Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:5]2[NH:6][C:7](=[O:9])[O:8][CH:4]2[CH:3]=1.[C:12]([C@@H:15]([C@H:17]([C:19]([O-:21])=[O:20])[OH:18])[OH:16])([O-:14])=[O:13]>>[C:12]([C@@H:15]([C@H:17]([C:19]([OH:21])=[O:20])[OH:18])[OH:16])([OH:14])=[O:13].[O:8]1[CH:4]2[CH:3]=[CH:2][CH:11]=[CH:10][CH:5]2[NH:6][C:7]1=[O:9]
Reactant: O=C1NC2C=CC(Br)=CC2O1
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Product: O=C1NC2C=CC=CC2O1

Procedure:
A procedure similar to Step C of Example 14 was used to couple 5-(4-chlorophenyl)-2,5-ethano-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-2-benzoazepine from Step B of Example 14 with 6-bromo-3,3a-dihydrobenzo[d]oxazol-2(7aH)-one. The desired coupling product was obtained and converted to the corresponding L-tartrate salt as in Step C to provide 64544-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-3,3a-dihydrobenzo[d]oxazol-2(7aH)-one, L-tartrate salt (34 mg, 11%, AUC HPLC >99%) as an off-white solid: 1H NMR (CD3OD, 500 MHz) δ 7.55 (s, 1H), 7.48-7.45 (m, 3H), 7.42 (dd, J=8.5, 2.0 Hz, 1H), 7.38-7.35 (m, 3H), 7.13 (d, J=8.5 Hz, 1H), 6.45 (d, J=8.5 Hz, 1H), 4.91 (s, 2H), 4.43 (s, 2H), 3.68-3.61 (m, 2H), 3.48-3.41 (m, 2H), 2.82-2.78 (m, 2H), 2.49-2.43 (m, 2H); ESI MS m/z 417 [M+H]+. Anal. Calcd. For C25H21ClN2O2.C4H6O6.3H2O: C, 56.09; H, 5.36; N, 4.51. Found: C, 56.42; H, 5.09; N, 4.29.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[I-:11].[K+].II.[NH:15]1[CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[SH:21]>CO.O>[IH:11].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:21][C:16]1[NH:17][CH2:18][CH2:19][CH2:20][N:15]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: [I-]
Reactant: SC1=NCCCN1
Agent: II
Agent: [K+]
Solvent: CO
Solvent: O
Product: Brc1ccc2[nH]cc(SC3=NCCCN3)c2c1
Product: I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 19.6 g of 5-bromo-indole in 50 ml of methanol is added to a stirred solution of 50 g potassium iodide and 25.4 g of iodine in 150 ml of water at room temperature. The mixture is further treated with a solution of 11.6 g of 1,4,5,6-tetrahydro-2-pyrimidinethiol in 270 ml of warm methanol. The reaction mixture is then stirred at room temperature for 2 hours, filtered and the filtrate is concentrated to one-fifth of the original volume and cooled. A crystalline precipitate is formed. This is filtered and recrystallised from a mixture of methanol, ethylacetate and ether to yield 5-bromo-3-(1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole hydriodide which melts at 241°-242°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([O:8][C@H:9]1[N:12]([CH:13]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])O)[C:11](=[O:31])[C@@H:10]1[NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:7])=[O:5])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:49])=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]([O:8][C@H:9]1[N:12]([CH:13]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[Cl:49])[C:11](=[O:31])[C@@H:10]1[NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:7])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)[C@@H](C)O[C@@H]1[C@@H](NC(=O)c2ccccc2)C(=O)N1C(O)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](C)O[C@@H]1[C@@H](NC(=O)c2ccccc2)C(=O)N1C(Cl)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
4.58 g of the product from step (2) above was dissolved in 50 ml of methylene chloride, and to the solution after ice-cooling were added 1.38 g of pyridine and 2.08 g of thionyl chloride, followed by agitation for 30 minutes to effect the chlorination.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].O[CH:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]1=[O:27]>>[CH2:14]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:27])=[CH:11][CH:12]=1)[CH3:15]
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(NC=C2C(=O)Nc3ccccc32)cc1
Yield: 51 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-diethylamino-ethoxy)-phenylamine (775 mg, 1.2 equiv.) and 3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 3.11 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (557 mg, 51%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[NH2:10][C@@H:11]1[CH2:30][C@@:29]2([CH3:31])[C@@H:22]([CH2:23][CH2:24][C@@H:25]2[C:26](=[O:28])[CH3:27])[C@H:21]2[C@H:12]1[C@:13]1([CH3:36])[C@@H:18]([CH2:19][CH2:20]2)[CH2:17][C@H:16]([OH:32])[C@@H:15]([O:33][CH2:34][CH3:35])[CH2:14]1>N1C=CC=CC=1.O>[CH2:34]([O:33][C@H:15]1[CH2:14][C@@:13]2([CH3:36])[C@@H:18]([CH2:19][CH2:20][C@@H:21]3[C@@H:12]2[C@H:11]([NH:10][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[CH2:30][C@@:29]2([CH3:31])[C@H:22]3[CH2:23][CH2:24][C@@H:25]2[C:26](=[O:28])[CH3:27])[CH2:17][C@@H:16]1[O:32][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[CH3:35]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Solvent: O
Solvent: c1ccncc1
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1OC(=O)OCC(Cl)(Cl)Cl

Procedure:
2,2,2-Trichloroethyl chloroformate (1 ml) was added to a stirred solution of 11α-amino-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one (2 g) in pyridine (20 ml). After 16 hours complete reaction was not obtained. A further quantity of 2,2,2-trichloroethyl chloroformate (1 ml) was added and after 30 minutes the mixture was diluted with water (30 ml). The mixture was extracted with ether (x 2) and the extracts were washed with 2 M-HCl (x 4) and water (x 2) and dried. Evaporation of the solution left a yellow froth which was purified by column chromatography on silica eluted with ethyl acetate:petrol (1:3) to give a solid (2.5 g). A portion was crystallised from ether/petrol to give the title compound m.p. 147°-149° C., [α]D +48°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:20][N:21]([CH2:27][CH2:28][O:29]C)[C:22]=2[C:23]([F:26])([F:25])[F:24])[O:11][N:10]=1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:20][N:21]([CH2:27][CH2:28][OH:29])[C:22]=2[C:23]([F:25])([F:24])[F:26])[O:11][N:10]=1
Reactant: COCCn1ncc(-c2onc(-c3c(F)cccc3Cl)c2C(=O)OC)c1C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(CCO)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(2-methoxyethyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate (example I-102) (27 mg, 0.06 mmol) in CH2Cl2 (1 mL) was added Bortribromide (0.06 mmol). The mixture was stirred at 0° C. for 1 h. The mixture was poured into iced water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by pTLC (PE:EE 1:1) to yield example I-83 as an oil (10 mg, 34%).
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]#[N:15])CC1.[CH3:16][NH:17][CH3:18].[CH2:19]([OH:21])[CH3:20]>[OH-].[Na+]>[CH3:16][N:17]([CH3:18])[C:14]([NH2:15])=[N:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH2:5][CH2:6][O:21][CH2:19][CH2:20]1
Reactant: N#CNc1ccccc1N1CCOCC1
Reactant: CCO
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1

Procedure:
N-(2-morpholinophenyl)cyanamide (2 g) was heated under reflux with a 33% solution of dimethylamine in ethanol (15 ml) for 4 hours. The mixture was then cooled and the solvent removed by evaporation to give a residue which was suspended in 20% aqueous sodium hydroxide solution. The suspension was extracted with dichloromethane (3×25 ml) and the extracts were washed with water, and then brine, dried and evaporated to give 1,1-dimethyl-2-(2-morpholinophenyl) guanidine (m.p. 142°-143° C.) which was recrystallised from hexane.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[C:4]([OH:6])=O.[CH2:15](N(CC)CC)[CH3:16].C1([C:25]23[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][CH:31]2[NH:30][C:29](=O)[O:28][C:26]3=O)CC1>O.C(#N)C>[Cl:36][C:34]1[CH:33]=[CH:32][C:31]2[N:30]([CH:29]3[CH2:16][CH2:15]3)[C:4](=[O:6])[CH:3]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[NH:2][C:26](=[O:28])[C:25]=2[CH:35]=1
Reactant: NC(Cc1ccccc1Cl)C(=O)O
Reactant: O=C1NC2C=CC(Cl)=CC2(C2CC2)C(=O)O1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC#N
Solvent: O
Product: O=C1NC(Cc2ccccc2Cl)C(=O)N(C2CC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
2-Amino-3-(2-chlorophenyl)propanoic acid hydrochloride (4.97 g, 1 eq) was dissolved in water/acetonitrile (84 mL/84 mL) and triethylamine (5.91 mL, 2 eq) was then added. 1-Cyclopropyl-5-chloroisatoic anhydride (5.00 g, 1 eq) was then added in about 10 portions giving time between each addition for the previous portion to dissolve. After all of the anhydride was added the reaction was stirred at room temperature overnight. Any solids present after reaction were filtered off. The filtrate was concentrated in vacuo, azeotroped with acetonitrile, re-dissolved in AcOH (210 mL) and heated to 130° C. for 6 h. The crude mixture was then concentrated, and the residue was washed with NaHCO3(aq), stirring the mixture for a while before collecting the solid by filtration. The crude product was chromatographed (gradient: 3:1 hex:EtOAc to EtOAc) delivering the product (126 mg, 2% yield).
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1.[OH-].[Na+]>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[N:14]=[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:5]
Reactant: Oc1nc2c(nc1Cc1ccccc1)CCCC2
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: O=c1c(Cc2ccccc2)nc2c(n1CCO)CCCC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
Ethylene chlorohydrin (16.10 g, 0.2M) was added to a solution of 2-hydroxy-3-benzyl-5,6,7,8-tetrahydro quinoxaline (9.60 g, 40 mM) in dilute aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. The residue was extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 220 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 643 (10.90 g, yield: 83.8%).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Cl:24][C:25]1[CH:32]=[C:31](F)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].CC(C)([O-])C.[K+].O>C1COCC1>[Cl:24][C:25]1[CH:32]=[C:31]([CH:30]=[CH:29][C:26]=1[C:27]#[N:28])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:23]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CCn1c2ccccc2c2cc(NC(=O)CCCCO)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CCCCOc3ccc(C#N)c(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.1 %

Procedure:
To a solution of the compound obtained in Step 1 (150 mg, 0.48 mmol) and 2-chloro-4-fluorobenzonitrile (75 mg, 0.48 mmol) in THF (6 mL) was added potassium t-butoxide (136 mg, 1.21 mmol), and the mixture was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 85% ethyl acetate/hexane) to give the title compound (79 mg, 0.178 mmol, 36.8%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH2:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[O:19][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C=CCc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1ccc(CC2CO2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(4-chlorophenyl)prop-1-ene (9.0 g) in chloroform (100 ml) was added portionwise metachloroperbenzoic acid (12.2 g), and the solution was stirred for 5 h at room temperature. The mixture was poured into water, the water layer was separated and the organic layer washed successively with sodium bicaronate, sodium sulphite and water. After drying, evaporation of the solvent gave 1-(4-chlorophenyl)-2,3-epoxypropane as a pale yellow oil. (9.51 g). NMR in CDCl3 :
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:20][NH:19][C:18]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])=[N:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH2:38]([O:40][CH2:41]Cl)[CH3:39].[CH3:43][CH2:44][O:45][CH2:46]C>ClCCl>[CH2:38]([O:40][CH2:41][N:19]1[CH2:20][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:29])[F:30])=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[N:17]=[C:18]1[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])[CH3:39].[CH2:44]([O:45][CH2:46][N:17]1[CH:16]([C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:29])[F:30])=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[CH2:20][N:19]=[C:18]1[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])[CH3:43]
Reactant: CCOCCl
Reactant: CCOCC
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCN1C(c2c(F)cccc2F)=NCC1c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Product: CCOCN1CC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)N=C1c1c(F)cccc1F
Reaction time: 8 h
Yield: 17 %
Yield: 20 %

Procedure:
At 0° C., a solution of 1.5 g (3.6 mmol) of 4-(4′-trifluoromethoxy-4-biphenylyl)-2-(2,6-difluorophenyl)-4,5-dihydro-1H-imidazole (for example from Example V-1) in 15 ml of dichloromethane was admixed first with 0.75 ml (0.55 g; 5.4 mmol) of triethylamine and then with 4 ml (0.41 g; 4.32 mmol) of chloromethyl ethyl ether. After the mixture had been stirred overnight, approximately 50% of starting material were still present (TLC). A further 0.25 ml of triethylamine and 0.17 ml of the ether were introduced. Since no further reaction could be detected, another 0.25 ml of triethylamine was added and the mixture was heated to the boil. For work-up, the reaction mixture was extracted with 10% strength citric acid and 1N aqueous sodium hydroxide solution, dried, concentrated and chromatographed over a silica gel column (Ø=3 cm, 1=30 cm). Elution with cyclohexane/ethyl acetate using a 5-stage gradient from 20:1 to 3:1 gave, as second fraction, 0.30 g (17% of theory) of 1-ethoxymethyl-4-(4′-trifluoromethoxy-4-biphenylyl)-2-(2,6-difluorophenyl)-4,5-di-hydro-1H-imidazole (I-6a) and, as third fraction, 0.34 g (20% of theory) of 3-ethoxymethyl-4-(4′-trifluoromethoxy-4-biphenylyl)-2-(2,6-difluorophenyl)-4,5-di-hydro-3H-imidazole (I-6b).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([NH2:36])=[S:35].[C:38]([O-])(=[O:40])C.[Na+]>>[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([NH:36][C:38]([NH:24][CH2:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)[CH:16]=1)=[O:40])=[S:35]
Reactant: CC(=O)[O-]
Reactant: NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: Cc1ccccc1NC(N)=S
Agent: [Na+]
Product: Cc1ccccc1NC(=S)NC(=O)NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CA18) and 1-(o-tolyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.075 g, 24%): 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 10.05 (s, 1H), 9.40 (s, 1H), 8.12-8.04 (m, 2H), 8.01-7.92 (m, 2H), 7.68-7.57 (m, 3H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (dt, J=7.7, 1.4 Hz, 1H), 7.29-7.24 (m, 1H), 7.24-7.13 (m, 2H), 7.10 (t, J=5.7 Hz, 1H), 3.18 (q, J=6.5 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.20 (s, 3H), 1.93-1.74 (m, 2H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 555 ([M+H]+), 553 ([M−H]−).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.C1(CC([NH:22][C@@H:23]2[C:49](=[O:50])[N:25]3[C:26]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)=[O:38])=[C:27]([CH:30]=[CH:31][C:32]4[CH:36]=[CH:35][S:34][N:33]=4)[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.CO>C(Cl)Cl>[NH2:22][C@@H:23]1[C:49](=[O:50])[N:25]2[C:26]([C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)=[O:38])=[C:27]([CH:30]=[CH:31][C:32]3[CH:36]=[CH:35][S:34][N:33]=3)[CH2:28][S:29][C@H:24]12
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3ccsn3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(C=Cc3ccsn3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reaction time: 3 h
Yield: 95.7 %

Procedure:
In 13 ml of methylene chloride were dissolved 913 mg of phosphorus pentachloride and 1.18 ml of pyridine, and 800 mg (1.46 mmol) of p-methoxybenzyl 7β-phenylacetamido-3-[2-(isothiazol-3-yl)vinyl]-3-cephem-4-carboxylate with 3.2 ml of methylene chloride were added therein at -30° C. After stirring for 3 hrs. under ice-cooling, the reaction solution was added to 13 ml of methanol at -30° C. After stirring for 1 hr. at the room temperature, the reaction solution was added to 30 ml of saturated saline solution and 30 ml of methylene chloride under ice-cooling, and stirred for 1 hr. as it was. The reaction solution was separated, and the aqueous layer was further extracted with 20 ml of methylene chloride. The layers of methylene chloride were combined, washed with saturated sodium hydrogen carbonate aqueous solution, and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated off to give 1.15 g of a caramel. The caramel was column chromatographed on silica gel by eluting with chloroform-ethyl acetate to give 600 mg of p-methoxybenzyl 7β-amino-3-[2-(isothiazol-3yl)vinyl]-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][Mg]Br.[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13](=[O:15])[CH3:14].[Cl-].[NH4+].O>C(OCC)C.O1CCCC1>[OH:15][C:13]([C:6]1[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=1[OH:4])([CH3:1])[CH3:14]
Reactant: COc1cccc(O)c1C(C)=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1cccc(O)c1C(C)(C)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl magnesium bromide (24 mL of a 3M solution in diethyl ether, 72.2 mmol) in anhydrous tetrahydrofuran (20 mL) at 0° C. was added a solution of 2′-hydroxy-6′-methoxyacetophenone (4 g, 24.1 mmol) in anhydrous tetrahydrofuran (40 mL), maintaining the temperature below 11° C. during the addition. After stirring for 1.5 hours at room temperature, a solution of 10% ammonium chloride (30 mL) was added slowly maintaining the temperature below 22° C. with the use of an ice bath. Water (300 mL) was slowly added and the reaction was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water, brine, dried using anhydrous sodium sulfate and concentrated to give 2-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-phenol (4.52 g) as pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[CH3:10][C:11]1[NH:12][C:13]([CH3:29])=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[N:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[CH3:10][C:11]1[NH:12][C:13]([CH3:29])=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:24][CH:23]=2)[N:17]=1
Reactant: Cc1cc(-c2cccc(-c3ccc(Br)cc3)n2)c(C)[nH]1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cccc(-c3ccc(-c4cccnc4)cc3)n2)c(C)[nH]1
Reaction time: 2 h

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 271 mg (2.20 mmol) 3-pyridylboronic acid (Rec. Trav. Chim., 93, 21 (1974)), 720 mg (2.20 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-bromophenyl)-pyridine, 933 mg (8.81 mmol) sodium carbonate, 128 mg (0.110 mmol) tetrakistriphenylphosphine palladium, 9 mL ethanol, and 1 mL water. The mixture was refluxed 20 hours 100 mg 3-pyridiylboronic acid added, and refluxing continued for 2 hours. The reaction was then cooled, poured into water and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford the product as an oil, 350 mg (49%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:29])=[C:7]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:29])=[C:7]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)cc2C2(CCOCC2)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2ccc(F)cc2C2(CCOCC2)C1=O
Yield: 39.2 %

Procedure:
1,1-Dimethylethyl N-((7-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (703 mg, 1.73 mmol) was stirred in TFA (2 mL, 26.9 mmol) at room temperature for 25 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as an off-white solid (237 mg). MS (m/e)=350.1 (M+H)+. Calculated for C18H16F3NO6 349.10.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:4][CH2:3]1.[C:23](#[N:26])[CH:24]=[CH2:25].N12CCCN=C1CCCCC2>C(#N)C>[OH:22][C@@H:20]([C:9]1[N:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:25][CH2:24][C:23]#[N:26])[CH2:3][CH2:4]2)[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=1)[CH3:21]
Reactant: C=CC#N
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCNCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a solution of (1R)-1-(1-piperidin-4-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol hydrochloride (21.7 mg, 0.0640 mmol) (Example 15, Step 4) in acetonitrile (0.40 mL) was added 2-propenenitrile (8.4 μL, 0.13 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (38 μL, 0.26 mmol). The resulting mixture was stirred at room temperature overnight. After evaporating to dryness, the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (11 mg, 48%). LCMS calculated for C18H22N5OS (M+H)+: m/z=356.2. Found: 356.0.