Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[C:18]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][C:21]=2[CH3:26])[CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][C:15]2=[O:27].ClCCl.CO>C(O)(=O)C>[NH2:9][C:10]1[C:19]([I:1])=[C:18]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][C:21]=2[CH3:26])[CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][C:15]2=[O:27]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1nnn(C)c1-c1cc(N)c2c(c1)C(=O)NCC2
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1nnn(C)c1-c1cc2c(c(N)c1I)CCNC2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.3 %

Procedure:
N-iodosuccinimide (5.27 g, 23.43 mmol) was added in portions to a solution of 5-amino-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293d, 5.5 g, 21.3 mmol) in glacial acetic acid (400 mL) and the resulting mixture stirred at room temperature for three days. A second portion of N-iodosuccinimide (2.6 g, 12.7 mmol) was then added and stirring continued at room temperature overnight. The mixture was concentrated under vacuum to remove acetic acid. The residue was dissolved in methanol (200 mL), concentrated to dryness, and purified by silica gel chromatography (eluting with 1:1 to 1:2 petroleum ether/ethyl acetate and then with 100:1 to 50:1 dichloromethane/methanol), to give 5-amino-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-iodo-3,4-dihydroisoquinolin-1(2H)-one (293e, 5.0 g, 60% yield) as a yellow solid.
Reaction SMILES: NO.[CH2:3]([OH:5])[CH3:4].[OH:6][NH:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]1[C:20]([OH:31])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1)=[NH:9].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:3]([O:6][NH:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]1[C:20]([OH:31])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1)=[NH:9])(=[O:5])[CH3:4]
Reactant: CCO
Reactant: N=C(NO)n1c(-c2cccc(-c3ccccc3)c2O)cc2ccccc21
Agent: NO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)ONC(=N)n1c(-c2cccc(-c3ccccc3)c2O)cc2ccccc21

Procedure:
The cyano group in compound 15 is then converted into the carbamimidoyl group by first treating 15 with hydrogen chloride gas in an anhydrous alcoholic solvent such as methanol, ethanol and the like, and then treating the resulting (5-methoxycarbonimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole 16 with an inorganic base such as ammonium carbonate, and the like in an alcoholic solvent such as methanol, ethanol, or with excess ammonia to give resulting (5-carbamimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole of Formula I. Alternatively, compound 15 can be converted to a compound of Formula I by first refluxing it with hydroxylamine in an alcoholic solvent such as ethanol and then treating the resulting (N-hydroxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole with acetic anhydride in acetic acid to give (N-acetoxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole. The acetoxy group is then removed under hydrogenation reaction conditions by treating N-acetoxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole with 10% palladium in an alcoholic solvent such as methanol, ethanol, and the like.
Reaction SMILES: [CH2:1]=[CH:2]C1C=CC=CC=1.[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].C([Mg]Br)C>CCOCC>[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]([OH:13])[CH2:1][CH3:2]
Reactant: C=Cc1ccccc1
Reactant: O=Cc1ccccc1Br
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCC(O)c1ccccc1Br

Procedure:
With the exception of three compounds, the styrene compounds disclosed herein to be utilized for preparing the α-chloro oximes ae known and their preparations are published in the prior art. The compounds not previously prepared are synthesized following well-known published procedures. Thus, 2-bromobenzaldehyde is allowed to react with a Grignard reagent, ethyl magnesium bromide in anhydrous ether, to yield 1(2-bromophenyl)propanol. This propanol derivative is then dehydrated by refluxing it in toluene in the presence of a catalytic quantity of p-toluenesulfonic acid to yield the desired 1-bromo-2-(1-propenyl)benzene. Another previously unknown substituted styrene, namely, 1,2-dichloro-4-(1-propenyl) benzene is prepared by the same general procedure from 3,4-dichlorobenzaldehyde and ethyl magnesium bromide, followed by dehydration of the intermediate substituted propanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][C:26]2[CH2:32][CH2:31][CH2:30][CH2:29][C:27]=2[N:28]=1>C(Cl)CCl>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:25][C:26]2[CH2:32][CH2:31][CH2:30][CH2:29][C:27]=2[N:28]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Nc1nc2c(s1)CCCC2
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: ClCCCl
Product: CN1C(C(=O)Nc2nc3c(s2)CCCC3)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 38 %

Procedure:
4-Hydroxy-2-methyl-N-(4,5,6,7-tetrahydro-2-benzothiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 2-amino4,5,6,7-tetrahydro-benzothiazole.Yield: 38% of theory; m.p. 255°-257° C, (decomp.; from ethylene chloride).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([NH:29][CH2:30][C:31]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[CH:32]=2)[CH2:28][CH2:27]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:29]([CH:26]2[CH2:28][CH2:27]2)[CH2:30][C:31]2[CH:32]=[C:33]([O:39][CH3:40])[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1cc(CNC2CC2)cc(OC)c1
Product: COc1cc(CN(C(=O)CN(c2ccc(C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc(OC)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3,5-dimethoxy-benzyl)-amine
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:7][NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([NH:19][CH2:20][C@H:21]3[CH2:23][C@@H:22]3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:12]=[CH:11][N:10]=2)=O)[CH2:3][CH2:2]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[CH:1]1([CH2:4][C:5]2[N:10]3[CH:11]=[CH:12][C:13]([NH:19][CH2:20][C@H:21]4[CH2:23][C@@H:22]4[C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]3=[N:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: O=C(CC1CC1)NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc([C@H]2C[C@@H]2CNc2ccn3c(CC4CC4)nnc3c2C(F)(F)F)cc1
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a mixture of 2-cyclopropyl-N′-(4-((((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)acetohydrazide (0.06 g, 0.142 mmol) in THF (4 mL) was added Burgess reagent (0.068 g, 0.284 mmol) and the resulting mixture was refluxed stirring for 6 hours. The reaction mixture diluted with EtOAc and extracted with aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×10 mL) and brine (10 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography to give 3-(cyclopropylmethyl)-N-(((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine as a white solid (0.045 g, 74% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.98 (d, J=7.5 Hz, 1H), 7.09-7.01 (m, 2H), 7.00-6.92 (m, 2H), 6.64 (d, J=7.8 Hz, 1H), 5.49 (d, J=4.0 Hz, 1H), 3.39 (tdd, J=19.0, 12.8, 5.6 Hz, 2H), 3.01 (d, J=6.8 Hz, 2H), 1.92 (dt, J=9.1, 4.9 Hz, 1H), 1.46-1.34 (m, 1H), 1.19-0.94 (m, 3H), 0.65-0.54 (m, 2H), 0.37-0.27 (m, 2H). LCMS M+1=405.05.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])O[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[O:17]=[S:18]1(=[O:34])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:20]([CH2:28]C(OCC)=O)=[N:19]1.[H-].[Na+].C(O)(=O)C>C1COCC1.Cl>[CH2:1]([N:5]1[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]([OH:15])=[C:28]([C:20]2[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:18](=[O:34])(=[O:17])[N:19]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2ccccc2N1
Reactant: CCCCn1c(=O)oc(=O)c2cccnc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Temperature: 0 °C
Yield: 32.6 %

Procedure:
To a solution of the product of Example 1B (0.220 g, 1.0 mmol) and the product of EXAMPLE 1C (0.268 g, 1.0 mmol) in anhydrous THF (10 mL) under nitrogen at 0° C. was added sodium hydride (95%, 0.10 g, 4.0 mmol). The reaction was heated to reflux for 3 hours, cooled to 0° C., and to it was added dropwise glacial acetic acid (2 mL). The resulting mixture was heated to reflux for 2 hours, cooled to ambient temperature, and diluted with aqueous hydrochloric acid (0.1 M, 10 mL). The resulting precipitate was collected by filtration, washed with water and diethyl ether and dried to give the title compound (0.130 g, 33%). MS (ESI−) m/z 397 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][C:12]2[N:8]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[N:9]=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]=2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(S)cc1
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)n(-c2cccnc2F)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Sc2ccc(F)cc2)n(-c2cccnc2F)n1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 1-(2-fluoropyridin-3-yl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-3-carboxylate (353 mg), 4-fluorobenzenethiol (130 mg) and sodium carbonate (146 mg) in toluene (5 mL) was sufficiently deaerated. Tris(dibenzylideneacetone)dipalladium(0) (8.4 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) were added and the mixture was further deaerated. The mixture was stirred under an argon atmosphere at 110° C. for 3 hr, allowed to cool to room temperature, ethyl acetate was added, and the mixture was filtered through a silica gel pad. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→2:1) to give the title compound as a crude yellow oil (yield 203 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:16][C:17]([OH:19])=[O:18])[N:14]=[N:13][N:12]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][O:18][C:17](=[O:19])[CH2:16][N:15]1[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12][N:13]=[N:14]1
Reactant: OCCO
Reactant: O=C(O)Cn1nnnc1-c1ccc2ccccc2c1
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccc2ccccc2c1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 64.4 %

Procedure:
To a solution of 1 g (3.94 mM) of [5-(2-naphthyl)tetrazol-1-yl] acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=9/1) for separation and purification, to give 750 mg (yield 64.4%) of [5-(2-naphthyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Boc-Ile-OH (12.01 @, 0.05 mole) in DMF (50 ml) was cooled to 0° C. and NMM (5.49 ml) was added. After cooling the solution to -15° C. isobutylchloroformate (6.48 ml) was added slowly while maintaining the temperature at -15° C. and st1rred for 10 minutes at which time HOBt (7.65 g) was added and stirring was continued for additional 10 minutes. A pre-cooled solution of HCL-H-Pro-OBzl (12.09 g. 0.05 mole) in DMF (50 ml) and NMM (5.49 ml) was added to the above solution and the completeness of the reaction was followed by TLC. The reaction mixture was poured into a cold saturated NaHCO3 solution and stirred for one hour. The peptide was extracted into CHCl3 and washed with acid and base (0.5 N NaOH to remove HOBt), and on evaporating the solvent the product was obtained as an oil in 92% yield. Rf1, 0.65. Anal. Calcd. for C23H34N2O5 : C 66.00, H 9.19, N 6.69%. Found: C 65.58, H 8.28, N 7.13%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([C:16]1[CH:17]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:20][CH:21]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].Cl>CO.Cl[Pd]Cl.O.C(Cl)Cl>[ClH:1].[C:12]([C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:19]=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccnc(-c2cccc(C(C)(C)C)c2)c1
Temperature: 100 °C
Yield: 70.6 %

Procedure:
Methyl 2-chloroisonicotinate (1.7 g, 9.91 mmol), 2-(3-tert-butylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.393 g, 13.04 mmol), potassium carbonate (2.054 g, 14.86 mmol) and PdCl2 (dppf) (0.215 g, 0.30 mmol) were mixed in methanol (14 mL) in a 20 mL microwave vial. The vial was capped and heated at 100° C. for 10 min in a single node microwave reactor. The reaction mixture was suspended in methanol, the solids removed by filtration and the filtrate evaporated to yield a dark red slurry. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to a brown solid. The solid was dissolved in MTBE (100 mL) and the solids were filtered off. Hydrogen chloride(4 M in dioxane, 3.50 mL, 13.99 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 3 days. The solid was collected by filtration and washed with MTBE to yield methyl 2-(3-tert-butylphenyl)isonicotinate hydrochloride (2.14 g, 70%) as a slightly brown solid. 1H NMR (600 MHz, cd3od) δ 1.41 (s, 9H), 4.07 (s, 3H), 7.62 (t, 1H), 7.77-7.80 (m, 2H), 8.00-8.02 (m, 1H), 8.37-8.40 (m, 1H), 8.69-8.71 (m, 1H), 8.94-8.97 (m, 1H).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)(=O)=O.[CH3:23]O.C[O-].[Na+]>CO>[CH3:23][O:5][CH2:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCCOS(C)(=O)=O)CC1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COCCCOC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 4-[3-(methanesulfonyloxy)propyloxy]-N-t-butyloxycarbonylpiperidine (3.76 g) in methanol (20 ml) was added 28% sodium methoxide methanol solution (22.7 ml), and the mixture was stirred under refluxing for 1.5 hours. The reaction mixture was evaporated in vacuo and dissolved in ethyl acetate (200 ml). The solution was washed twice with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give 4-(3-methoxypropyloxy)-N-t-butyloxycarbonylpiperidine (2.66 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:22](=[O:24])[CH3:23])[C:15]([O:17]C(C)(C)C)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[BrH:34].[NH+]1C=CC=CC=1.O>O1CCCC1>[CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:22](=[O:24])[CH2:23][Br:34])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: CC(=O)C(=NOCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: FB(F)F
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CON=C(C(=O)O)C(=O)CBr)OCc1ccccc1
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 2-benzyloxycarbonylmethoxyimino-3-oxobutyrate (2.0 g) in dry tetrahydrofuran (20 ml) were added boron trifluoride diethyl etherate (3.0 ml) and pyridinium hydrobromide perbromide (3.0 g) at ambient temperature, followed by stirring for 6 hours. The reaction mixture was poured into water (50 ml) and then extracted twice with ethyl acetate (70 ml). The combined extracts were washed with 10% hydrochloric acid and then a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave 2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyric acid (2.0 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[CH:19]=[C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]4=[CH:16][C:15]=3[N:14]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]2=[O:32])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][N:14]1[C:15]2[CH:16]=[C:17]3[O:24][CH2:23][CH2:22][O:21][C:18]3=[CH:19][C:20]=2[C:12]2([C:3]3[C:2](=[CH:11][C:6]4[O:7][CH2:8][CH2:9][O:10][C:5]=4[CH:4]=3)[O:1][CH2:33]2)[C:13]1=[O:32]
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COCCOCCN1C(=O)C(c2cc3c(cc2O)OCCO3)c2cc3c(cc21)OCCO3
Product: COCCOCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-[2-(2-methoxyethoxy)ethyl]-2,2′,3,3′-tetrahydrospiro[1,4-dioxino[2,3-f]indole-8,8′-furo[2,3-g][1,4]benzodioxin]-7(6H)-one was obtained (74%): mp 146-148° C.; 1H NMR (300 MHz, CDCl3) δ6.64 (s, 1H), 6.56 (s, 1H), 6.43 (s, 1H), 6.22 (s, 1H), 4.67 (ABq, 2H), 4.27-4.03 (m, 8H), 3.98-3.65 (m, 4H), 3.65-3.55 (m, 2H), 3.52-3.45 (m, 2H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.6, 155.0, 144.4, 143.8, 139.6, 138.2, 136.4, 124.7, 121.4, 113.3, 111.5, 99.3, 99.2, 80.1, 71.9, 70.4, 68.1, 64.6, 64.5, 64.1, 63.9, 59.0, 57.8, 40.3; MS (ES+) m/z 455.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].C[Sn+](C)C.ClCCl.CC(O)=O>ClCCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cn(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)O)cn2C(=O)c1ccc(Cl)cc1
Temperature: 130 °C

Procedure:
In a microwave process vial methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetate (10 mg, 0.028 mmol) was dissolved in 1,2-dichloro ethane (1 mL) and after addition of trimethyltin hydroxide (25 mg, 0.14 mmol) the reaction mixture was heated for 30 min at 130° C. in a microwave (TLC analysis indicated complete reaction). Dichloromethane (1 mL) and 50% AcOH (2 mL) were added to the cold reaction solution and the resulting biphasic mixture was agitated until both layers were clear. The organic phase was collected, washed with brine, dried over Na2SO4 and filtered (using a phase separator syringe with drying cartridge). Removal of the solvent (dichloromethane) in vacuo and following silica gel chromatography using an ethyl acetate/hexane gradient (0.5% AcOH) afforded the pure title compound quantitatively. C18H14ClNO4, Mr=343.76; 1H NMR (400 MHz, DMSO-d6) d: 3.67 (s, 2H), 3.81 (s, 3H), 6.99 (dd, J=2.4/9.2 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.32 (s, 1H), 7.65-7.77 (m, 4H), 8.17 (d, J=9.2 Hz, 1H); LCMS (ESI) tR: 2.60 min (>99%, ELSD), m/z: 344.0 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:7]=1)C.[OH-].[Na+]>CO.Cl.O>[CH3:25][S:22]([N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:26])=[O:3])[CH:11]=[CH:10][CH:9]=1)[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)Cc1cccc(CN(Cc2ccc(C)cc2)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(CN(Cc2cccc(CC(=O)O)c2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of (3-{[methanesulfonyl-(4-methyl-benzyl)-amino]-methyl}-phenyl)-acetic acid ethyl ester (101.4 mg, 0.27 mmol) in MeOH (3 mL) was added aqueous NaOH (2N, 0.4 mL). The reaction was stirred at room temperature for 1 h and was diluted with a 1:1 mixture of 1N HCl and water. The product was extracted into CH2Cl2 (3×) and the organic solution was dried over MgSO4, filtered, and concentrated to provide the title compound (87 mg). 1H NMR (400 MHz, CDCl3) δ 7.13–7.34 (m, 8H), 4.28 (d, 4H), 3.65 (s, 2H), 2.75 (s, 3H), 2.33 (s, 2H); MS 346 (M−1).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.Br[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=1[Cl:22]>>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=1
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: Clc1cncc(Cl)c1CBr
Product: Oc1cc(C(F)(F)F)nc(SCc2c(Cl)cncc2Cl)n1

Procedure:
This example was synthesized from 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol and 4-(bromomethyl)-3,5-dichloropyridine by following general procedure as described in the last step of Example 22. The title compound was obtained as a white solid (660 mg, 37% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.72 (s, 2H), 6.69 (br, 1H), 8.64 (s, 2H); M+ 356.