Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([N:26]4[CH2:31][CH2:30][N:29]([C:32]([C@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[O:33])[C@H:28]([CH3:46])[CH2:27]4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([F:47])[CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([N:26]4[CH2:31][CH2:30][N:29]([C:32]([C@H:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)=[O:33])[C@H:28]([CH3:46])[CH2:27]4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([F:47])[CH:10]=1
Reactant: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4F)c3c2)CCN1C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4F)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((R)-4-(1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.022 g, 0.039 mmol) in dichloromethane (2 mL) and the resulting solution was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-25% methanol in dichloromethane) to give the title compound as a white solid (0.008 g, 0.017 mmol, 44%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1 H), 7.67 (dd, J=4.0, 8.8 Hz, 1 H), 7.13 (d, J=10.0 Hz, 1 H), 7.06 (d, J=8.4 Hz, 1 H), 6.94-6.87 (m, 2 H), 6.58 (d, J=6.8 Hz, 1 H), 5.77 (q, J=6.8 Hz, 1 H), 4.71-4.78 (m, 1 H), 4.51-4.12 (m, 1 H), 3.64-3.62 (m, 1 H), 3.50-3.31 (m, 5 H), 3.26-3.20 (m, 1 H), 2.96-2.84 (m, 1 H), 2.74-2.70 (m, 1 H), 2.54-2.46 (m, 1 H), 2.15-2.02 (m, 2 H), 1.99 (d, J=6.8 Hz, 3 H), 1.52 and 1.38 (d, J=6.4 and 6.8 Hz, 3 H); MS: (ES) m/z calculated for C25H30ClFN5O [M+H]+ 470.2, found 470.3.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([CH:24]([CH3:26])[CH3:25])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]CC2C=CC=CC=2)[CH:11]=1.CSC.ClCCl.B(F)(F)F.CCOCC>CCCCCC>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([CH:24]([CH3:25])[CH3:26])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1
Reactant: CC(C)n1ncc(NCc2cccc(OCc3ccccc3)c2)c(Cl)c1=O
Agent: FB(F)F
Solvent: CSC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)n1ncc(NCc2cccc(O)c2)c(Cl)c1=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Into a mixture comprising 1.15 g of 4-chloro-5-(3-benzyloxybenzylamino)-2-i-propyl-3(2H)pyridazinone (Compound No. 95) prepared in Example 1A, 10 ml of dimethyl sulfide and 4 ml of dichloromethane, 3.41 g of boron trifluoride etherate was added under cooling with ice. The mixture was stirred at 0° C. for 30 minutes and at room temperature for further 24 hours. The reaction solution was cooled with ice and 40 ml of n-hexane was added thereto, whereby a pale yellow solid substance was precipitated. The solid substance was collected by filtration, and washed with n-hexane, and then treated with ethyl acetate and water. The organic layer was separated, and washed with water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off to obtain a pale yellow solid substance. This substance was crystallized from ethyl acetate-ether to obtain 730 mg of the above identified compound having a melting point of from 194.5 to 196° C. as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[CH:8]2.[Br:14]Br>>[Br:14][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11]2
Reactant: COc1cccc2ccc(C)nc12
Reactant: BrBr
Product: COc1ccc(Br)c2ccc(C)nc12
Yield: 86.6 %

Procedure:
Prepared using the same procedure described in Example 78 from 8-methoxy-2-methyl-quinoline [CAS 3033-80-5] (1.21 g, 6.96 mmol) and bromine (1.35 g, 8.42 mmol) to afford titled compound as a yellow solid (1.52 g, 86%). 1H NMR (DMSO-d6) 8.30 (d. J=8.4, 1H), 7.76 (d. J=8.4, 1H), 7.57 (d. J=8.4, 1H), 7.10 (d. J=8.4, 1H), 3.93 (s, 3H), 2.66 (s, 3H). LC/MS (Method B) 2.07 min, [M+1]+ 252/254.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=O)=[CH:26][CH:25]=1.N1C=CC=CC=1>C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH:9][CH2:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:8]=1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(CCNc2cc(OC)ccc2C2CCc3cc(OC)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
A mixture of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (700 mg), 4-methoxyphenylacetyl chloride (680 mg) and pyridine (10 ml) was stirred for 2 hours at room temperature. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate, the crystal that was precipitated was filtered, rinsed with water, then dried at 50° C. overnight. The total amount of the resulting N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2-(4-methoxyphenyl)acetamide (crude product) was used according to an analogous synthetic method to Example 337 described below to provide the title compound (690 mg).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:23][C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]([CH2:23][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]3[CH:14]=[CH:15][C:16]([O:20][CH3:21])=[C:17]([O:18][CH3:19])[C:5]=3[O:4][CH3:3])[CH2:9][CH2:10]2)=[O:25])=[CH:28][CH:29]=1
Reactant: COc1ccc(OC(=O)CCl)cc1
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC(=O)CN2CCN(Cc3ccc(OC)c(OC)c3OC)CC2)cc1

Procedure:
A mixture of 1-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (prepared by the method disclosed in Japanese Patent First Publication (Kokai) No. 32889/1973) (17.0 g), 4-methoxyphenyl chloroacetate (prepared by the method disclosed in U.S. Pat. No. 3,657,318) (10 g), potassium carbonate (27.6 g) and N,N-dimethylformamide (200 ml) is stirred at 50° C. for 4 hours. To the reaction mixture is added water (400 ml), and the mixture is extracted with chloroform (400 ml). The organic layer is washed with water twice and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to give crude 1-[(4-methoxyphenoxy)carbonylmethyl]-4-(2,3,4-trimethoxybenzyl)piperazine (free base) (20 g) as an oily substance. This crude free base (20 g) is dissolved in ethanol (100 ml) and thereto is added a solution of hydrochloric acid in ethanol (10% w/w) (50 ml) and the precipitated crystals are separated by filtration. The crystals are recrystallized from methanol to give 1-[(4-methoxyphenoxy)carbonylmethyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (11.5 g) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:11]([Cl:21])[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:11]([Cl:21])[CH:10]=1
Reactant: Cc1cc(CNC(=O)OC(C)(C)C)cc(Cl)c1NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CN)cc(Cl)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 145.8 %

Procedure:
(3-Chloro-4-methanesulfonylamino-5-methyl-benzyl)-carbamic acid t-butyl ester (153.8 mg, 0.44 mmol) and CF3COOH (5˜6 drops) were added into methylene chloride. The mixture was stirred for 12 hrs. A reaction solvent was concentrated in vacuo to yield syrup (159.6 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:32]=[C:31]([N:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:16]=2[C:17]([NH:19][C:20]2[C:21]([C:25]([O:27]C)=[O:26])=[CH:22][S:23][CH:24]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:32]=[C:31]([N:33]([CH3:34])[CH3:35])[CH:30]=[CH:29][C:16]=2[C:17]2[O:26][C:25](=[O:27])[C:21]3[C:20](=[CH:24][S:23][CH:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1cscc1NC(=O)c1ccc(N(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2nc3cscc3c(=O)o2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A solution of methyl 4-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-4-(dimethylamino)benzoylamino]thiophene-3-carboxylate (2.3 g, 4.6 mmol) in MeOH (100 mL) and THF (50 mL) was treated with a solution of 1 N aqueous NaOH (10 mL) at 60° C. for 24 h. The mixture was concentrated to dryness, mixed with brine (25 mL) and glacial acetic acid (0.65 mL), then extracted with CHCl3 (2×100 mL). The extracts were dried over MgSO4, cooled to 0° C. and treated with Et3N (1 g) followed by a 2 M CH2Cl2 solution of oxalyl chloride (3.5 mL). The mixture was stirred overnight, concentrated to dryness, and treated sequentially with potassium carbonate (11 g), THF (20 mL), water (20 mL), and di-tert-butyl dicarbonate (8 g). The mixture was stirred overnight, diluted with more THF (50 mL) and treated with NaCl (20 g). The organic layer was separated, dried over MgSO4, and concentrated to an oil which was purified by silica chromatography using 15% EtOAc in hexanes to give 2 g of product as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]([OH:17])[C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([C@@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C(OCC)(=O)C>[C:20]1([C@@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([C@H:13]([OH:17])[C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(OCc2ccccc2)cc1
Agent: C[C@H](N)c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H](O)c1ccc(OCc2ccccc2)cc1

Procedure:
4-Benzyloxymandelic acid (40.8 g) was dissolved in methanol (405 ml) and ethyl acetate (405 ml), and a solution of (S)-1-phenylethylamine (20.4 ml) in methanol (200 ml) and ethyl acetate (200 ml) was added to the solution. After the mixture was allowed to stand at room temperature, the resulting precipitates (37.9 g) were obtained. Recrystallization of the precipitates from methanol (926 ml) gave a salt of (S)-1-phenylethylamine and (S)-4-benzyloxymandelic acid (24.8 g) having a melting point of 174-180° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[CH:11]1[O:15][CH:7]2[CH2:8][N:9]([CH2:16][C:17]#[CH:18])[CH2:10]1)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:16]([N:9]1[CH2:8][CH:7]2[O:15][CH:11]([C:12]3[C:6]2=[CH:5][C:4]([NH2:1])=[CH:14][CH:13]=3)[CH2:10]1)[C:17]#[CH:18]
Reactant: C#CCN1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCN1CC2OC(C1)c1cc(N)ccc12

Procedure:
4-Nitro-10-prop-2-ynyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (120 mg, 0.49 mmol) and tin chloride dihydrate (554 mg, 2.45 mmol) were heated at reflux in EtOAc (10 mL) for 2 h. The resulting mixture was then diluted with saturated aqueous NaHCO3 (10 mL), extracted with EtOAc (2×15 mL), dried over MgSO4, filtered and concentrated to obtain 10-Prop-2-ynyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine as a brown, viscous oil (71 mg, 68%). MS (m/e) 215 (M+1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH2:10][N:11](C(OCC)=O)[CH2:12][CH2:13][C:14]=3[N:15]=2)=[CH:3][CH:2]=1.[OH-].[K+].[ClH:23]>>[ClH:23].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:14]=3[N:15]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)N1CCc2nc(-c3ccncc3)sc2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: c1cc(-c2nc3c(s2)CNCC3)ccn1
Temperature: 0 °C
Yield: 30 %

Procedure:
A solution of ethyl 2-(pyridin-4-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (1.8 mmol) in a 3.5 N potassium hydroxide solution (3 ml) was heated under reflux for 3 hours. The course of the reaction was monitored by thin layer chromatography. The reaction mixture was then cooled to 0° C. and acidified with concentrated hydrochloric acid. The solid which had precipitated was filtered out and dried. The product was obtained in the form of the HCl salt. The yield was 30%.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:8](Br)[CH:9]=[CH2:10]>C(N(CC)CC)C>[CH2:10]([S:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[CH:9]=[CH2:8]
Reactant: Sc1cnccn1
Reactant: C=CCBr
Solvent: CCN(CC)CC
Product: C=CCSc1cnccn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
6.57 g of 2-mercaptopyrazine prepared in Reference Example 1 was dissolved in 80 ml of dimethylformaind and 8.6 ml of triethylamine was added thereto. 6.84 ml of allyl bromide was added to the solution and the mixture was stirred at 50° C. for 2 hours. 500 ml of ice water was added to the reaction solution and the resulting mixture was extracted with diethylether and concentrated. The residues were distilled under vacuum to give 7.85 g(85%) of oily pale yellow liquid.
Reaction SMILES: [Br:1][CH:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([CH3:17])[C:6]=2[C:5](=O)[CH2:4][C:3]1([CH3:20])[CH3:19].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>O1CCOCC1>[Br:1][CH:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([CH3:17])[C:6]=2[C:5](=[N:22][OH:23])[CH2:4][C:3]1([CH3:20])[CH3:19]
Reactant: NO
Reactant: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nn(-c2ccccn2)c2c1C(=NO)CC(C)(C)C2Br
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A mixture of 7-bromo-1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazole (0.3 g, 0.9 mmol), prepared as described in example 4, hydroxylamine hydrochloride (0.37 g, 4.5 mmol), and sodium acetate (0.44 g, 5.4 mmol) in 1,4-dioxane (50 ml) was heated under reflux for about 4 hours. Additional hydroxylamine hydrochloride (0.123 g, 1.6 eq) and sodium acetate (0.146 g, 2 eq) were added and heating was continued for further 4 hours. The reaction mixture was poured onto ice/water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel (cyclohexane:ethyl acetate=90:10) to give the title compound as a colourless solid (0.14 g, 45%): m.p. 195-196° C.
Reaction SMILES: [CH3:1][S:2][C:3]([NH:5][NH2:6])=[S:4].[F:7][C:8]([F:30])([F:29])[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1>CCO.O>[F:30][C:8]([F:7])([F:29])[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][C:18]([C:21]3[CH:28]=[CH:27][C:24](/[CH:25]=[N:6]/[NH:5][C:3]([S:2][CH3:1])=[S:4])=[CH:23][CH:22]=3)=[N:17]2)=[CH:12][CH:11]=1
Reactant: CSC(=S)NN
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: O
Solvent: CCO
Product: CSC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 80 °C

Procedure:
To a 250 mL round-bottom flask containing hydrazinecarbodithioic acid methyl ester (2.38 g, 1.95 mmol) in EtOH (100 mL) was added 4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (5.00 g, 1.50 mmol). The vessel was heated at 80° C. for 3 h before being diluted with H2O (300 mL) and cooled to 0° C. The precipitated product was collected by vacuum filtration as an off-white solid (6.13 g, 93%): mp 204-206° C.; 1H NMR (400 MHz, DMSO-d6) δ 13.39 (s, 1H), 9.43 (s, 1H), 8.38 (s, 1H), 8.21 (d, J=8.3 Hz, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 2.57 (s, 3H); ESIMS m/z 438 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:5][C:4]1[C:3]([O:9][CH3:10])=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:11]([OH:13])=[O:12])[CH:19]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: COc1c(N)cccc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1c(N)cccc1-c1cccc(C(=O)O)c1
Reaction time: 28 h

Procedure:
A mixture of 3-bromo-2-methoxyaniline (3 g), 3-carboxyphenylboronic acid (2.94 g), bis(triphenylphosphine)palladium(II)chloride [PdCl2(PPh3)2] (0.30 g) and potassium carbonate (5.2 g) in ethanol (100 mL) and water (20 mL) was heated to about reflux temperature and stirred for about 28 hours. The hot mixture was filtered to remove the catalyst. The clear filtrate was concentrated under vacuum. To the residue, water (50 mL) and methanol (50 mL) was added, acidified to pH 3-5 using hydrochloric acid and stirred for about 30 minutes at about room temperature. The slurry was filtered, washed with n-hexane (50 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours. Yield: 1.8 g
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10](O)=[O:11])[N:8]=1)=[O:2].S(Cl)([Cl:18])=O>CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([Cl:18])=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)Cl)c1csc(NC=O)n1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
N,N-Dimethylformamide (3 drops) was added to a suspension of 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 23 g.) in thionyl chloride (230 ml), and stirred at 60° C. for 5 minutes. After concentrating the solution in vacuo, benzene was added to the residue. The presipitates were collected by filtration, washed with benzene (30 ml.) three times and diethyl ether in turn to give 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetyl chloride (anti isomer, 18 g.). On the other hand, trimethylsilylacetamide (46 g.) was added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (16.8 g.) in methylene chloride (168 ml.), and stirred at 40° C. for an hour. To the suspension was gradually added 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetyl chloride (anti isomer, 13.6 g.) at -5° to 0° C., and stirred at the same temperature for an hour. Water (150 ml.) was added to the resultant solution and stirred for 15 minutes. The recipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (anti isomer, 25.7 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=O.[CH3:16][C:17]([CH3:19])=[O:18].CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:16]/[C:17](=[O:18])[CH3:19])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)/C=C/c1ccc(C2CCCCC2)c(Cl)c1
Yield: 40 %

Procedure:
222.72 Gm (1.0 mol) of 3-chloro-4-cyclohexyl-benzaldehyde, 3,500 gm (60.3 mols) of acetone and 200 ml of methanol were charged into a 6-liter three-necked flask equipped with a stirrer, dropping funnel and internal thermometer. While thoroughly stirring the contents of the flask, a solution of 2.805 gm (0.05 mol) of potassium hydroxide in 16 ml of water was added dropwise thereto, while an internal temperature of 20° to 25°C was maintained. The mixture was then stirred for 3 hours more. The precipitate solid by-product was filtered off, and the filtrate was neutralized by dropwise addition of glacial acetic acid, and concentrated by evaporation in vacuo. The residue was shaken with a mixture of water and ether. The ether phase separated, dried over sodium sulfate, clarified with charcoal, and evaporated. The residual oil was distilled in a high vacuum (b.p. 162°-175°C at 0.2 mm Hg), crystallized by trituration with a small quantity methanol, and finally recrystallized once from methanol. The colorless crystals melted at 48°-49°C. Yield: 40 % of theory.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:30][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH2:26][CH3:27])[C:20]([CH2:28][CH3:29])=[N:19]4)(=O)=O)=CC=1.[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][CH:36]=[C:35]2[C:41]1[CH2:42][CH2:43][NH:44][CH2:45][CH:46]=1>CS(C)=O.C(OCC)(=O)C>[CH2:26]([C:21]1[C:20]([CH2:28][CH3:29])=[N:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:44]4[CH2:43][CH:42]=[C:41]([C:35]5[C:34]6[C:38](=[CH:39][CH:40]=[C:32]([F:31])[CH:33]=6)[NH:37][CH:36]=5)[CH2:46][CH2:45]4)[O:30][C:17]3=2)[N:22]=1)[CH3:27]
Reactant: CCc1nc2ccc3c(c2nc1CC)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO3
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1nc2ccc3c(c2nc1CC)OC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of (2R)-8,9-diethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.300 g, 0.700 mmole) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1 H-indole (0.606 g, 2.800 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.161 g (49%) of the (S)-enantiomer of the title compound as a yellow crystalline solid. Rf =0.38 (silica, methanol:ethyl acetate 1:9); mp>120° C. dec.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[Sn]([N:33]=[N+:34]=[N-:35])(C)(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][C:17]=3[C:22]3[NH:35][N:34]=[N:33][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cccc2n1Cc1ccc(-c2ccncc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)cccc2n1Cc1ccc(-c2ccncc2-c2nnn[nH]2)cc1

Procedure:
The title compound may be prepared by treatment of 2-propyl-4-methyl-1-[4-[3-cyano-4-pyridinyl]phenyl]methylbenzimidazole with one or more equivalents of Me3SnN3 in toluene at reflux over a period of 1-3 days. The title compound may be purified in a manner similar to that stated in Example 1, Step F.