Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([CH3:21])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[C:6]=2[C:19]=1[CH3:20].[C:23]1([C@@H:29]([NH2:31])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:23]1([C@@H:29]([NH:31][C:2]2[C:3]([CH3:22])=[C:4]([CH3:21])[C:5]3[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[C:6]=3[C:19]=2[CH3:20])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C2c3c(C)c(Br)c(C)c(C)c3OC2(C)C)cc1
Reactant: C[C@H](N)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C2c3c(C)c(N[C@@H](C)c4ccccc4)c(C)c(C)c3OC2(C)C)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere, to toluene (10 mL) were added 5-bromo-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran (2 g) and (S)-(−)-1-phenylethylamine (0.94 g), then palladium acetate (5 mg) and (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-dinaphthyl (41.6 mg), and further sodium tert-butoxide (0.86 g). The mixture was stirred at 100° C. for 6 hours. Diluted hydrochloric acid was added to the reaction solution. The organic layer was separated and washed with a 10% aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was subjected silica gel column chromatography, which was eluted with ethyl acetate-n-hexane [1:19], to obtain the title compound (2.13 g, 96.0%
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][C@@H:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH2:20]Cl)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:46])[C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([OH:45])[CH:39]=2)[CH2:33][CH2:32]1.C(OCC)(=O)C>CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][C@@H:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([O-:24])=[O:23])=[C:17]([CH2:20][N+:31]4([CH3:30])[CH2:36][CH2:35][N:34]([C:37](=[O:46])[C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([OH:45])[CH:39]=5)[CH2:33][CH2:32]4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CN1CCN(C(=O)c2ccc(O)c(O)c2)CC1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1csc(NC=O)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4ccc(O)c(O)c4)CC3)CS[C@H]12)c1csc(NC=O)n1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 115.9 %

Procedure:
To a solution of 7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid (syn isomer) (920 mg) in N,N-dimethylformamide (5 ml) was added 1-methyl-4-(3,4-dihydroxybenzoyl)piperazine (945 mg) at 0° C. and the mixture was stirred at 0° C. for 3.5 hours. The mixture was added dropwise to ethyl acetate (200 ml) under stirring and the pulverized product was collected by filtration and washed with ethyl acetate to give 7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-methyl-4-(3,4-dihydroxybenzoyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (1.53 g).
Reaction SMILES: [CH:1]12[CH2:18][CH:8]([CH2:9][N:10]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:11]1)[C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=1.[C:19](Cl)([CH3:21])=[O:20].[Cl-].[Al+3].[Cl-].[Cl-].C([O-])(O)=O.[Na+]>ClCCCl>[C:19]([C:5]1[CH:4]=[CH:3][C:2]2[CH:1]3[CH2:18][CH:8]([CH2:9][N:10]([C:12](=[O:17])[C:13]([F:15])([F:16])[F:14])[CH2:11]3)[C:7]=2[CH:6]=1)(=[O:20])[CH3:21]
Reactant: CC(=O)Cl
Reactant: O=C(N1CC2CC(C1)c1ccccc12)C(F)(F)F
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Reaction time: 0.5 h

Procedure:
1-(10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (253 mg, 1.0 mmol) and AcCl (0.68 mL, 10 mmol) were dissolved in DCE (3 mL) and treated with aluminum chloride (AlCl3) (667 mg, 5.0 mmol). The resulting yellow mixture was stirred for 30 minutes then poured over ice and saturated aqueous NaHCO3 solution. After stirring 20 minutes the mixture was extracted with CH2Cl2 (3×30 mL). The organic layer was dried through a cotton plug then concentrated to a orange-yellow oil (255 mg, 86%).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:43]1[C:48]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=2[F:56])=[C:47]([F:57])[C:46]([O:58][CH3:59])=[C:45]([CH:60]=[O:61])[CH:44]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:1]1([C:43]2[C:48]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=3[F:56])=[C:47]([F:57])[C:46]([O:58][CH3:59])=[C:45]([CH:60]=[O:61])[CH:44]=2)[CH2:3][CH2:2]1
Reactant: COc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2F)c1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Cyclopropylboronic acid (1.01 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.323 g), a 2 M aqueous sodium carbonate solution (7.87 mL), and tris(dibenzylideneacetone)dipalladium(0) (0.360 g) were added at room temperature to a toluene (30 mL) solution of 6-bromo-2,2′,4′-trifluoro-3-methoxybiphenyl-4-carbaldehyde (1.36 g), and the mixture was stirred at 100° C. for 16 hours in an argon atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.11 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30].O>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C:3]([OH:4])([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[CH2:2][NH:1][C:29](=[O:30])[CH2:28][Cl:27])=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cccc(C(O)(CN)c2ccc(Br)cc2)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cccc(C(O)(CNC(=O)CCl)c2ccc(Br)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 2-amino-1-(4-bromo-phenyl)-1-(3-methoxy-phenyl)-ethanol (0.94 g, 2.92 mmol) in toluene (10 mL) at 0° C. was added triethylamine (0.41 mL, 3.07 mmol). To the reaction mixture was added a solution of chloroacetylchloride (0.23 mL, 2.92 mmol) in toluene (1 mL) and the reaction was stirred at 0° C. for 30 min. and at room temperature for 1 h. To the reaction was added cold water (10 mL) and the mixture was stirred for 10 min. EtOAc was added (20 mL) and the layers were separated. The aqueous layer was washed with EtOAc (2×20 mL) and the combined organic extracts were dried over MgSO4, and concentrated. Purification by flash chromatography with hexanes/EtOAc (4:1) afforded 1.08 g of N-[2-(4-bromo-phenyl)-2-hydroxy-2-(3-methoxy-phenyl)-ethyl]-2-chloro-acetamide. 1HNMR (400 MHz, CDCl3) δ 7.45-7.41 (comp, 2H), 7.29-7.20 (comp, 3H), 6.97-6.96 (m, 1H), 6.93-6.90 (m, 1H), 6.86-6.85 (m, 1H), 6.85-6.79 (m, 1H), 4.14-3.98 (comp, 2H), 3.95 (s, 2H), 3.77 (s, 3H), MS (M+1) 380.0, 382.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1.[CH3:19][O:20][CH2:21][C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.C(#N)C.O.C(OCC)(=O)C>[Cl:14][C:12]1[CH:13]=[C:8]2[C:7](=[O:17])[C:6]3[CH:18]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][O:20][CH3:19])[CH:3]=[CH:4][C:5]=3[CH:16]=[CH:15][C:9]2=[N:10][CH:11]=1
Reactant: COCC(=O)O
Reactant: Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COCC(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7-amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.70 g, 2.7 mmol) was dissolved in 20 mL of dry dichloromethane and 5 mL of dry acetonitrile. Methoxyacetic acid (0.32 mL, 4.1 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (0.79 g, 4.1 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (0.55 g, 4.1 mmol) were added and the solution was stirred at ambient temperature. After 12 hours, the reaction solution was poured into 300 mL of ethyl acetate and 100 mL of water. The organic layer was separated and washed with 100 mL of brine. The organic layer was separated, dried with magnesium sulfate, filtered, concentrated and purified by flash column chromatography (0-100% ethyl acetate/hexanes gradient) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.29 (s, 1H); 8.94 (d, 1H); 8.58 (d, 1H); 8.46 (d, 1H); 8.10 (dd, 1H); 7.77 (d, 1H); 7.40 (d, 1H); 7.20 (d, 1H); 4.04 (s, 2H); 3.36 (s, 3H). LRMS (APCI) calculated for C17H14ClN2O3 [M+H]+, 329.1; found 329.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][CH3:21])[N:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=3)([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][CH3:21])[N:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C2C(=O)Nc3cc(Cl)ccc32)nc(OC)n1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)nc(OC)n1
Temperature: 80 °C

Procedure:
A mixture of rac-6-chloro-3-(2,6-dimethoxy-pyrimidin-4-yl)-1,3-dihydro-indol-2-one (0.23 g, 0.75 mmol) (from Example 29a supra), 3-chlorobenzyl bromide (0.19 g, 0.9 mmol) (Aldrich), potassium iodide (0.15 g, 0.9 mmol) and potassium carbonate (0.23 g, 1.66 mmol) in acetone (20 mL) was heated at 80° C. for 30 minutes. After cooling, mixture was diluted with ethyl acetate and washed with water and brine. Aqueous layers were back washed with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-hexanes, 1:6, V/V) to give rac-6-chloro-3-(3-chloro-benzyl)-3-(2,6-dimethoxy-pyrimidin-4-yl)-1,3-dihydro-indol-2-one as an orange solid. (Yield 0.21 g, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].ClCCC(C)(C)C(O)=O.Cl[CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Brc1cnc2[nH]nc(I)c2c1
Agent: CC(C)(CCCl)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nc(I)c2cc(Br)cnc21
Temperature: -40 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
5-Bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (4 g, 12.4 mmol) in DMF (50 ml) under nitrogen was stirred at −40° C. for 10 minutes. Sodium hydride (0.9 g, 37 mmol) was added to the DMF solution and the resulting mixture was allowed to stir at −40° C. for 1 hour. Then 2,2-dimethyl-propionic acid chloromethyl ester (chloromethyl pivalate) was added dropwise to the mixture. The reaction was stirred for another 2 hours. The reaction was quenched with saturated NH4Cl (20 ml) and worked up with ethyl acetate, brine, dried with Na2SO4, concentrated to dryness. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2,2-dimethyl-propionic acid 5-bromo-3-iodo-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (5 g, 92% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.07 (s, 9H), 6.37 (s, 2H), 8.30 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:13][C:12]=1[CH3:24])C.[Cl-].[Na+].Cl>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[N:13]=[C:12]([CH3:24])[C:11]([CH2:10][OH:9])=[CH:16][CH:15]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2)nc1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(F)cc2)ccc1CO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4.67 g (123 mmol) lithium aluminium hydride was suspended in 220 ml tetrahydrofuran (THF) and stirred for 20 min. at room temperature. The mixture was cooled to 0° C. and a solution of 15.95 g (61.5 mmol) 6-(4-Fluoro-phenyl)-2-methyl-nicotinic acid ethyl ester (WO 03/068749) in 100 ml added within 15 min. at the same temperature. The mixture was stirred overnight at room temperature (r.t.) and cooled to 0° C. 200 ml of saturated sodium chloride solution were added drop by drop and stirring continued for 60 min. Concentrated HCl was added carefully to adjust the pH to 5. Precipitated salts were filtered off and washed with THF. The combined THF-solutions were evaporated and the residue extracted twice with ethyl acetate. The organic phase was dried (sodium sulphate) and evaporated. The orange resin crystallized after a short time, was stirred with ethyl acetate/n-heptane 1:3, isolated by filtration, washed with tert-butyl-methyl ether and dried. The combined mother liquor from the washings was evaporated and the crystalline precipitate treated as above. The combined yield was 9.25 g (69%) of pale yellow powder.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C[O-].[Na+].[C:25]([P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])([P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH2:26].[Cl-].[NH4+].[Cl-].[Na+]>C(O)(C)C>[CH2:37]([O:36][P:35]([O:39][CH2:40][CH3:41])([CH:25]([P:27]([O:28][CH2:29][CH3:30])([O:31][CH2:32][CH3:33])=[O:34])[CH2:26][CH:2]([C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:42])[CH3:38]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CCOP(=O)(OCC)C(CC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Under a nitrogen atmosphere, dibenzyl malonate (1.71 g) was dissolved in isopropanol (10 ml) and sodium methoxide (27 mg) was suspended therein. A solution of tetraethyl ethenylidenebisphosphonate (1.51 g) in isopropanol (5 ml) was added dropwise thereto at room temperature and stirred for 2 hours. A saturated aqueous ammonium chloride solution (2.5 ml) and a saturated aqueous sodium chloride solution were added to the reaction mixture, followed by extraction (twice) with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (chloroform:acetone=9:1 to 2:1) to obtain benzyl 4,4-bis(diethoxyphosphinoyl)-2-benzyloxycarbonylbutyrate (1.91 g, yield 65%).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH3:9])C.[C:26]1([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38][O:39]S(C3C=CC(C)=CC=3)(=O)=O)[N:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:50][C:34]1[O:33][C:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:36][C:35]=1[CH2:37][CH2:38][O:39][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:25])=[O:3])=[CH:19][CH:20]=1
Reactant: CCCCC(Cc1ccc(O)cc1)(Oc1ccccc1)C(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: CCCCC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 2-(4-hydroxybenzyl)-2-phenoxy-hexanoic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.97-7.94 (m, 2H), 7.42-7.40 (m, 3H), 7.31-7.27 (m, 2H), 7.06 (t, 1H, J=7.43 Hz), 6.98 (t, 4H, J=8.99 Hz), 6.75 (d, 2H, J=8.60 Hz), 4.17 (t, 2H, J=6.65 Hz), 3.29 (s, 2H), 2.96 (t, 2H, J=6.65 Hz), 2.36 (s, 3H), 2.10-1.98 (m, 2H), 1.42-1.16 (m, 4H), 0.79 (t, 3H, J=7.04 Hz); MS (ES+) calcd for C31H34NO5: Found m/e 500.2 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][C@@H:15]([C:17]2[CH:28]=[CH:27][C:20]3[O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24][C:19]=3[CH:18]=2)[O:14][C:13]1=[O:29])[CH2:2][CH:3]=[CH2:4].C12BC(CCC1)CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:47]([CH:50]([S:54]([C:57]1[CH:62]=[CH:61][CH:60]=[C:59](Br)[CH:58]=1)(=[O:56])=[O:55])[CH2:51][CH:52]=[CH2:53])[CH:48]=[CH2:49]>C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:22]1([CH3:25])[O:21][C:20]2[CH:27]=[CH:28][C:17]([C@H:15]3[O:14][C:13](=[O:29])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH2:4][C:61]4[CH:60]=[CH:59][CH:58]=[C:57]([S:54]([CH:50]([CH2:51][CH:52]=[CH2:53])[CH2:47][CH:48]=[CH2:49])(=[O:55])=[O:56])[CH:62]=4)[CH2:16]3)=[CH:18][C:19]=2[CH2:24][O:23]1
Reactant: C=CCC(CC=C)S(=O)(=O)c1cccc(Br)c1
Reactant: C=CCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(CC=C)S(=O)(=O)c1cccc(CCCCOCCCCCCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of (5R)-3-[6-(3-buten-1-yloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.00 g) in THF (2 ml) was added a 0.5M solution of 9-borabicyclo[3.3.1]nonane (9-BBN) in THF (6 ml). The solution was stirred at room temperature under nitrogen for 2 h. Tripotassium phosphate (1.05 g) in water (1.5 ml) was added followed by 1-[(1-allylbut-3-enyl)sulfonyl]-3-bromobenzene (0.78 g), palladium acetate (6 mg), and PPh3 (13 mg). The mixture was heated at 600 with vigorous stirring for 22 h. The mixture was allowed to return to room temperature then partitioned between water and EtOAc. The organic phase was washed with brine, dried (MgSO4), and evaporated to dryness. The residual oil was purified on silica SPE bond elut cartridge (50 g) using a gradient of 30%-50% EtOAc in cyclohexane (Gradmaster™). The appropriate fractions were evaporated to give the title compound (1.20 g) LCMS RT=3.91 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](O)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:44]2[CH:45]=[CH:46][CH:47]=C[C:43]=2[N:42]=[N:41]1.NN1CCCCC1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cn(-c2ccc(Br)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NN1CCCCC1)c1cn(-c2ccc(Br)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reaction time: 16 h
Yield: 56.2 %

Procedure:
Part B: To a stirred suspension of 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (1.23 gram, 2.99 mmol) in dry acetonitrile (40 mL) is successively added diisopropylethylamine (DIPEA) (1.15 mL, 6.6 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophos-phate (HBTU) (1.36 gram, 3.6 mmol) and 1-aminopiperidine (0.39 mL, 3.6 mmol). After stirring for 16 hours, the resulting mixture is concentrated in vacuo. The residue is dissolved in ethylacetate and an aqueous NaHCO3 solution is added. The ethylacetate layer is collected, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give a crude solid. This solid is further purified by recrystallisation from acetonitrile to give 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide (830 mg, 56% yield). Melting point: 219-221° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:19])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:9][C:10]=2[O:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Reactant: OCCCN1CCCC1
Product: Clc1ncnc2cc(OCCCN3CCCC3)cc(OC3CCOCC3)c12
Yield: 79.9 %

Procedure:
Using an analogous procedure to that described in Note [6] below Example 19, 4-chloro-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.112 g) was reacted with 1-(3-hydroxypropyl)pyrrolidine (0.062 g) to give 4-chloro-7-(3-pyrrolidin-1-ylpropoxy)-5-tetrahydropyran-4-yloxyquinazoline (0.125 g); NMR Spectrum: (CDCl3) 1.7-1.9 (m, 4H), 1.95-2.2 (m, 6H), 2.55 (br s, 4H), 2.65 (m, 2H), 3.65-3.75 (m, 2H), 4.0-4.1 (m, 2H), 4.2 (m, 2H), 4.75 (m, 1H), 6.6 (d, 1H), 6.95 (d, 1H), 8.8 (s, 1H); Mass Spectrum: M+H+ 392 and 394.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].[CH3:10][C:11]1[CH:15]=[CH:14][O:13][C:12]=1[C:16](O)=[O:17].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][C:16]([C:12]2[O:13][CH:14]=[CH:15][C:11]=2[CH3:10])=[O:17])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: Cc1ccoc1C(=O)O
Reactant: C#Cc1cccc(N)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#Cc1cccc(NC(=O)c2occc2C)c1
Temperature: 60 °C

Procedure:
To the solution of 3-ethynylaniline (1.2 mL, 11.2 mmol, 1.0 eq) in anhydrous DMF (25 mL) was added 3-methyl-furan-2-carboxylic acid (1.84 g, 1.3 eq), diisopropylethyl amine (7.85 mL, 4.0 eq), and BOP (6.72 g, 1.35 eq). After the reaction solution was heated at 60° C. for two hours, it was cooled to room temperature, diluted with EtOAc, washed sequentially with aqueous NH4Cl, water, brine, and lastly dried with anhydrous sodium sulfate. The clear solution was decanted, concentrated, and the yellow oily residue was subject to column chromatography (EtOAc-Hex from 1:100 to 1:10). The product eluting fractions were concentrated to give the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([S:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[CH2:13][CH3:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])=[N:8]1)=[O:17])[CH2:13][CH3:14]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CCCCS(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCS(=O)c1ncn(C(=O)N(CCC)CCC)n1

Procedure:
A mixture of 6.9 g. 3-n-butylsulphinyl-1,2,4-triazole, 8.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give an oily residue which subsequently solidified. This solid product was recrystallized from petroleum ether to give 1-dipropylcarbamoyl-3-n-butylsulphinyl-1,2,4-triazole, m.p. 39° - 40° C. Elemental analysis satisfactory.