Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]([OH:15])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]([O:15][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cn1nnn(-c2cc(N)c(F)cc2O)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cc(F)c(N)cc1-n1nnn(C)c1=O
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A mixture of 1-(5-amino-4-fluoro-2-hydroxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (5.00 g, 22.2 mmol, 1.00 equiv), ethyl 2-bromo-2-methylpropanoate (6.50 g, 4.94 mL, 33.3 mmol, 1.50 equiv), K2CO3 (6.15 g, 44.4 mmol, 2.00 equiv), and tetra-n-butylammonium bromide (716 mg, 2.22 mmol, 0.10 equiv) in acetone (220 mL) was heated at reflux overnight. After cooling to RT, the reaction mixture was concentrated to dryness. The crude product was taken in excess water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc 2×. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The crude product was absorbed onto silica gel and purified by flash chromatography and eluted with DCM:MeOH=100:0 to 98% MeOH using 1% MeOH increments to provide ethyl 2-(4-amino-5-fluoro-2-(4-methyl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenoxy)-2-methylpropanoate (5.60 g, 74%) as a clear brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7](=O)[CH2:8][CH3:9])[CH3:2].O.[NH2:17][NH2:18]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([CH2:12][CH3:13])=[N:17][NH:18][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CC(C(=O)CC)C(=O)CC
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(CC)n[nH]c1CC
Yield: 98.4 %

Procedure:
Combine 4-oxo-3-propionylhexanoic acid ethyl ester (2.49 g, 11.6 mmol) and hydrazine hydrate (0.70 g, 13.9 mmol) in glacial acetic acid (20 mL) and stir at room temperature for 88 hr. Concentrate to an oil. Partition this residue between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). Separate the organic layer; dry (sodium sulfate), filter and concentrate to provide (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (2.4 g, 98%). 1H-NMR (400 MHz, CDCl3) δ 8.64 (bs, 1H), 4.08 (q, 2H), 3.35 (s, 2H), 2.61 (q, 4H), 1.21 (m, 9H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)C1C=CC=CC=1.[OH-].[Na+]>O.CS(C)=O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6]/[N:7]=[CH:15]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: O=Cc1ccccc1
Product: CCOC(=O)C/N=C/c1ccccc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 87.2 %

Procedure:
Glycine ethyl ester hydrochloride (13.8 g (98.9 mmol)) and 50 g of toluene were mixed, and 10 g of dimethyl sulfoxide was flown thereinto at room temperature. Benzaldehyde (10.0 g (94.2 mmol)) was flown into the obtained mixture. The obtained mixture was adjusted to 12° C., and 16.5 g of a 25% aqueous sodium hydroxide solution (sodium hydroxide 104 mmol) was added dropwise over 3 hours. After completion of the dropwise addition, the obtained mixture was stirred at a temperature in a range from 11° C. to 13° C. for 20 hours. After completion of the reaction, the reaction mixture was cooled to 5° C., and 11.4 mL of water was added dropwise thereto. Thereafter, stirring was stopped to perform liquid separation, and the obtained organic layer was washed with 19 g of 20% by weight brine. The obtained organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure to obtain 43.6 g of a toluene solution of (E)-N-phenylmethyleneglycine ethyl ester (16.5 g of pure (E)-N-phenylmethyleneglycine ethyl ester). Yield: 92%
Reaction SMILES: [CH3:1][N:2]([CH:22]([CH3:24])[CH3:23])[C:3]1[C:4]([C:17]2[CH:21]=[CH:20][NH:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO>[CH3:1][N:2]([CH:22]([CH3:24])[CH3:23])[C:3]1[C:4]([C:17]2[CH:21]=[CH:20][NH:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3cc[nH]c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc[nH]c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(1H-pyrrol-3-yl)quinoxaline-6-carboxylate (70 mg, 0.22 mmol) in methanol (40 mL) was added NaOH (34.6 mg, 0.87 mmol) with stirring for 2 h at room temperature. The resulting mixture was concentrated under vacuum and extracted with dichloromethane (20 mL). The aqueous layers were combined, adjusted to pH 6 with HCl (3 N), and the product was collected by filtration to give 3-[methyl(propan-2-yl)amino]-2-(1H-pyrrol-3-yl)quinoxaline-6-carboxylic acid as a yellow solid (18.6 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=2)=[CH:4][CH:3]=1.[NH2:16][CH:17]1[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]1>>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:16][CH:17]3[CH2:18][C:19]([CH3:26])([CH3:25])[NH:20][C:21]([CH3:24])([CH3:23])[CH2:22]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CS(=O)c1nccc(-c2ccc(Br)s2)n1
Product: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1

Procedure:
4-(5-Bromo-thiophen-2-yl)-2-methanesulfinyl-pyrimidine (110 mg, 0.36 mmol) and 4-amino-2,2,6,6,-tetramethyl piperidine (0.6 ml) were heated to 130° C. for 45 minutes. Evaporation and chromatography on silicagel (TBDME/MeOH/ammonia:90/9/1) gave the title compound as slightly coloured crystals. Yield: 100 mg (70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1.C([O-])(O)=O.[Na+].Br[C:25]1[CH:30]=[CH:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[C:27](=[O:35])[C:26]=1[C:36]#[N:37]>O1CCOCC1.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>[CH2:31]([N:28]1[CH:29]=[CH:30][C:25]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=3)=[C:2]([F:1])[CH:3]=2)=[C:26]([C:36]#[N:37])[C:27]1=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCn1ccc(Br)c(C#N)c1=O
Reactant: Cc1cc(Oc2ccc(B(O)O)cc2F)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCn1ccc(-c2ccc(Oc3ccnc(C)c3)c(F)c2)c(C#N)c1=O
Yield: 67.4 %

Procedure:
To a solution of intermediate 16 (1.77 mmol) in 1,4-dioxane (6 ml) and a saturated solution of NaHCO3 (6 ml) was added intermediate 6 (0.451 g, 1.77 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.204 mg, 0.177 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 3% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 5 (0.45 g, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([O:29][CH3:30])=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:16]([O:27][CH3:28])[CH:15]=1)[O:7]2.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>N1C=CC=CC=1>[C:32]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([O:29][CH3:30])=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])=[C:16]([O:27][CH3:28])[CH:15]=1)[O:7]2)(=[O:36])[CH:33]([CH3:35])[CH3:34]
Reactant: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(OC(=O)C(C)(C)C)c(OC)c3)oc2c1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(OC(=O)C(C)C)c2c(=O)c(OC)c(-c3ccc(OC(=O)C(C)(C)C)c(OC)c3)oc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution containing 0.2 g of 5-hydroxy-3,3',7-trimethoxy-4'-(pivaloyloxy)-flavone in 3 ml of pyridine was added 0.05 ml of isobutyryl chloride and the mixture was stirred at room temperature for 3 hours. After removal of the solvent by evaporation under reduced pressure, the resulting oily residue was dissolved in 5 ml of a mixed solvent of ethanol and hexane (1:1, v/v). The solution was allowed to stand in a refrigerator overnight, during which time crystallisation occurred. The crystals were collected by filtration, washed with hexane and dried. There were obtained 200 mg of 5-(isobutyryloxy)-3,3',7-trimethoxy-4'-(pivaloyloxy)-flavone as colourless needles: m.p. 151°-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[OH-].[NH4+:14].C1COCC1>C(Cl)(Cl)Cl.CC(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:14])=[O:11]
Reactant: O=C(Cl)Cc1ccc(F)cc1Br
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)Cc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 2872.9 %

Procedure:
Combine (2-bromo-4-fluoro-phenyl)-acetyl chloride (3.5 g, 14 mmol), ammonium hydroxide (8.8 M in water, 50 mL, 0.45 mmol) and THF (10 mL) in a pressure vessel. Seal the vessel and stir the mixture overnight at RT. Dilute the mixture with chloroform-IPA (3:1, 100 mL). Wash the organic phase with aqueous saturated sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to give the title compound as a white solid (3.0 g, 93%). MS (ES) m/z 232/234 [M+1]+.
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]C.C(O)CCCCCCCCCCCCC.C(O)CCCCCCCCCCCCCC.C(O)CCCCCCCCCCCCCCC>>[CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCO
Agent: CCCCCCCCCCCCCCCCO
Agent: CCCCCCCCCCCCCCCO
Agent: CCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCO

Procedure:
1-tridecanol; 1-tetradecanol; 1-pentadecanol; 1-hexadecanol;
Reaction SMILES: [C:1]1([Se:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>[Os](=O)(=O)(=O)=O.CC(C)=O>[C:9]1([Se:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=[Se](c1ccccc1)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc([Se]c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A 100 ml Fischer-Porter glass pressure reactor, equipped with a magnetic stirring bar was successively charged with 2.5 g (0.01 moles) of diphenylselenoxide, 10 ml acetone, 10 ml 0.1 N potassium carbonate solution, and 0.63 ml of an osmium tetroxide solution (4% OsO4 in 0.1 N K2CO3). The reactor was attached to a gas manifold, flushed with nitrogen and then pressurized with 80 psig ethylene. The mixture was magnetically stirred at room temperature for two hours until the reaction of the gaseous olefin ceased as evidenced by a constant gas pressure. Sodium bisulfate (5 ml of a 10 wt. % aqueous solution) was added to reduce both the remaining selenoxide and osmium tetroxide. The reaction mixture was transferred to a separatory funnel and the oily layer of diphenylselenide, formed during reaction, separated from the aqueous layer containing the solvent and glycol product. The wateracetone layer contained 0.49 g ethylene glycol (80% yield based on the amount of diphenylselenoxide used) as determined by gas chromatographic analysis.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:19](/B(O)O)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:19](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCC/C=C/B(O)O
Reactant: CN(C)CCCCNc1ccc2ncc(Br)n2n1
Product: CCCC/C=C/c1cnc2ccc(NCCCCN(C)C)nn12
Yield: 42 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the title compound (51 mg, 42%) as a brown solid; 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=9.5 Hz, 1H), 7.49 (s, 1H), 6.72-6.58 (m, 2H), 6.32 (d, J=9.5 Hz, 1H), 5.60 (br, 1H), 3.39 (q, J=6.2 Hz, 2H), 2.38 (t, J=6.7 Hz, 1H), 2.31-2.22 (m, 8H), 1.78-1.72 (m, 2H), 1.69-1.63 (m, 2H), 1.52-1.36 (m, 4H), 0.94 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 153.3, 136.9, 131.4, 129.4, 127.2, 125.7, 115.9, 110.5, 59.2, 45.1, 41.8, 33.4, 31.7, 26.9, 25.4, 22.3, 13.9; HPLC tR=11.4 min (Luna), 96.8%; ES-MS: (M+H)=316 m/z.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[Cl:12][CH2:13][NH:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[Cl:12][CH2:13][N:14]([CH2:15][CH:16]=[O:17])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11]
Reactant: O=CCNCCl
Reactant: CS(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CS(=O)c1nnc(NC(=O)N(CCl)CC=O)s1

Procedure:
A mixture of 5-methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-chloromethylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-chloromethyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[C:11]([CH:12]([CH3:16])[C:13](O)=[O:14])=[C:10]([F:17])[C:9]([F:18])=[C:8]([F:19])[C:7]=1[F:20]>>[F:5][C:6]1[C:11]([CH:12]([CH3:16])[C:13]([Cl:3])=[O:14])=[C:10]([F:17])[C:9]([F:18])=[C:8]([F:19])[C:7]=1[F:20]
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)O)c1c(F)c(F)c(F)c(F)c1F
Product: CC(C(=O)Cl)c1c(F)c(F)c(F)c(F)c1F
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of 4.8 ml of thionyl chloride and 8.10 g of (-)-2-(pentafluorophenyl)propionic acid obtained in Example 4 was stirred for 10 hours at 80° C. Excess thionyl chloride was distilled off under reduced pressure, and the subsequent distillation under reduced pressure gave 6.61 g of (-)-2-(pentafluorophenyl)propionyl chloride having the aforementioned physical properties.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[B:10]([O:19]C(C)C)([O:15]C(C)C)[O:11]C(C)C>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([O:11][B:10]([OH:19])[OH:15])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Product: COc1cccc(OB(O)O)c1
Yield: 82 %

Procedure:
3-Methoxyphenylboric acid was prepared in the same manner as described in Example 33B from 3-bromoanisole and triisopropyl borate in 82% yield. This was used in the next step without any further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][S:8][C:4]1[N:3]=[C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:7]=[CH:6][N:5]=1)[CH3:14]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)CSc1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nccc(NCc2ccc(Cl)cc2)n1
Yield: 38.4 %

Procedure:
A stirred mixture of 10.0 g of (4-chloro-2-pyrimidinylthio)acetic acid, ethyl ester, 6.0 g of p-chlorobenzylamine and 4.5 g of sodium carbonate in 150 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate to induce crystallization. After cooling in ice the precipitate was collected on a filter. Recrystallization from benzene-petroleum ether afforded 5.5 g of product, mp. 175-178°C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:31])[CH2:14][CH2:15][C@@:16]1([OH:30])[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:26])[CH:22]=2)[C@@H:17]1[CH:27]([CH3:29])[CH3:28].[CH3:32][O:33][CH2:34][C:35]([OH:37])=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([OH:37])=[O:36].[CH3:32][O:33][CH2:34][C:35]([O:30][C@:16]1([CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH3:31])[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:26])[CH:22]=2)[C@@H:17]1[CH:27]([CH3:28])[CH3:29])=[O:36]
Reactant: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CCN(C)CCCc1nc2ccccc2[nH]1
Agent: COCC(=O)O
Product: COCC(=O)O[C@]1(CCN(C)CCCc2nc3ccccc3[nH]2)CCc2cc(F)ccc2[C@@H]1C(C)C

Procedure:
The method of claim 10 further including the step of contacting the thus-formed (1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid to form (1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>C1COCC1>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CCOC(=O)c1ccc(CCNC)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 0.326 g (0.961 mmol) of 1f in 1 mL of THF and a separate solution of 0.292 g (1.41 mmol) of 2c in 1 mL of THF were combined. The resulting solution was heated in a 90° C. oil bath and the THF was evaporated under a slow stream of nitrogen. The resulting mixture was stirred under nitrogen at 85° C. for 18 h, cooled to 22° C. and partitioned between saturated NaHCO3 and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated and the residue purified by flash chromatography on silica gel, eluting first with DCM and then gradually increasing to 2% methanol/DCM to give 3r as a colorless oil; MS found M+H=467. The oxalate salt of 3r was recrystallized from ethyl acetate; mp 111-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](O)([CH3:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[CH:3]=1
Reactant: CC(C)(O)c1cncc(Br)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(5-bromo-pyridin-3-yl)-propan-2-ol, prepared as described in Example 16a (200 mg, 0.93 mmol) in dichloromethane (8 mL) at 0° C. was added diisopropylethylamine (0.63 mL 3.7 mmol) followed by methanesulfonyl chloride (0.14 mL, 1.85 mmol). After 5 minutes the reaction was place at room temperature and stirred for an additional half hour. The reaction was quenched with saturated aqueous sodium bicarbonate, diluted with brine and ethyl acetate and the layers were separated. The aqueous layer was extracted two additional times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 50%) to furnish 3-bromo-5-isopropenyl-pyridine; MS: (ES+) m/z 198.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([F:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].C1OCCOCCOCCOCCOC1.[C:36]1([S:42](Cl)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]([S:42]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:44])=[O:43])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([F:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(Cl)[nH]c(-c2ccccc2)c1F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(F)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a solution (60 mL) of ethyl 2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (330 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 296 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (1.63 g) was added dropwise and the mixture was stirred for 30 min. Benzenesulfonyl chloride (1.13 g) was added, and the mixture was further stirred for 120 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→8:2) to give the title compound as a pale-yellow oil (yield 260 mg, 52%).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:14]([OH:16])=[O:15])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[N+]([O-])([O-])=O.[Nd+3:28].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(O)C>[Nd:28].[CH2:1]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:14]([OH:16])=[O:15])[CH:2]([CH3:4])[CH3:3]
Reactant: [Nd+3]
Agent: CC(C)Cc1cccc(C(=O)O)c1C(=O)O
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: [Nd]
Temperature: 20 °C

Procedure:
The monoisobutylphthalic acid obtained in 1-1 was formed into a triethylamine salt in anhydrous ethanol, after which an ethanol solution of neodymium nitrate was added while stirring. That is, a reactor similar to that of 1-1 was used to stir a solution obtained by adding 30 ml of an anhydrous ethanol to 70.0 g of the monoisobutylphthalic acid obtained in 1-1, while dripping 30.4 g of triethylamine while maintaining at 20° C. by cooling in an ice water bath. After dripping, the solution was heated for 30 minutes at 40° C. to prepare a synthesis solution of monoisobutylphthalic acid-triethylamine salts. Next, this synthesis solution was adjusted to 20° C., and a solution obtained by dissolving 43.8 g of neodymium nitrate into 100 ml of ethanol was dripped in while stirring. After dripping, the solution was heated to 40° C. for 30 minutes, to produce a synthesis solution of a neodymium salt of monoisobutylphthalic acid. Then, ethanol was distilled from this synthesis solution to concentrate, 150 ml of chloroform and 200 ml of water were added to the concentrate and stirred, and the resulting neodymium salt of monoisobutylphthalic acid was extracted and washed. After further washing this chloroform solution with water twice, it was transferred to a 2 L cylindrical separable flask, and 800 ml of hexane were slowly added while stirring to crystallize. Crystals obtained by filtering this slurry solution, then further the filtered crystals were added to 400 ml of hexane, stirred and washed, then refiltered, and the crystals were dried under reduced pressure at 50° C., to obtain 68.1 g of a neodymium salt of monoisobutylphthalic acid (yield 84%).