Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([S:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([S:16][C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH:15]=1)[C:9]([O:11]C)=[O:10])=[O:4].[OH-].[Na+]>>[CH3:1][N:2]([CH3:22])[C:3]([S:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([S:16][C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH:15]=1)[C:9]([OH:11])=[O:10])=[O:4]
Reactant: COC(=O)c1cc(SC(=O)N(C)C)cc(SC(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C(=O)Sc1cc(SC(=O)N(C)C)cc(C(=O)O)c1
Temperature: 0 °C
Yield: 87.1 %

Procedure:
Methyl 3,5-bis(dimethylcarbamoylthio)benzoate (3.42 g, 10 mmol) was made to react with 5% aqueous sodium hydroxide solution (10 ml. 12.5 mmol) for 3 hours at 22–25° C. with stirring. After cooling by the addition of 50 ml of ice-water, the reaction mixture was extracted with ethyl acetate (300 ml×3) and the extract was dried over magnesium sulfate. The ethyl acetate was evaporated under reduced pressure and the colorless crystals thus obtained was recrystallized from ethanol to give 2.86 g (87.2%) of 3,5-bis(dimethylcarbamoylthio)benzoic acid as colorless needles. The melting point is 196–198° C. (with decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:18]=1.C([Li])CCC.[C:24](=[O:26])=[O:25].Cl>C1COCC1.CCCCCC>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH2:9][O:10][C:5]3[CH:4]=[CH:3][C:2]([C:24]([OH:26])=[O:25])=[CH:18][C:6]=3[CH:7]=2)=[CH:12][CH:13]=1
Reactant: O=C=O
Reactant: Cc1ccc(C2=Cc3cc(Br)ccc3OC2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=Cc3cc(C(=O)O)ccc3OC2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a solution of 6-bromo-3-(4-methylphenyl)-2H-1-benzopyran (0.5 g) in THF (15 ml) was added at −78° C. 1.6 M butyl lithium (a hexane solution) (1.14 ml) under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for one hour, was then mixed with dry ice and was stirred for additional one hour. After addition of 1 N hydrochloric acid (10 ml), the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration, and the crystals were washed with diethyl ether and hexane to obtain 3-(4-methylphenyl)-2H-1-benzopyran-6-carboxylic acid (218 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.[CH:15]([N:18]([CH:21](C)C)[CH2:19]C)(C)[CH3:16].BrCC(Cl)=[O:27].CNC.O1CCCC1>ClCCl>[CH3:19][N:18]([CH3:21])[CH2:15][C:16]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1)=[O:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)CBr
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CC2
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (1.00 g, 5.2 mmol) in dichloromethane (50 mL) was added polymer supported diisopropylethylamine (Argonaut Technologies Inc., 4.0 g, ca 15 mmol base) and bromoacetylchloride (0.650 mL, 7.82 mmol). The resulting solution was stirred for three hours and filtered through a plug of celite. Dichloromethane was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (50 mL). To the solution was added dimethylamine as a 2.0M solution in tetrahydrofuran (60 mmol, Aldrich) and the resulting solution was stirred overnight. The next morning the volatiles were removed under reduced pressure and the residue was purified via chromatography on SiO2 (0-10% MeOH/CH2CL2 with 0.2% NH3) to afford N,N-dimethyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethanamine as a yellow solid (1.20 g, 4.33 mmol, 84% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.59 (s, 6 H), 3.24 (t, J=8.24 Hz, 2 H), 3.52 (s, 2 H), 3.89 (s, 3 H), 4.19 (t, J=8.52 Hz, 2 H), 6.89 (s, 1 H), 8.60 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH2:30]([N:32]=[C:33]=[S:34])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:33]([NH:32][CH2:30][CH3:31])=[S:34])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Reactant: CCN=C=S
Product: CCNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(ethylaminothiocarbonylaminosulfonyl)-7-methoxychroman ##STR35## 4-(5-Chloro-2-methoxybenzamidomethyl)-6-(ethylaminothiocarbonylaminosulfonyl)-7-methoxychroman is synthesize as described in Example 4 from 4-(5-chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and ethyl isothiocyanate. Melting point: 196°-197° C.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][O:7][C:8]([N:10]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:13]=1[CH2:14]O)[CH3:11])=[O:9].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:6][O:7][C:8]([N:10]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:13]=1[CH2:14][Cl:5])[CH3:11])=[O:9]
Reactant: COC(=O)N(C)c1cccc(C)c1CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(C)c1cccc(C)c1CCl
Yield: 123.7 %

Procedure:
A solution of methanesulfonyl chloride 1.7 g) in methylene chloride (3 ml) was added dropwise to a solution of 2-(N-methoxycarbonyl-N-methylamino)-6-methylbenzyl alcohol (1.04 g) and triethylamine (2.5 g) in methylene chloride (15 ml) at room temperature and the mixture was refluxed for 3 hours and the cooled. To the mixture was added an aqueous solution of sodium bicarbonate and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo to give 2-(N-methoxycarbonyl-N-methylamino)-6-methylbenzyl chloride (1.4 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]3[CH:50]=[N:51][N:52]([CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH:53]=3)=[CH:45][C:41]=2[C:42](O)=[O:43])=[CH:34][CH:33]=1>CN(C)C=O>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([C:49]3[CH:50]=[N:51][N:52]([CH2:54][CH2:55][N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)[CH:53]=3)=[CH:45][C:41]=2[C:42]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:43])=[CH:36][CH:37]=1
Reactant: O=C(O)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1
Reactant: Nc1cccnc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pyridinamine (26.5 mg, 0.28 mmol), 1-hydroxy-7-azabenzotriazole (30.7 mg, 0.23 mmol), EDC (43.3 mg, 0.23 mmol) and diisopropylethylamine (0.07 ml, 0.38 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-{1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl}benzoic acid (may be prepared as described in Description 114; 80 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml), and the reaction was stirred at room temperature overnight. The DMF was removed on a buchi. The residue was taken up into ethyl acetate (50 ml), washed with water (1×25 ml). The ethyl acetate layer was evaporated on a buchi under reduced pressure and the residue was purified using the MDAP to yield the title compound. 45 mg.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C)C=O.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1.[OH-].[Na+]>O>[Br:14][C:15]1[CH:16]=[C:17]([Cl:1])[C:18]([NH2:21])=[N:19][CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(Br)cc1Cl
Reaction time: 4 h
Yield: 88 %

Procedure:
With cooling with ice, 1-chloropyrrolidine-2,5-dione (10 g, 76 mmol) was added to an N,N-dimethylformamide solution (30 ml) of 5-bromopyridine-2-amine (12 g, 69 mmol), and stirred for 4 hours. The reaction solution was diluted with water, neutralized with aqueous 5 N sodium hydroxide solution, and extracted with diethyl ether. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:chloroform:ethyl acetate=25:25:50) to obtain 5-bromo-3-chloropyridine-2-amine (12.6 g, yield: 88%) as a brown solid.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:13]([O-])(=O)=O.[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[I:13][C:4]1[CH:5]=[CH:6][C:1]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[CH:2][CH:3]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)C1(c2ccc(I)cc2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 106 %

Procedure:
A mixture of 1-phenylcyclopropane carboxylic acid (16.5 g, 101 mmol), sodium iodate (5.04 g) and concentrated sulfuric acid (1 mL) in acetic acid (70 mL) was stirred and heated at 70° C. for 2 days. Additional sodium iodate (1.88 g) and sulfuric acid (1 mL) were added, and stirring was continued for 1 day. The acetic acid was evaporated, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with aqueous sodium thiosulfate, dried, filtered, and evaporated. The solid residue was recrystallized from methanol/water to give 1-(4-iodophenyl)cyclopropane-1-carboxylic acid (7.98 g, 27 mmol, 27%).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:53][C:54]1[CH:63]=[CH:62][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:56][CH:55]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:62][CH:63]=3)[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(C(=O)OC)cc2)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.05 M) was added methyl 4-(bromomethyl)benzoate (1.6 eq.) and cesium carbonate (1.3 eq.). The reaction was heated to 80° C. and stirred for 12 h. After cooling to rt, the reaction was diluted with ether and quenched with water. The aqueous layer was extracted with ether. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 5% EtOAc in Hex→100% EtOAc) to afford the title compound as a foam.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[NH:12]([C:16]1[O:20][N:19]=[C:18]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:17]=1)[C:13]([NH2:15])=[NH:14].[CH3:26][NH2:27]>>[NH:12]([C:16]1[O:20][N:19]=[C:18]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:7]2[C:3]([NH:27][CH3:26])=[N:4][S:5](=[O:10])(=[O:11])[N:6]=2)[N:17]=1)[C:13]([NH2:15])=[NH:14]
Reactant: CN
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: N=C(N)Nc1nc(CSCCN)no1
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1noc(NC(=N)N)n1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is successively treated with an equimolar amount of 2-[(5-guanidino-1,2,4-oxadiazol-3-yl)methylthio]ethylamine [prepared according to the procedure described in published European Patent Application 6286] and excess methylamine, the title compound is thereby produced.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[CH2:9]([N:11](CC)CC)[CH3:10].[I-].ClC1C=CC=C[N+]=1C.NCC[N:28]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36]2[N:44]([CH2:45][C:46]3[O:47][C:48]([CH3:51])=[CH:49][CH:50]=3)[C:39]3=[N:40][CH:41]=[CH:42][CH:43]=[C:38]3[N:37]=2)[CH2:30][CH2:29]1>O.ClCCl>[CH3:51][C:48]1[O:47][C:46]([CH2:45][N:44]2[C:39]3=[N:40][CH:41]=[CH:42][CH:43]=[C:38]3[N:37]=[C:36]2[NH:35][C:31]2([CH2:10][CH2:9][NH:11][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:8])[CH2:32][CH2:33][CH2:34][NH:28][CH2:29][CH2:30]2)=[CH:50][CH:49]=1
Reactant: O=C(O)c1ccoc1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(Cn2c(NC3CCCN(CCN)CC3)nc3cccnc32)o1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(Cn2c(NC3(CCNC(=O)c4ccoc4)CCCNCC3)nc3cccnc32)o1
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a stirred mixture of 1.12 parts of 3-furancarboxylic acid, 2.02 parts of N,N-diethylethanamine and 195 parts of dichloromethane are added 2.6 parts of 2-chloro-1-methylpyridinium iodide at room temperature. After stirring for 1 hour, 3.3 parts of N-[1-(2-aminoethyl)hexahydro-1H-azepin-4-yl]-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-amine are added and stirred overnight at room temperature. The mixture is poured into water and the layers are separated. The organic layer is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 2.19 parts (36.1%) of N-[2-[hexahydro-4-[[3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1H-azepin-4-yl]ethyl]-3-furancarboxamide as a residue (compound 190).
Reaction SMILES: F[N:2]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[S:3]([C:6]([F:9])([F:8])[F:7])(=[O:5])=[O:4].FC1C=CC=CC=1C.FC1C=C(C)C=CC=1.FC1C=CC(C)=CC=1>C1(C)C=CC=CC=1>[NH:2]([S:3]([C:6]([F:9])([F:7])[F:8])(=[O:5])=[O:4])[S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11]
Reactant: O=S(=O)(N(F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cc1cccc(F)c1
Agent: Cc1ccccc1F
Solvent: Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h

Procedure:
By vacuum transfer, FN(SO2CF3)2 (1.7 mmol) was added to 2.0 ml of toluene at -196° C. The mixture was warmed to room temperature and agitated by hand. A slow color change ensues near 22° C. After 10 hours, 19F NMR shows the presence of 2-fluorotoluene (74%), 3-fluorotoluene (4%) and 4-fluorotoluene (21%). The ratio of unreacted FN(SO2CF )3)2 to the HN(SO2CF3)2 formed in the reaction indicates an 80% conversion to the monofluorotoluene isomers. No other fluorine containing products are observed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26]Br.[H-].[Na+].C(OCC)C>CN(C)P(=O)(N(C)C)N(C)C>[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COC(CBr)OC
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: COc1ccc(-c2nc(SCC(OC)OC)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.0 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 100 ml of hexamethylphosphoric acid triamide at 35°. The mixture is allowed to cool to 20°, first 11.2 g of 2-bromoacetaldehyde-dimethylacetal and then, in portions, 2.9 g of 50% strength sodium hydride suspension (in mineral oil, de-oiled with hexane) are added, the reaction temperature being maintained at 25°-30° by cooling. The mixture is then stirred at room temperature for 1 hour, poured onto ice, the oil which separates is brought into solution with diethyl ether, and the organic phase is removed. The aqueous phase is extracted by shaking again with 200 ml of diethyl ether. The organic phases are combined, washed with 200 ml of 2 N sodium hydroxide solution, dried over magnesium sulphate and concentrated by evaporation. The oily crude product is crystallised from hexane and made into a slurry with methanol. 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-acetaldehyde-dimethylacetal having a melting point of 60°-61° is obtained.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:50][B-](F)(F)F.ClC1C=CC=C(Cl)[N+]=1F.O.O[Li].O>CC#N>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([F:50])[N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Agent: F[n+]1c(Cl)cccc1Cl
Agent: [Li]O
Solvent: CC#N
Solvent: O
Product: Cc1cc2nc3c(F)n2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 5.2 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-17,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (22 mg, 0.033 mmol, 1 equiv) in MeCN (0.33 mL) was added 2,6-dichloro-1-fluoropyridin-1-ium, tetrafluoroborate salt (8 mg, 0.031 mmol, 1 equiv). The reaction turned dark orange. After 3 h, the reaction was concentrated in vacuo. The crude fluoride product was taken up in 9:1 MeOH:water (1.8 mL) and LiOH.H2O (27 mg, 0.651 mmol, 20 equiv) was added. The reaction was heated to 60° C. for 4 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-90% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (1.1 mg, 5%) 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=1.5 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.37-7.33 (m, 1H), 7.32-7.27 (m, 1H), 7.19 (s, 1H), 7.11 (dd, J=12.8, 7.0 Hz, 1H), 6.04 (br. s., 1H), 4.56 (d, J=5.9 Hz, 1H), 3.76-3.48 (m, 4H), 3.28 (d, J=11.0 Hz, 1H), 2.71 (d, J=6.8 Hz, 1H), 2.53 (s, 3H), 2.09-1.64 (m, 10H), 1.28 (s, 9H), 1.27 (s, 3H), 1.19 (d, J=6.1 Hz, 3H); LCMS (ESI, M): 679.3.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)C>[CH3:17][CH:16]([NH:19][CH2:3][C@H:2]([OH:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=1)[CH3:18]
Reactant: CC(C)N
Reactant: COCCc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: COCCc1ccc(OC[C@@H](O)CNC(C)C)cc1

Procedure:
171 mg of (+)-4-(2-methoxyethyl)-phenyl glycidyl ether were reacted with isopropylamine (method as in Example 2) to obtain 154 mg of (-)-metoprolol melting at 44-45° C. with [α]D25= - 5.27° (c =0.967 in ethanol). Optical purity was determined to be 98.4% based on HPLC of the S-leucyl diastereomeric derivatives as in Example 2. Evaporation of the mother liquor gave 6 mg of (-)-metoprolol of 92.2% optical purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].Cl[CH:20]([CH3:24])[C:21](O)=[O:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:21](=[O:22])[CH:20]([CH3:24])[S:13]1
Reactant: CC(C)CN
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(Cl)C(=O)O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(C)C(=O)N1CC(C)C

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by α-chloropropionic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-methyl-1,3-thiazolidin4-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(Cl)Cl>[C:21]([N:28]1[CH2:29][CH2:30][N:31]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:32][CH2:33]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: OC(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 48 h

Procedure:
To a stirring solution of bis(4-bromophenyl)methanol (0.060 mmol) in CH2Cl2 (0.3 mL) was added thionyl chloride (40 μL, 0.60 mmol) and the reaction mixture was stirred for 48 h. The reaction was evaporated to dryness under a stream of N2 and the crude product redissolved in acetonitrile (1.0 mL). 1-Boc-piperazine (22.3 mg, 0.12 mmol) was added and the reaction mixture was refluxed for 4 h. The reaction mixture was concentrated under reduced pressure, redissolved in CH2Cl2 and passed through a short pad of SiO2, providing the 1-Boc-4-diphenylmethylpiperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[CH3:11][O:12][C:13]([C:15]1[CH:20]=[N:19][C:18](Cl)=[CH:17][N:16]=1)=[O:14].O>CN(C=O)C>[CH3:11][O:12][C:13]([C:15]1[CH:20]=[N:19][C:18]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:17][N:16]=1)=[O:14]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Oc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(Oc2ccccc2F)cn1
Temperature: 0 °C

Procedure:
2-Fluorophenol (21.6 g, 233 mmol) was dissolved in DMF (250 mL) under a calcium chloride drying tube. The solution was cooled to 0° C., and then 60% NaH in paraffin oil (9.3 g, 233 mmol) was added in small portions. After the main portion of NaH had dissolved, 5-chloro-pyrazine-2-carboxylic acid methyl ester (Preparation 41, 40.2 g, 233 mmol) was added. The mixture was refluxed for 1 hour and then poured into water (1 L). The aqueous mixture was extracted with ether (3×300 mL), and the combined organic layers were washed with 2% sodium hydroxide aqueous solution (400 mL) and filtered through a layer of silica gel (40/60 prn). The filtrate was concentrated in vacuo to yield the title compound which was used without further purification.