Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:13]([C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17](OC)=O)=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C>[O:14]=[C:13]1[C:15]2[C:16](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][N:12]1[CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: COC(=O)c1ccccc1C=O
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2Cc3ccccc3C2=O)C1
Reaction time: 5.5 h
Yield: 87.3 %

Procedure:
To a solution of 1-Boc-3-aminoazetidine 1a (1.0 g, 5.8 mmol) and methyl 2-formylbenzoate 2a (0.95 g, 5.8 mmol) in 1,2-dichloroethane (30 mL) and acetic acid (1.5 mL) was added Na(OAc)3BH (1.29 g, 6.08 mmol) at room temperature. The reaction was stirred for 5.5 h. It was quenched with aq. NaHCO3, and the resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 40% EtOAc/heptane) gave compound 2b (1.46 g).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([C:13]2([CH2:27][O:28]CC3C=CC=CC=3)[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[C:9](=[O:12])[CH2:10][CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[ClH:1].[OH:28][CH2:27][C:13]1([N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:12])[CH2:10][CH3:11])[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:18]1
Reactant: [H][H]
Reactant: CCC(=O)N(c1ccccc1)C1(COCc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1(CO)CCN(CCc2ccccc2)CC1

Procedure:
A mixture of 5.9 parts of N-phenyl-N-[1-(2-phenylethyl)-4-(phenylmethoxymethyl)-4-piperidinyl]propanamide hydrochloride and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and washed on the filter with methanol. The filtrate is evaporated. The oily residue solidifies on scratching. The solid product is crystallized from 20 parts of 2-propanone at room temperature. It is filtered off and recrystallized from 2-propanol at 0° C., yielding N-[4-(hydroxymethyl)-1-(2-phenylethyl)-4-piperidinyl]-N-phenylpropanamide hydrochloride; mp. 218.4° C.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:11][CH:12]=[CH2:13])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20]O>C(O)=O>[OH:20][CH2:13][CH:12]1[O:9][C:8](=[O:10])[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11]1
Reactant: C=CCC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: OO
Solvent: O=CO
Product: O=C1OC(CO)CC1(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
2,2-Diphenyl-4-pentenoic acid (5.0 g, 20 mmol.), 20 mL of formic acid and 2.4 mL (22 mmol.) of 30% hydrogen peroxide were stirred at 70° C. for 25 hours at ambient temperature. The solvents were evaporated at reduced pressure, the residue taken up in 20 mL of methanol and a solution of 750 mg solid NaOH in 10 mL of water was added. The mixture was warmed at 70° C. to solution, about 1 hour before cooling and acidifying with 6N hydrochloric acid. The product was extracted with ether, the organics dried (MgSO4) and evaporated at reduced pressure to give an oil in quantitative yield, the H NMR indicated a clean reaction product which was carried on without further purification. Analytical TLC (silica, 9:1, methylene chloride: EtAc) R.function. 0.35; IR (neat) 3419, 3060, 2936, 1763, 1177, 786, 763, 699 cm-1 ; 1H NMR (CDCl3)δ 2.5-2.65 (bs, 1H), 2.84-3.02 (m, 2H), 3.64-3.72 (m, 1H), 3.92-4.00 (m, 1H), 4.41-4.51 (m, 1H), 7.2-7.4 (m, 10H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:44]1[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=3)=[CH:27][N:28]=2)=[CH:19][CH:18]=1)[C:13]([N:44]1[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:45]1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CCNC1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)O)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N4CC[C@H](C(=O)OC)C4)cc3)nc2)cc1
Reaction time: 4 h
Yield: 52 %

Procedure:
Prepared using General Procedure 7. To a stirring solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid INT-22 (2082 mg, 2.75 mmol), methyl (S)-pyrrolidine-3-carboxlate HCl (545 mg, 3.30 mmol), and DIEA (1523 μl, 8.25 mmol) in DMF (6 mL) cooled to 0° C. was slowly added a solution of HATU (1254 mg, 3.30 mmol) in DMF (5 mL) in a drop-wise fashion The reaction mixture was allowed to warm slowly and stirring continued for 4 h. The reaction mixture was poured onto ice-water and the solid was filtered. The solid was dissolved in EA (50 mL), dried over MgSO4, evaporated and purified by chromatography (EA/hexane) to provide 932 mg (52%) of methyl (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate. LCMS-ESI (m/z) calculated for C40H46N4O6: 678.3. found 679.3 [M+H]+, tR=4.50 min (Method 16).
Reaction SMILES: C[O:2][C:3]([C:5]1(CCC)[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[C:22]([OH:33])[C:21]=3[CH2:34][CH:35]=[CH2:36])=[CH:14][C:7]=2[O:6]1)=[O:4].[OH-].[Li+].[CH3:42]O.[CH2:44]1[CH2:48]OC[CH2:45]1>C(OCC)(=O)C>[CH3:42][O:33][C:22]1[C:21]([CH2:34][CH:35]=[CH2:36])=[C:20]([CH:25]=[CH:24][C:23]=1[C:26]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:27])[O:19][CH2:18][CH2:17][CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][CH:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=2[C:14]=1[CH2:45][CH2:44][CH3:48]
Reactant: C=CCc1c(OCCCOc2ccc3c(c2)OC(CCC)(C(=O)OC)CC3)ccc(C(=O)N2CCCC2)c1O
Reactant: CO
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)O)CC3)ccc(C(=O)N2CCCC2)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 27 (150 mg, 0.27 mmol) and an excess amount of lithium hydroxide were added to 2 to 3 ml of methanol and about I0 ml of THF. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. Chromatography of the reaction mixture on silica gel with 90% ethyl acetate/9.5% methanol/0.5% acetic acid as eluant gave the product.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=4)=[CH:15][C:10]=3[CH:9]=[C:8]([C:29]([O:31]C)=[O:30])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=4)=[CH:15][C:10]=3[CH:9]=[C:8]([C:29]([OH:31])=[O:30])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34 g). To the solution was added 1N sodium hydroxide solution (7.5 ml), and the mixture was stirred at room temperature overnight, heated at 50° C. for 1 hour, concentrated, which was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-cyclopropylmethyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.30 g) as yellow crystals.
Reaction SMILES: [CH:1](=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[C:7]1([S:13]([C:16]#[N:17])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.B(O)(O)O>C(O)CCC>[C:7]1([S:13]([C:16]2[CH:4]=[C:3]([CH3:5])[CH:2]=[CH:1][N:17]=2)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)=CC=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: OB(O)O
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: Cc1ccnc(S(=O)(=O)c2ccccc2)c1
Temperature: 119 °C
Yield: 72.9 %

Procedure:
First, 9.00 g (107 mmol) of senecialdehyde (3-methyl-2-butenal) and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 0.30 g (4.85 mmol) boric acid were added. Then the mixture was heated under reflux for 3 hours while agitating at an internal temperature of 119° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 8.50 g of 2-benzenesulfonyl-4-methylpyridine with the following properties as colorless crystals (purity of 99%, yield of 72% based on benzenesulfonyl cyanide).
Reaction SMILES: [O:1]=[C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=O.C(N(CC)CC)C.C(Cl)[Cl:23]>>[O:1]=[C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([Cl:23])=[O:14]
Reactant: Cc1[nH]cc(OCC(=O)O)c(=O)c1Cl
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: Cc1[nH]cc(OCC(=O)Cl)c(=O)c1Cl
Reaction time: 0.25 h

Procedure:
A mixture of 2-(4-oxo-5-chloro-6-methyl-1,4-dihydropyridin-3-yloxy)acetic acid (2.17 g) and triethylamine (5 ml) in methylene chloride (50 ml) was stirred for 15 minutes. After evaporation to dryness, methylene chloride (50 ml) and then thionyl chloride (1.2 g) were added to the residue under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes and at room temperature for 30 minutes. Precipitated crystals were collected by filtration, washed with methylene chloride and diethyl ether and dried to give powder (2.3 g) of 2-(4-oxo-5-chloro-6-methyl-1,4-dihydropyridin-3-yloxy)acetyl chloride. A solution of 7-[D-2-(4-hydroxyphenyl)glycinamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (2.1 g) and bis(trimethylsilyl)acetamide (10 ml) in methylene chloride (50 ml) was stirred at 0° C. and the powder (1.2 g) obtained above was added thereto. The reaction mixture was stirred at 0° C. for 2.5 hours and kept in an ice-box over-night. After removal of the solvent, water was added to the residue, and appearing precipitates were collected by filtration, washed with water and dried. The resulting powder (2.5 g) in dry acetone (200 ml) was stirred for 3 hours and collected by filtration, washed with a mixture of acetone and diethyl ether and dried. The resultant powder was dissolved in a mixture of water and an aqueous solution of sodium bicarbonate, whereby the solution was adjusted to pH 7.5, and ethyl acetate (5 ml) was added thereto. To the mixture was added Diaion HP-20 resin (Trade name of the product of Mitsubishi Kasei Co.) (1 ml) and the mixture was stirred for 30 minutes and filtered. The filtrate was adjusted to pH 3 with 10% hydrochloric acid. The resulting crystals were collected by filtration, washed with water, and dissolved in hydrous acetone. The solution was treated with active charcoal (0.3 g), and, after removal of the solvent, the resulting crystals were collected by filtration, washed with water and dried to give crystals (0.85 g) of 7-{D-2-[2-(4-oxo-5-chloro-6-methyl-1,4-dihydropyridin-3-yloxy]acetamido-2-(4-hydroxyphenyl)acetamido}-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, m.p. 210°-215° C. (dec).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([Li])CCC.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](OCC)=[O:19]>O1CCCC1.CCCCCC.[Cl-].[NH4+]>[NH:4]1[CH:3]=[C:2]([C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)=[O:19])[CH:6]=[N:5]1
Reactant: CCOC(=O)c1ccccn1
Reactant: Ic1cn[nH]c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1cn[nH]c1)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
To a solution of 4-iodopyrazole (1.0 g) in tetrahydrofuran (10 mL), a solution of n-butyllithium in hexane (2.6 M, 4.8 mL) was added dropwise at −10° C. and stirred at room temperature for 1 hour. The reaction mixture was cooled to −10° C. and ethyl picolinate (0.86 g) was added thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: hexane:ethyl acetate=1:1 to 1:2) to give the titled compound (0.090 g) as a colorless solid.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH3:46][O:47][C:48]1[C:53]([CH2:54][NH2:55])=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=[C:50]([CH3:60])[N:49]=1>ClCCl.O>[CH3:46][O:47][C:48]1[C:53]([CH2:54][NH:55][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:52]([C:56]([F:59])([F:57])[F:58])[CH:51]=[C:50]([CH3:60])[N:49]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: COc1nc(C)cc(C(F)(F)F)c1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1nc(C)cc(C(F)(F)F)c1CNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 4-phenoxybenzoic acid (640 mg, 3 mmol) in anhydrous dichloromethane (30 mL) were added 1H-benzo[d][1,2,3]triazol-1-ol (600 mg, 4.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (864 mg, 4.5 mmol) and triethylamine (1.1 g, 10 mmol). After stirring at room temperature for 0.5 hour, (2-methoxy-6-methyl-4-(trifluoromethyl)pyridin-3-yl)methanamine (0.47 g, 2.1 mmol) was added. After stirring at room temperature for 4 hours, to the mixture was added water (20 mL). The resultant mixture was extracted with dichloromethane (20 mL×2). Organic layers were combined and concentrated to give a residue. The residue was purified by chromatography (petroleum ether/ethyl acetate=1:1) to give N-((2-methoxy-6-methyl-4-(trifluoromethyl)pyridin-3-yl)methyl)-4-phenoxybenzamide (600 mg, 67.5%). LRMS (M+H) m/z: calcd 416.13. found 416. 1H NMR (300 MHz, CD3OD): δ 7.78 (d, J=8.7 Hz, 2H), 7.40 (t, J=7.8 Hz, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.12 (s, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 4.63 (s, 2H), 4.01 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].CC(O)=O.[CH:15]([O-])([O-])[O:16][CH2:17][CH3:18]>>[CH2:17]([O:16][C:15]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[N:10]=1)[CH3:18]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)O
Product: CCOc1nc2ccc(C#N)cc2[nH]1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 3,4-diaminobenzonitrile (400 mg) in ethyl orthoformate (6.48 ml) was added AcOH (238 mg), followed by stirring at 80° C. for 2 hours. The reaction solution was cooled to room temperature, and partitioned between EtOAc and a 1M aqueous NaOH solution. The organic layer was washed with saturated brine, dried over anhydrous Na2SO3, and then collected by filtration, and the filtrate was concentrated, and purified by silica gel chromatography to obtain 2-ethoxy-1H-benzimidazole-6-carbonitrile (164 mg) as colorless powders.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1([CH3:12])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13](Br)[CH:14]=C>>[C:1]([NH:5][S:6]([C:9]1([CH2:12][CH:13]=[CH2:14])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)C1(C)CC1
Reactant: C=CCBr
Product: C=CCC1(S(=O)(=O)NC(C)(C)C)CC1
Yield: 97 %

Procedure:
This compound was obtained in 97% yield according to the procedure described in the synthesis of N-tert-butyl-(1-methyl)cyclopropylsulfonamide using 1.25 equivalents of allyl bromide as the electrophile. The compound was used in the next reaction without further purification: 1H NMR (CDCl3) δ 0.83 (m, 2H), 1.34 (s, 9H), 1.37 (m, 2H), 2.64 (d, J=7.3 Hz, 2H), 4.25 (br s, 1H), 5.07-5.10 (m, 2H), 6.70-6.85 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[N:11][OH:12])[CH:5]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(Br)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(-c2ccc(S(C)(=O)=O)cc2)c1

Procedure:
In analogy to example 22, from 3-(3-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 11) and (4-methylsulfonylphenyl)boronic acid was prepared the title compound as a mixture of E and Z isomers (3:1) as a yellow oil, MS (ESI+): m/z=471.1 ([M+H]+).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([NH2:14])=[N:8][NH:9]2.ClC1SC(S(N(S(C2SC(Cl)=CC=2)(=O)=O)C2C3C(=CC=CC=3OC)N(C(OC(C)(C)C)=O)N=2)(=O)=O)=CC=1.Cl[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[C:56]([O:62][CH3:63])[CH:55]=1>CS(C)=O.O>[CH3:63][O:62][C:56]1[CH:55]=[C:54]([CH2:53][N:9]2[C:10]3[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=3)[C:7]([NH2:14])=[N:8]2)[CH:59]=[CH:58][C:57]=1[O:60][CH3:61]
Reactant: COc1ccc(CCl)cc1OC
Reactant: COc1cccc2[nH]nc(N)c12
Agent: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(N)c3c(OC)cccc32)cc1OC
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Powdered KOH (0.494 g, 8.80 mmol) was dissolved in DMSO (20 mL) under nitrogen and 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (0.653 g, 4 mmol) was added. The mixture was stirred for 15 min to give a deep red solution. 4-(Chloromethyl)-1,2-bis(methyloxy)benzene (0.896 g, 4.80 mmol) was added in one portion and the mixture was stirred for 2 h. The mixture was added to water (150 mL) and extracted with dichloromethane (3×50 mL). The dried (Na2SO4) extract was evaporated and the residue was triturated with diethyl ether (3×3 mL) to give the title compound (1.05 g, 84%) as an orange solid. LCMS (System B) RT=1.42 min, ES+ve m/z 314 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:38])[C@@H:27]([NH2:37])[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:22][CH2:21]1)=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:15]([O:17][C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:38])[C@@H:27]([NH:37][C:12]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:14])[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:24][CH2:25]1)=[O:19])[CH3:16]
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.7 g 4-Hydroxy-quinoline-2-carboxylic acid and 5 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 25 ml of DMF, 2.2 g of HOBT and 2.8 g of EDC was added and the reaction mixture was stirred for 3 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by re-crystallisation from n-heptane/ethyl acetate and dried under reduced pressure. Yield: 7.2 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C(C)C)=[C:22]([O:30][CH3:31])[CH:21]=1)([CH3:19])[CH3:18])=O)C.CS(O)(=O)=O.CCCCCC>CC#N>[OH:26][C:23]1[C:22]([O:30][CH3:31])=[CH:21][C:20]2[C:17]([CH3:19])([CH3:18])[C:7]3[NH:8][C:9]4[C:14]([C:6]=3[C:4](=[O:3])[C:25]=2[CH:24]=1)=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=4
Reactant: CCOC(=O)c1c(C(C)(C)c2ccc(OC(C)C)c(OC)c2)[nH]c2cc(C#N)ccc12
Agent: CS(=O)(=O)O
Solvent: CCCCCC
Solvent: CC#N
Product: COc1cc2c(cc1O)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
6-Cyano-2-[1-(4-isopropoxy-3-methoxy-phenyl)-1-methyl-ethyl]-1H-indole-3-carboxylic acid ethyl ester (Compound L7, 1.25 g, 2.97 mmol) was dissolved in MeCN (18 mL), added with methanesulfonic acid (3.75 mL), and then stirred at 50° C. for 8 hr. Hexane was added to the reaction solution, and the precipitated solid was filtered to obtain the title compound (yellow solid, 185 mg, 19%).