Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)([CH3:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([CH3:26])([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]3[N:34]=[N:7][NH:6][C:5]=3[Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:28]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(c2cccc(C#N)c2)CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(c2cccc(-c3nn[nH]c3[Si](C)(C)C)c2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 0.55 mL, 1.10 mmol) in tetrahydrofuran (5 mL) at 0° C. under an atmosphere of nitrogen was added n-butyllithium (1.6 M in hexane, 0.69 mL, 1.10 mmol) dropwise. After 1 h, a solution of 1-benzyl-4-(3-cyanophenyl)-4-methylpiperidine (Preparation 9, 300 mg, 1.03 mmol) in tetrahydrofuran (10 mL) was added such that the internal temperature remained at 0° C. After 4.5 h, the reaction was quenched with saturated sodium hydrogencarbonate (25 mL) and the mixture was extracted with diethyl ether (3×25 mL). The extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a foam (360 mg, 86%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[BH4-].[Na+].Cl>CO.O>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
tert-Butyl 3-oxopyrrolidine-1-carboxylate (3.00 g, 16.20 mmol) was dissolved in dry MeOH (60 mL) and cooled in an ice-water bath. Sodium borohydride (0.61 g, 16.20 mmol) was added carefully and the reaction mixture was stirred at 0° C. for 15 mins. The reaction mixture was diluted with water and pH was set to −9 with HCl (1% aqueous solution). The aqueous layer was extracted with EtOAc and the organic layers were combined, dried with MgSO4, filtered and evaporated to give the title compound (3.00 g, 98.9%). 1H NMR (500 MHz, CDCl3): δ 1.42 (s, 9H), 1.85-1.96 (m, 2H), 3.26-3.33 (m, 2H), 3.38-3.47 (m, 3H), 4.38-4.40 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 28.72, 33.95, 43.99, 54.38, 70.60, 79.57, 155.07.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C@H:21](CS([O-])(=O)=O)[CH2:22][CH3:23].S(=O)(=O)(O)O>CN(C=O)C.O>[CH3:20][C@@H:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)[CH2:22][CH3:23]
Reactant: CC[C@H](C)CS(=O)(=O)[O-]
Reactant: COC(=O)COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H](C)Oc1ccc(OCC(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl 4-hydroxyphenoxyacetate (25.50 g, 140.0 mmol) and potassium carbonate (18.67 g, 135.0 mmol) in 70 ml of DMF is heated to 75°, with stirring, for 40 min. The above methanesulfonate (10.66 g, 70.0 mmol) in 5 ml of DMF is added slowly over 5 min. The reaction mixture is allowed to stand at 60° overnight. To the cooled reaction mixture is added ice water, followed by cold sulfuric acid to bring it to pH 4-5. Additional water is added and the mixture is extracted with ether (3X). The combined ether extracts are washed with 1% sulfuric acid/1% potassium dihydrophosphate, with 1% potassium dihydrophosphate (2X), then hexane is added and the organic layer is washed with 10% sodium hydroxide (5X), with water and with brine; dried; filtered and the filtrate evaporated to give methyl (R)-(-)-4-(1-methylpropoxy)phenoxyacetate, [α]D20 -20.67.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:18][CH:19]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:18][CH:19]=2)=[N:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCOC(=O)CCCCCOc1ccc(C#N)cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCOc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 14.5 %

Procedure:
A mixture of methyl thiosalicylate (0.71 g, 4.2 mmol), ethyl 6-(5-cyanopyridin-2-yl)oxyhexanoate (1.00 g, 3.8 mmol), triethylamine (0.63 ml, 4.5 mmol) and toluene (12 ml) was refluxed under nitrogen atmosphere for 30 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) and recrystallized from ethyl acetate-isopropylether to give the titled compound (0.22 g, 14%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[S:47][C:46]([S:48](Cl)(=[O:50])=[O:49])=[CH:45][CH:44]=1>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:48]([C:46]2[S:47][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=3)=[CH:44][CH:45]=2)(=[O:49])=[O:50])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (111 mg, 0.270 mmol), prepared in Step A of Example 13i, triethylamine (120 mg, 1.19 mmol) and dichloroethane (10 mL) was added 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (77.2 mg, 0.297 mmol). The reaction was stirred for 72 h and additional 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (38.5 mg) was added. The reaction was stirred for an additional 48 h. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (58 mg). MS 633 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[C@H:9]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=2)[CH2:8]1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:17]=1)[C:13]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=2)[CH2:8][C@H:9]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:28]
Reactant: Cc1ccc(C[C@@H]2CN(CCCN)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: O=C(O)c1cccnc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CN(CCCNC(=O)c3cccnc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a stirred mixture of (2R)-4-(3-aminopropyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (160 mg), nicotinic acid (33 mg) and triethylamine (0.17 ml) in dichloromethane (2 ml) was added 2-chloro-1-methylpyridinium iodide (78 mg) at room temperature. After stirring for 1.5 hours, the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (30 ml) and water (10 ml). The organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on a silica gel with dichloromethane-methanol (40:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(nicotinoylamino)propyl]piperazine (70 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19]C)=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CS(O[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])(=O)=O>>[C:17]([C:12]1[C:13](=[O:16])[N:14]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:15]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:11]=1)([OH:19])=[O:18]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCCc1ccccc1Cl
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(CCCc3ccccc3Cl)n2)cc1F
Yield: 56 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1 (7) to yield the title compound as a pale yellow solid (yield: 56.0%).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)cc3C)CC2)nn1C(C)(C)C

Procedure:
96mg (98%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(2,4-dimethylphenyl)piperazine (43 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:17](=[O:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 110 °C
Reaction time: 0.67 h

Procedure:
To a solution of 3-bromo-4-fluoronitrobenzene (696 mg, 3.16 mmol) and tributyl(1-ethoxyvinyl)tin (1.07 ml, 3.5 mmol) in 10 mL toluene, was added tetrakis(triphenylphosphine)palladium(0) (183 mg, 016 mmol). The mixture was purged with argon for 3 minutes, and then heated to 110° C. under argon for 2 days. The reaction mixture was cooled to room temperature, 3 mL 1 N HCl was added and stirred at room temperature for 40 minutes. Workup followed by column chromatographic purification (silica 10%-30% EtOAc/hexane) to give pure 1-(2-fluoro-5-nitro-phenyl)-ethanone.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:39]=[CH:40][C:41](N2CCSC2=S)=[O:42])[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38]>O1CCCC1>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:39]=[CH:40][C:41]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:19][CH2:20]2)=[O:42])[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38]
Reactant: COCCOCOc1ccc(C=CC(=O)N2CCSC2=S)cc1OC
Reactant: c1ccc(C(OCCCN2CCNCC2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCOc1ccc(C=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 94 %

Procedure:
To a solution of 620 mg (2 mmol) of the piperazine derivative in dry tetrahydrofuran (5 ml) was added a solution of 766 mg (2.0 mmol) of N-[3-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl) thiazolidine-2-thione in dry tetrahydrofuran (5 ml), and the mixture was allowed to react at room temperature overnight under argon atmosphere. The reaction mixture was concentrated by evaporation under reduced pressure, diluted with N'chloroform and washed, in turn, with 2N aqueous solution of sodium hydroxide and water. The organic layer was dried over anhydrous scdium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform - methanol ((50 : 1), to give 1.08 g (1.88 mmol) of N-[3-[3-methoxy-4-(β-methoxyethoxymetoxy) phenyl]-2-propenoyl]-N'-(3-benzhydroxypropyl)-piperazine.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH:7]1[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:8]1=[O:14].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirred solution of 42.8 parts of sodium hydride dispersion 50% in 200 parts of dimethyl sulfoxide was added dropwise slowly a solution of 50 parts of 2,4(1H,3H)-pyrimidinedione in 800 parts of dimethyl sulfoxide while the temperature was kept constant (20° C.) by cooling in an ice/water bath. 62.9 Parts of 1-fluoro-4-nitrobenzene were added and the whole was stirred overnight at 50° C. After cooling, the reaction mixture was poured into 2500 parts of water. The whole was washed with dichloromethane. The aqueous phase was brought to pH 5-6. The product was filtered off and stirred in 2-propanone. The product was filtered off and dried in vacuo at 60° C., yielding 60 parts (57.6%) of 1-(4-nitrophenyl)-2,4(1H,3H)-pyrimidinedione; mp.>300° C. (int. 23).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[Cl:32])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[O:33]([C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42][CH2:41]1)=[O:39])[C:34]([CH3:37])([CH3:36])[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:34]([O:33][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=3[Cl:32])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 2,3-dichlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (644 mg, 2.0 mmol), as prepared in the preceding step, N-tert-butoxylcarbonyl-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step (b) of Example 1, and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (1:3 ethyl acetate/hexane) to give the title compound as a colorless syrup (930 mg, 88%). 1H-NMR (300 MHz, CDCl3) δ 1.26 (m, 2 H), 1.47 (s, 9 H), 1.75 (m, 2 H), 1.90 (m, 1 H), 2.25 (s, 3 H), 2.73 (t, 2 H, J=2.0 Hz), 3.68 (d, 2 H, J=3.2 Hz), 4.13 (m, 2 H), 6.47 (d, 1 H, J=1.1 Hz), 6.53 (d, 1 H, J=0.4 Hz), 6.59 (s, 1 H), 7.34 (t, 1 H, J=8.2 Hz), 7.75 (m, 1 H), and 7.92 (m, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Mg].[Br:15][C:16]1[CH:17]=[C:18]([C:23]([C:25]2[CH:30]=[C:29]([Br:31])[CH:28]=[C:27]([Br:32])[CH:26]=2)=O)[CH:19]=[C:20]([Br:22])[CH:21]=1>O1CCCC1.C(COC)OC>[Br:15][C:16]1[CH:17]=[C:18]([C:23]2([C:25]3[CH:30]=[C:29]([Br:31])[CH:28]=[C:27]([Br:32])[CH:26]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:19]=[C:20]([Br:22])[CH:21]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: O=C(c1cc(Br)cc(Br)c1)c1cc(Br)cc(Br)c1
Agent: [Mg]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(C2(c3cc(Br)cc(Br)c3)c3ccccc3-c3ccccc32)c1

Procedure:
The corresponding Grignard compound is prepared from 144.5 g (620 mmol) of 2-bromobiphenyl and 15.3 g (580 mmol) of magnesium in a mixture of 500 ml of tetrahydrofuran and 250 ml of dimethoxyethane. A suspension of 224.0 g (450 mmol) of bis(3,5-dibromophenyl) ketone in 1000 ml of tetrahydrofuran is then added at room temperature, and the mixture is stirred for a further twelve hours. The solvent is removed in vacuo, 1000 ml of glacial acetic acid and 5 ml of hydrogen bromide are added to the residue, and the mixture is stirred for one hour. The suspension is heated under reflux for half an hour and stirred at room temperature for twelve hours. The solid is filtered off with suction, washed three times with 300 ml of ethanol and recrystallised twice from toluene. Yield: 183.2 g (289 mmol), 64.3%, purity about 99.8% (HPLC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:22]1([O:28][C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:32]2[CH:33]=[CH:34][C:29]([O:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:30][CH:31]=2)=[CH:16][CH:15]=1)[C:3]([O:2][CH3:1])=[O:21])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
To a solution of Boc-L-Tyrosine methyl ester (2.37 g, 8.0 mmol), 4-phenyoxyphenylboronic acid (2.57 g, 12.0 mmol) and pyridine (3.16 g) in CH2Cl2 (200 mL) was added copper(II) acetate (1.46 g, 8.0 mmol). After stirring at rt for 24 h, the reaction mixture was concentrated in vacuo. The remaining material was dissolved in EtOAc (200 mL) and this solution was washed with water (2×100 mL). The organic layer was concentrated in vacuo and the crude product was purified by chromatography (7:3 hexane/ethyl acetate) to give 2.39 g of product (64%). 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H), 2.95-3.14 (m, 2H), 3.72 (s, 3H), 4.57 (q, J=7.2 Hz, 1H), 5.00 (br d, J=8.0 Hz, 1H), 6.90-7.11 (m, 11H), 7.30-7.36 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.C(B1OB(C=C)OB([CH:17]=[CH2:18])O1)=C.[CH2:19]([O:26][C:27]1[N:28]=[N:29][C:30](Cl)=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:19]([O:26][C:27]1[N:28]=[N:29][C:30]([CH:17]=[CH2:18])=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 80 °C
Yield: 75.3 %

Procedure:
A vessel containing 2,4,6-triethenyl-1,3,5,2,4,6-trioxatriborinane compound with pyridine (1:1) (1.105 g, 4.59 mmol), 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1, 3 g, 9.18 mmol) and potassium carbonate (3.17 g, 22.95 mmol) was evacuated and flushed with nitrogen. Dioxane (30 ml) and water (3 ml) were added in vacuo and the reaction was degassed before tetrakis(triphenyl-phosphine)palladium(0) (0.530 g, 0.459 mmol) was added. The resulting mixture was then heated at 80° C. for 18 hours and upon cooling, was diluted with ethyl acetate and washed with saturated aqueous sodium carbonate solution. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil. This was purified by column chromatography (silica, eluting with 0-30% ethyl acetate in petrol) to afford 3,4-bis(benzyloxy)-6-ethenylpyridazine (1.1 g, 38% yield).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][CH:11]([CH2:14][OH:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[C:9]2[NH:10][CH:11]([CH2:14][O:15][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc2c1NC(CO)CO2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc([N+](=O)[O-])c3N2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
(5-Nitro-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl)-methanol (6.5 g, 31.0 mmole) was dissolved in methylene chloride (200 mL), N, N-diisopropylethylamine (10.8 mL, 62 mmole) and 4-DMAP (1.18 g) were added, followed by p-toluenesulfonyl chloride (12.85 g, 67.4 mmole) and the mixture stirred at room temperature under nitrogen overnight. The mixture was diluted with methylene chloride (100 mL), washed with HCl (1N, 200 mL), saturated sodium bicarbonate (200 mL), saturated sodium chloride (200 mL) and dried (Na2SO4). Filtration, evaporation in vacuum and column chromatography on silica gel with 1:1 hexane/methylene chloride as eluent gave 10.5 g (93%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 8.20 (d, 1H); 7.70 (d, 1H); 7.65 (dd, 1H); 7.40 (d, 2H); 7.05 (dd, 1H); 6.55 (dd, 1H); 4.10 (m, 5H); 2.40 (s, 3H).