, filtered, concentrated in vacuo, and purified on a short plug of silica gel (20% ethyl acetate/hexane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentan-1-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12])[CH3:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][N:9]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[C:10]=1[CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)Cc1c(CC)n[nH]c1CC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cc1c(CC)nn(Cc2ccc([N+](=O)[O-])cc2)c1CC
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.5 %

Procedure:
To a solution of (3,5-diethyl-1H-pyrazol-4-yl) acetic acid ethyl ester (10.95 g, 52.1 mmol) and 4-nitrobenzyl bromide (14.625 g, 68 mmol) in acetonitrile (110 mL) is added K2CO3 (10.80 g, 78.1 mmol) and the mixture is stirred for 48 hours at room temperature. The reaction mixture is poured into water and extracted twice with ethyl acetate. The organic phase is dried over MgSO4 and evaporated under reduced pressure. The residue is purified by MPLC with ethyl acetate/cyclohexane to yield 12.50 g [3,5-diethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]acetic acid ethyl ester (ESI mass spectrum: [M+H]+=346; Retention time HPLC: 1.42 min (method B)). b) To a solution of [3,5-diethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]acetic acid ethyl ester (6.66 g, 19.3 mmol) in methanol (500 mL) is added Raney nickel (500 mg) and the mixture is hydrogenated at 50 psi and room temperature. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 4.38 g of the title compound (ESI mass spectrum: [M+H]+=316; Retention time HPLC: 1.09 min (method B)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O.CCOC(C)=O>C(O)C.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:27]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=2[Cl:25])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])c(Cl)c1
Yield: 36 %

Procedure:
To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (3.0 g, 11.3 mmol) in ethanol (10 mL) and toluene (40 mL), was added Na2CO3 (14.17 mL, 2 M), 2-chloro-4-methoxyphenylboronic acid (3.17 g, 17.0 mmol), and Pd(PPh3)2Cl2 (0.48 g, 0.68 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H2O (500 mL). The EtOAc layer was washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc-Hexane) gave 1.51 g (36%) of 2-benzyloxy-4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridine as a viscous oil: MS (AP) m/z 370.8 [(M+H)+, 100].
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[C:22]([O:30][CH2:31]Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH2:31][O:30][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19]
Reactant: O=C(OCCl)c1ccccc1
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)OCOC(=O)c1ccccc1
Yield: 35.1 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 500 mg) and chloromethyl benzoate (712 mg) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-9, 198 mg) as a colorless solid.