Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])=[CH:22][C:18]=1[C:19](Cl)=[O:20])[CH3:15]>C1(C)C=CC=CC=1>[CH2:14]([S:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])=[CH:22][C:18]=1[C:19]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:20])[CH3:15]
Reactant: OC1CCOC1
Reactant: CCSc1ccc(Oc2ccc(Br)cc2Cl)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCSc1ccc(Oc2ccc(Br)cc2Cl)cc1C(=O)OC1CCOC1
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-ethylthio-5-(2-chloro-4-bromophenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-ethylthio-5-(2-chloro-4-bromophenoxy)benzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2[CH3:18])=[CH:6][CH:5]=1)([O-])=O.O.NN>C(O)C.[Pd]>[CH3:18][C:12]1[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1C
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(Oc2ccc(N)cc2)c1C
Temperature: 90 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
2,3-dimethylphenyl 4-nitrophenyl ether (Intermediate 73, 865 mg) was dissolved in ethanol (10 mL) to give a pale yellow solution. Hydrazine hydrate 50% (0.698 mL, 7.1 mmol) and Pd/C (37.8 mg, 0.36 mmol) were added. The reaction mixture was stirred at 90° C. for 1 hour. The reaction mixture was filtered and the organic phase was evaporated under vacuum to afford the title compound as a pale yellow oil (796 mg).
Reaction SMILES: CSC.B.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH2:13][C:14](O)=[O:15]>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH2:13][CH2:14][OH:15]
Reactant: O=C(O)Cc1c(F)cccc1F
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of borane dimethyl sulfide complex (2M in THF, 26 mL) was added cautiously to a solution of 2-(2,6-difluorophenyl)acetic acid (3 g) in THF (50 mL) at 0° C. The reaction was then allowed to warm to RT and stirred for 3 h. The reaction was cooled in an ice bath and cautiously quenched with methanol (10 mL). The solvent was evaporated and the residue purified by silica gel chromatography eluting with 9:1 to 4:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 2.2 g.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)=[O:2].[BH4-].[Na+].C(O)C>O>[OH:2][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(CO)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
A mixture of methyl 4-formyl-2-methylbenzoate (200 mg, 1.1 mmol), sodium borohydride (210 mg, 5.5 mmol) and ethanol (10 mL) was stirred at room temperature for 4 hours. To the resultant mixture, water (0.4 mL) was added. The organic phase was separated, concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give methyl 4-(hydroxymethyl)-2-methylbenzoate (126 mg, 64%). 1H NMR (300 MHz, d6-DMSO): δ 7.78 (d, J=7.8 Hz, 1H), 7.15 (dd, J=7.8 Hz, J=1.8 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 5.39 (t, J=5.7 Hz, 1H), 4.79 (d, J=5.7 Hz, 2H), 3.88 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([O:19][CH3:18])[CH:21]=2)=[CH:7][C:6]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCBr
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2ccc(OCCBr)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.1 %

Procedure:
A mixture of 4-(2-Bromoethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (1.012 g, 3.417 mmole), 3-methoxy-benzoyl chloride (700 mg, 1.2 eq), and triethylamine (1.0 mL, 2 eq) in 5 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give title compound as white solid (957 mg, 52%). Exact mass calculated for C20H20BrN3O3429.1. found 430.3 (M+H 79Br, 100), 432.5 (M+H 18Br, 98).
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]1([CH:21]([NH:24][C:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][CH:31]=[CH:30]3)=[O:26])[CH2:22][CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]1([S:11]([N:32]2[C:33]3[C:29](=[CH:28][C:27]([C:25]([NH:24][CH:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:22][CH3:23])=[O:26])=[CH:35][CH:34]=3)[CH:30]=[CH:31]2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: CCC(NC(=O)c1ccc2c(ccn2S(=O)(=O)c2cccc3ccccc23)c1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Example 28, using 1-naphthylsulfonyl chloride and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 469 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[F:38][C:39]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[C:49]([CH:57]([CH3:59])[CH3:58])[CH:50]=[C:51]3[C:56]=2[N:55]=[CH:54][CH:53]=[CH:52]3)=[CH:43][C:40]=1[CH:41]=O>C(#N)C.C1COCC1.Cl.C(OCC)(=O)C>[F:38][C:39]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[C:49]([CH:57]([CH3:58])[CH3:59])[CH:50]=[C:51]3[C:56]=2[N:55]=[CH:54][CH:53]=[CH:52]3)=[CH:43][C:40]=1[CH:41]=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: CC(C)c1cc(-c2ccc(F)c(C=O)c2)c2ncccc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)c1cc(-c2ccc(F)c(C=Cc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methanesulfonylbenzyl chloride (10 g, 49 mmol) and triphenylphosphine (12.8 g, 49 mmol) in acetonitrile (100 mL) was stirred for 18 h at reflux. The resulting reaction mixture was cooled to 21° C. and the phosphorus salt crystallised from CH3CN/ether. To a suspension of the salt (875 mg, 1.87 mmol) in THF (15 mL) at 0° C. was added potassium tert-butoxide (1M, THF, 1.87 mL, 1.87 mmol) dropwise and the resulting mixture stirred 30 min at 0° C. The mixture was cooled to −78° C. and the 2-fluoro-5-(6-isopropyl-quinolin-8-yl)-benzaldehyde from Step 3 (0.5 g, 1.7 mmol, in THF) was added. After 90 min. at 21° C., the reaction mixture was diluted with HCl 10% and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 60:40) provided the 8-{4-fluoro-3-[2-(4-methanesulfonyl-phenyl)-vinyl]-phenyl}-6-isopropyl-quinoline compound as a mixture of isomer (3:1).
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]=[CH:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:5]([CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH:4]=[O:3]
Reactant: COC(=O)c1ccc(CCC=CO[Si](C)(C)C)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CCC(Br)C=O)cc1
Yield: 100.8 %

Procedure:
To 4.46 g (16 mmol) of methyl 4-(4-trimethylsilyloxy-3-butenyl)benzoate, prepared in Preparation 1, in 16 ml carbon tetrachloride at -20° C. was slowly added 2.56 g (16 mmol) of bromine in 16 ml carbon tetrachloride over 4 hours. The mixture was allowed to come to room temperature then decanted from a small amount of insoluble material. The solvent was removed by vacuum rotary evaporation to give 4.60 g of 2-bromo-4-(4-carbomethoxyphenyl)butanal. Chromatography purification (silica; hexane - ethyl acetate 7:3) of the above product gave 4.0 g in a yield of 87.8 percent. 1H NMR (CDCl3) δ 2.24 (m, 1H), 2,36 (m, 1H), 2.81 (m, 1H), 2.90 (m, 1H), 3.90 (s, 3H), 4.16 (m, 1H), 7.27 (d, J=8.2 Hz, 2H), 7.97 (d, J=8.2 Hz, 2H) , 9.46 (d, J=2.1 Hz, 1H) ; 13C NMR (CDCl3) δ 32.5, 32.7, 51.7, 54.3, 128.3, 128.4, 129.8, 145.0, 166.6, 192.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[N+:25]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#Cc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#Cc1ccccc1

Procedure:
The title compound was prepared from (5-dimethylamino-2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example H1) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a brown solid (1.927 g).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:10][C:11]([CH:13]1[CH2:21][C:17]2[S:18][CH:19]=[CH:20][C:16]=2C(O)C1)=[O:12])[CH3:9].N1C=CC=CC=1.Cl>O.CCOC(C)=O>[C:5]([O:4][CH:1]1[C:16]2[CH:20]=[CH:19][S:18][C:17]=2[CH2:21][CH:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])[CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1Cc2sccc2C(O)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1Cc2sccc2C(OC(C)=O)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Acetic anhydride (4.1 ml) was added to a mixture of 6-ethoxycarbonyl-4-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene (2.06 g) and pyridine (8 ml) under water cooling, and was stirred at r.t. for 2.5 hours. The reaction mixture was added into a mixture of AcOEt and water, and was adjusted to pH 1.6 with 6N HCl. The separated organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (sat. NaHCO3 aq.), water, and brine, and dried over MgSO4, and then evaporated in vacuo to give 4-acetoxy-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (2.36 g) as an oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:20])=[CH:15][CH:14]=1
Reactant: O=C(Cl)COc1ccc(F)cc1
Reactant: c1ccc(C2CCNC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COc1ccc(F)cc1)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and (4-fluoro-phenoxy)-acetyl chloride (471.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 2-(4-fluorophenoxy)-1-(3-phenylpyrrolidin-1-yl)ethan-1-one are collected and the solvent is removed in vacuo to give 495 mg of colorless oil.
Reaction SMILES: [C:1]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[C@H:2]([C@@H:4]([C:6]([O:8][CH3:9])=[O:7])[OH:5])[OH:3].[CH:25](OCC)(OCC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[CH2:27]([O:26][CH:25]1[O:5][C@H:4]([C:6]([O:8][CH3:9])=[O:7])[C@@H:2]([C:1]([O:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])[O:3]1)[CH3:28]
Reactant: COC(=O)[C@@H](O)[C@H](O)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC1O[C@H](C(=O)OC)[C@@H](C(=O)OC(c2ccccc2)c2ccccc2)O1

Procedure:
400 mg of diphenylmethyl methyl D-tartarate was dissolved in 7 ml of toluene, and a catalytic amount of Amberlyst 15 and 1 ml of triethyl orthoformate were added, followed by refluxing under heating for one hour. Amberlyst was filtered off. Then, the filtrate was extracted by an addition of water and ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 195 mg of the above identified compound as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.C[Si](C)(C)[C:15]([F:18])([F:17])[F:16].Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[K+].CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[C:15]([F:18])([F:17])[F:16])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 95.2 %

Procedure:
DMF (10 mL) was added to a reaction vessel containing 4-formyl-benzoic acid methyl ester (501.1 mg, 3.053 mmol) and potassium acetate (15.0 mg, 0.153 mmol), and the mixture was cooled to 0° C. Trimethyl(trifluoromethyl)silane (0.96 mL, 6.105 mmol) was added dropwise and the mixture was stirred for 50 minutes. 2 N hydrochloric acid (10 mL) was then added to the reaction mixture, and the mixture was stirred at room temperature overnight and then diluted with ethyl acetate. A saturated aqueous sodium bicarbonate solution was added, and the organic layer and the aqueous layer were separated. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoic acid methyl ester (680.8 mg, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (30 mg, 0.14 mmol) in dichloromethane (1 mL) was added pyrrolidine (11 mg, 0.16 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C15H16N2O2: 256.1212, found 256.1214.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc(C=Nc2cccc(Cl)c2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2cccc(Cl)c2)cc1
Yield: 59.7 %

Procedure:
(a) To 60 ml of absolute ethanol is added 0.58 g of sodium, and 4.6 g of 4-[N-(3-chlorophenyl)formimidoyl]phenol and then 5.84 g of ethyl 2-bromo-2-methylpropionate are added to the solution at room temperature with stirring. The mixture is refluxed under heating and with stirring for 5 hours. After distilling off the ethanol from the reaction mixture, the residue is dissolved in ether. The solution is washed with 5% aqueous solution of sodium hydroxide until disappearance of the color of the aqueous layer, then washed with water and dried. After drying, the solvent is distilled off to give 4.1 g of ethyl 2-[4-{N-(3-chlorophenyl)formimidoyl}phenoxy]-2-methylpropionate.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.[C:17]1([C:23]2[N:24]=[CH:25][C:26]([NH:29][C:30](=O)[O:31]C3C=CC=CC=3)=[N:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([C:30]([NH:29][C:26]3[CH:25]=[N:24][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:28][N:27]=3)=[O:31])[CH2:3][CH2:4]2)[O:8]1
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2ccccc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (6.24 g, 26.6 mmol), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (7.59 g, 26.0 mmol) and triethylamine (18 mL, 180 mmol) in chloroform (200 mL) was stirred at 80° C. for 3 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (100 mL). After the organic layer was washed with 10% citric acid aqueous solution (100 mL), 1N aqueous sodium hydroxide (100 mL) and then saturated saline solution (100 mL), the organic layer was dried over anhydrous Na2SO4 and then concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/2) to provide the subject compound as a colorless solid. The solid was washed with diethyl ether (30 mL) to provide the subject compound (8.23 g) as a crude crystal. The crystal was dissolved in hot ethyl acetate (300 mL). After removal of about 100 mL of ethyl acetate by distillation, the white suspension began to occur. At this point the distillation was stopped and the whole was cooled and then kept at room temperature for 14 hours. The colorless prisms formed was collected by filtration, which was washed with heptane (20 mL). The obtained crystal was dried at 50° C. in vacuo for 6 hours to provide the subject compound (Crystal Form A) (5.17 g) as colorless prisms (melting point 210-211° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[S:28](=[O:30])(=[O:29])[N:27](CC[Si](C)(C)C)[C:26](=[O:37])[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:37])[CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccnc(Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CCc1ccnc(Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[2-benzyloxy-4-(4-ethylpyridin-2-ylmethyl) -phenyl]-1,1-dioxo-2-(2-trimethylsilanyl-ethyl)-1,2,5-thiadiazolidin-3-one (47 mg, 0.088 mmol) in DMF (1 mL) is added CsF (80 mg, 0.53 mmol). The reaction is stirred at 60° C. for 2 h. The reaction is allowed to cool to ambient temperature and the solvent is evaporated under a stream of N2. The crude residue is taken up in acetonitrile and filtered, washing with acetonitrile several times. The solvent is removed under reduced pressure and the crude cesium salt of 5-[2-benzyloxy-4-(6-benzyloxypyridin-2-ylmethyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one is used in the next step without further purification: MS (M+H)+=516.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]=1[C:15]([OH:17])=[O:16].N.[Li].[Cl-].[NH4+].[CH3:22]COCC>>[CH3:1][O:2][C:3]1[CH:4]([C:15]([O:17][CH3:22])=[O:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[C:7]([O:13][CH3:14])[CH:6]=2
Reactant: CCOCC
Reactant: COc1ccc2ccc(OC)c(C(=O)O)c2c1
Agent: N
Agent: [Cl-]
Agent: [Li]
Product: COC(=O)C1C(OC)=CCc2ccc(OC)cc21
Temperature: -33 °C

Procedure:
A solution of 2,7-dimethoxy-1-naphthoic acid (I) (0.1 mole) in 150 ml. ether and 600 ml. liquid ammonia was treated with 1.73 g. lithium wire in small portions with stirring under argon. This was allowed to reflux (-33° C.) for 11/2 hours. Ammonium chloride was added to quench the reaction and the ammonia was allowed to evaporate. The residue was taken up in water and washed with ether. The aqueos layer was acidified with 6 N hydrochloric acid and quickly extracted three times with ether. The ether extracts were washed with saturated sodium chloride; and then treated with an ethereal solution of excess diazomethane (prepared from 20.6 g. N-methyl-N-nitrosourea).1After 1/2 hr., acetic acid was added to destroy the excess diazomethane. The solution was washed with dilute sodium carbonate, dried (MgSO4), and concentrated. The residue was crystallized from methanol; mp 90°-91° C.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+].CC(O)C>O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CN(C)C(=N)NC(=N)N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Metformin hydrochloride (49.68 g: 0.3 mol) was dissolved in pure water, and neutralized with 2N sodium hydroxide aqueous solution (150 mL). The mixture was condensed in vacuo until it contained about 30 mL of water. To the mixture was added 2-propanol (300 mL) and stirred at room temperature for 30 minutes. The mixture was filtered and the residue was washed with acetone. The filtrate and the acetone were gathered and the solvent was evaporated in vacuo. Acetone (500 mL) and magnesium sulfate were added to the residue, stirred and filtered. The filtrate was concentrated in vacuo to give free metformin (32.9 g: yield 85%) as white prisms.