Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][S:34][C:30]=3[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[S:34]1[C:30]2[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:39][CH:38]=3)=[O:24])[C:31]=2[CH:32]=[CH:33]1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3sccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3sccc32)cc1
Reaction time: 5 h

Procedure:
To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 4,10-dihydro-4-(4-aminobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]diazepine. The mixture is stirred for 5 hours. The reaction mixture is washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid, m.p. 162°-188° C. (amorphous)
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]1([S:21](Cl)(=[O:23])=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:21]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)(=[O:23])=[O:22])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 1-naphthalenesulfonyl chloride (2.27 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 3% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.15 g, 68%). 1H-NMR (300 MHz, CDCl3) δ 8.79 (d, J=8.5 Hz, 1H), 8.14 (d, J=7.0 Hz, 2H), 7.98 (d, J=8.4 Hz, 1H), 7.78 (t, J=8.5 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 6.46 (s, 1H), 6.34 (s, 1H), 6.17 (s, 1H), 2.14 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]=CC2C=CC=C([N+]([O-])=O)C=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2].Cl>C(O)C>[C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)[CH2:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:32][CH2:33][CH3:34])[CH2:35][CH2:36][CH3:37])(=[O:3])[CH3:2]
Reactant: CCCN(CCC)CCCCN(CCOC(C)=O)Cc1ccc(CN=Cc2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Solvent: CCO
Product: CCCN(CCC)CCCCN(CCOC(C)=O)Cc1ccc(CN)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 866.3 %

Procedure:
In a 50 ml recovery flask, 326.4 mg (0.639 mmol, 1.0 equivalent) of {(4-dipropylaminobutyl)-[4-(3-nitrobenzylidene)aminomethylbenzyl]amino}ethyl acetate (34) was dissolved in 3.3 ml of ethanol. The solution was cooled to 0° C. After the dropwise addition of 3.3 ml of a 2N hydrochloric acid aqueous solution over about five minutes, the mixture was reacted at 0° C. for three hours. After the addition of 3.3 ml of a 2N hydrochloric acid aqueous solution, the mixture was allowed to stand at 5° C. for 12 hours. The mixture was extracted five times with 25 ml of chloroform. The aqueous layer was added with 50 ml of chloroform and 40 ml of a 3N sodium hydroxide aqueous solution to make the mixture basic. The mixture was then subjected to phase separation and extracted three times with 25 ml of chloroform. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated, thereby obtaining 2.09 g of [(4-aminomethylbenzyl)-(4-dipropylaminobutyl)amino]ethyl acetate (14) as a slightly yellow oily substance (yield: 79%). [HPLC: 96.0% (HPLC measurement conditions A)]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=1.[CH:32](OCC)=[O:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][CH:32]=[O:33])[N:20]=[C:15]2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CN)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: CCOC=O
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC=O)cnc3n1COCC[Si](C)(C)C)cn2C
Yield: 97.6 %

Procedure:
(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (0.095 g, 0.22 mmol, Example #20, Step G) in ethyl formate (4.4 mL, 54.0 mmol) was heated at about 60° C. in an oil bath for about 45 min. The mixture was cooled and evaporated to give N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide (0.10 g, 100%): LC/MS (Table 2, Method a) Rt=2.65 min; MS m/z: 466 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4][CH2:3]1.[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:29]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[C:13]([F:14])=[CH:12][C:11]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:10][C:9]=3[F:26])[CH2:6][CH2:7]2)[O:1][CH2:27][CH2:28]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Yield: 77 %

Procedure:
The compound was prepared by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3,5-difluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.5 mmol), ethylene glycol (0.5 mmol), p-toluene sulfonic acid (0.3 mmol) in toluene and by purifying on silica gel column chromatography to provide title compound in 77% yield.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH:21](O)([CH3:23])[CH3:22]>>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH:21]([CH3:23])[CH3:22])=[O:2]
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)C=Nc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Yield: 78 %

Procedure:
5 g (21.8 mmol) of N-carboxymethylene-4-chloro-anthranilic acid are suspended in 50 ml of isopropanol, and 222 mg (2.3 mmol) of sulfuric acid are added. The mixture is heated under reflux for 8.25 hours. It is then cooled to room temperature and the product which has precipitated out is washed with petroleum ether and dried. 4.6 g (16.9 mmol; 78%) of N-carboisopropoxymethylene-4-chloro-anthranilic acid are obtained.
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1)[C:30]([O:32]C)=[O:31])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[OH-].[Na+].Cl>C1COCC1>[C:1]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1)[C:30]([OH:32])=[O:31])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](NC(=O)c1cccnc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](NC(=O)c1cccnc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
(S)-Methyl 6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-(nicotinamido)hexanoate (40 mg, 0.0695 mmol) was taken up in 2 mL of THF along with 80 μL of a 5 M NaOH solution. The resulting reaction mixture was stirred at room temperature for 2 h. It was then acidified to pH 4 with 2 N HCl and then extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 31 mg of (S)-6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-(nicotinamido)hexanoic acid. MS calculated for C34H47N3O4: 561.36; found: [M+H]+562.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][C:35]#[N:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.CO.Cl>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][C:35]#[N:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: N#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: N#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.), methanol (12 ml.), conc hydrochloric acid (0.55 g.) and tetrahydrofuran (10 ml.) was stirred at room temperature for 3 hours. After concentrating the resultant solution in vacuo, the residue was dissolved in an aqueous solution of sodium bicarbonate. The solution was adjusted to pH 3.5 with 10% hydrochloric acid and stirred for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.56 g.).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:12][CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=2)[CH2:15]1>C(OCC)(=O)C>[CH3:25][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([CH2:13][NH:12][C:1](=[O:3])[CH3:2])[CH2:23][CH2:22]2
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CCC(CN)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCC(CNC(C)=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
Acetyl chloride (0.67 g) was added to a pyridine solution (15 ml) of 2-aminomethyl-6-methoxytetralin hydrochloride (1.5 g; obtained in Reference Example 11), and the reaction mixture was stirred at room temperature for 16 hours, to which was added ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and a saturated aqueous sodium bicarbonate solution, then dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-diisopropyl ether to obtain the entitled compound (960 mg).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[C:8]1([CH2:7][NH:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: CC[C@@H](N)CO
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](CO)NCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 108.6 %

Procedure:
To (R)-(−)-2-amino-1-butanol (5 g, 56.1 mmol) in CH3OH (120 mL) was added benzaldehyde (6.24 mL, 61.7 mmol), and the reaction mixture was stirred under nitrogen for 15 minutes. The mixture was then cooled in an ice bath and sodium borohydride (2.33 g, 61.7 mmol) was added portionwise. The mixture was stirred in the ice bath for 1.5 hours. NaOH (6 N, 25 mL) was added and the mixture was concentrated. The resulting residue was taken up in 100 mL H2O and extracted with Et2O (2×). The organics were combined, dried over Na2SO4 and concentrated to afford the title compound (10.92 g) as a fluffy white solid. LC-MS (ES) m/z=180 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.[Li]C(CC)C.CN(C)[CH:20]=[O:21]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:3]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: CC(C)COc1cccc(F)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)COc1cccc(F)c1C=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 1-fluoro-3-isobutoxybenzene (1.7 g, 10 mmol, EXAMPLE 16, Step 1) in tetrahydrofuran (15 mL) was added dropwise s-BuLi (0.99 M in cyclohexane, 12 mL, 12 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 1 h. N,N-dimethylformamide (1.2 mL, 15 mmol) was added to the mixture, and the mixture was warm to −20° C. After being stirred at −20° C. for 1 h, the mixture was quenched with aq. sodium hydrogencarbonate (30 mL). The mixture was extracted with ethyl acetate (60 mL) and washed with water (30 mL). The extract was dried over magnesium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 30:1) to give 1.2 g (61%) of the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C@@H:6]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:15]([CH2:22][C:23]2[C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[S:25][N:24]=2)[C:14]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Li+]>O1CCOCC1.O>[CH3:33][C:28]1[C:27]2[C:23]([CH2:22][N:15]3[C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[N:13]([C@@H:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:5][C:4]([OH:35])=[O:3])[C:14]3=[O:34])=[N:24][S:25][C:26]=2[CH:31]=[C:30]([CH3:32])[CH:29]=1
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2nsc3cc(C)cc(C)c23)c2cnccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c2c(Cn3c(=O)n([C@H](CC(=O)O)c4ccccc4)c4ccncc43)nsc2c1
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a solution of (R)-3-[3-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2-oxo-2,3-dihydro-imidazo[4,5-c]pyridin-1-yl]-3-phenyl-propionic acid ethyl ester (10 mg, 0.021 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added lithium hydroxide (LiOH) (0.9 mg, 0.042 mmol) at room temperature. The solution was stirred at the same temperature for 4 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solution was concentrated and the residue was purified by preparative TLC with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (8.3 mg, 88%): LCMS, M++1, m/z: 459.13 as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnn(Cc2ccccc2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cnn(Cc2ccccc2)c1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of (1-benzyl-1H-pyrazol-4-yl)methanol (3.84 g) in methylene chloride (100 mL) were added triethylamine (2.80 mL), 4-dimethylaminopyridine (100 mg) and tert-butyldimethylsilyl chloride (3.80 g) at room temperature, and the mixture was stirred for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and insoluble material was removed by filtration. Ethyl acetate (100 mL) was added to extract the filtrate, and the organic layer was washed with brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.00 g).
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].N1C=CC=CC=1.[O:35]=[C:36]1[O:40][CH:39]([C:41](Cl)=[O:42])[CH2:38][CH2:37]1>C1COCC1>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:41]([CH:39]3[CH2:38][CH2:37][C:36](=[O:35])[O:40]3)=[O:42])[CH:23]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1c(-c2cccc(N)c2)cc(-c2ccccc2O)nc1N
Reactant: O=C1CCC(C(=O)Cl)O1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1c(-c2cccc(NC(=O)C3CCC(=O)O3)c2)cc(-c2ccccc2O)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-amino-4-(3-aminophenyl)-6-(2-hydroxyphenyl)nicotinate (starting compound 6, 0.626 g, 1.659 mmol) in THF (7 mL) including pyridine (0.148 mL, 1.824 mmol) was added a solution of 5-oxotetrahydro-2-furancarbonyl chloride (0.271 g, 1.824 mmol) in THF (3 mL). After 1 hr., the mixture was allowed to warm to room temperature and the stirring was continued for 2 hrs. The mixture was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (hexane:ethyl acetate, 1:4-1:19) to give tert-butyl 2-amino-6-(2-hydroxyphenyl)-4-(3-{[(5-oxotetrahydro-2-furanyl)carbonyl]amino}-phenyl)-nicotinate as a pale yellow foam (0.677 g, yield 83%).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[C:5]([F:14])[C:4]=1[O:15][CH3:16].[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[O:23])[CH2:12][C:11](=[O:13])/[CH:10]=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([O:15][CH3:16])[C:5]=1[F:14])[CH3:22]
Reactant: COc1c(Cl)ccc(/C=C/C(C)=O)c1F
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)c(OC)c1F
Yield: 92.9 %

Procedure:
Using the procedure of Example 2, sodium pellets (5.52 g, 0.24 mol), (E)-4-(4-chloro-2-fluoro-3-methoxyphenyl)-but-3-en-2-one (2; 45.73 g, 0.20 mol) and diethyl oxalate (36.54 g, 0.25 mol) were reacted to give (E)-6-(4-chloro-2-fluoro-3-methoxyphenyl-2,4-dioxo-hex-5-enoic acid ethyl ester (5; 61.1 g, 93%) as yellow crystals: mp 67.5-69° C.; 1H NMR (400 MHz, CDCl3) δ 14.71 (s, 1H), 7.78 (d, J=16.1 Hz, 1H), 7.27-7.18 (m, 2H), 6.73 (d, J=16.1 Hz, 1H), 6.54 (s, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.99 (d, J=1.2 Hz, 3H), 1.41 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C15H14ClFNO5, 328.051. found, 328.051.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(#N)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2CCn1ccnc1
Yield: 77.4 %

Procedure:
Methanesulfonic acid 2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester (0.250 g, 0.634 mmol), imidazole (0.173 g, 2.54 mmol), potassium carbonate (0.175 g, 1.27 mmol) and potassium iodide (0.25 g) were added to 50 mL of acetonitrile, and the reaction mixture was refluxed for 16 hours under argon. The reaction mixture was cooled and poured into 300 mL of water, extracted twice with 250 mL of EtOAc, and the combined organic layers were washed with water, saturated brine, and dried (MgSO4). The solvent was removed under reduced pressure to yield an oil that was purified via silica gel column, eluting with MeOH/CHCl3 (5:95). Solvent was removed under reduced pressure to afford 0.180 g (0.491 mmol, 77.5% of 1-[2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-1H-imidazole as an oil. The oil was recrystallized from EtOH/HCl to give 0.130 g of the corresponding hydrochloride salt (0.323 mol, 50.9%). MS: 367 (M+H)+.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13](OS(C)(=O)=O)[CH2:14]2)[N:11]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:9])#[N:2].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:14]2)[N:11]1[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[O:9])#[N:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OS(C)(=O)=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2N2CCCC2)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 80 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-[(methylsulfonyl) oxy]-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 12-1 (153 mg) in dimethylformamide (2.0 mL), was added pyrrolidine (79 mg). The mixture was stirred at 80° C. for 1 hr. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform and methanol (19:1) to give the target compound (91 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[N+:18]([C:21]1[CH:35]=[CH:34][C:24]2[N:25]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:27][C:23]=2[CH:22]=1)([O-:20])=[O:19]>O1CCCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:31]1[CH2:32][CH2:33][N:28]([C:26]2[S:27][C:23]3[CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:35]=[CH:34][C:24]=3[N:25]=2)[CH2:29][CH2:30]1)=[O:9])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc2nc(N3CCNCC3)sc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3ccc([N+](=O)[O-])cc3s2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-Isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 6-Nitro-2-piperazin-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH2:2][C:3]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4]1)(=[O:19])=[O:18]
Reactant: N#CCC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(CC#N)CC1
Temperature: -10 °C

Procedure:
To a solution of [1-(hydroxymethyl)cyclopropyl]acetonitrile (prepared according to the procedure described in WO2005/105749 Example 2/Step 4, incorporated by reference) (1 eq.) in DCM at −40° C. was added triethylamine (3 eq.) and then methanesulfonyl chloride (1.5 eq.). The reaction was warmed to −10° C. over 1 h, and it was diluted with DCM and quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex) to afford the title compound as an oil.