Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][C:7]=1[C:19]([F:22])([F:21])[F:20])=[O:5])C.[OH-].[K+].O.Cl>C1COCC1.C(O)C>[C:15]([O:14][C:12]([NH:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:19]([F:21])([F:22])[F:20])[N:8]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1sc(NC(=O)OC(C)(C)C)nc1C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(C(F)(F)F)c(C(=O)O)s1
Temperature: 60 °C
Yield: 98.5 %

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester (6.67 g, 19.60 mmol) in THF (42 mL) and ethanol (63 mL) was added aqueous 6N potassium hydroxide (100 mL) cautiously at 25° C. and heated at 60° C. for 20 h. The reaction mixture was cooled to room temperature, added water (200 mL), cooled in an ice bath with stirring at 0° C., cautiously acidified to pH 1 with concentrated HCl and extracted with ethyl acetate (3×200 mL). The organic layers were combined, washed with brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 2-tert-Butoxycarbonylamino-4-trifluoromethyl-thiazole-5-carboxylic acid (6.03 g, 100%) as a pale yellow solid.
Reaction SMILES: [B:1]([F:4])([F:3])[F:2].[F:5][H-]F.[F:8][N+:9]([F:12])([F:11])[F:10].F>>[F:2][B-:1]([F:8])([F:4])[F:3].[F:8][N+:9]([F:12])([F:11])[F:10].[FH:5]
Reactant: F[H-]F
Reactant: FB(F)F
Agent: F
Agent: F[N+](F)(F)F
Product: F[B-](F)(F)F

Procedure:
adding boron trifluoride to the separated solution of tetrafluorammonium bifluoride in anhydrous liquid hydrogen fluoride to form tetrafluorammonium tetrafluoroborate in solution with hydrogen fluoride;
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>[CH2:13]([O:11][C:1](=[O:12])[CH:2]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)C(CO)c1ccccc1
Reactant: CCCCCCCCO
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)C(CO)c1ccccc1
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a mixture of 49.9 g (300 mmol) of tropic acid and 5.00 g of montmorillonite K10 in 200 ml of toluene is added dropwise at 110° C. 104 g (800 mmol) of 1-octanol. The reaction mixture is stirred for 8 hours, and then toluene/water are removed by azeotropical distillation. The catalyst residue is filtered off and the filtrate is evaporated to dryness to afford 60.4 g (72%) of 3-hydroxy-2-phenyl-propionic acid octyl ester.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:27])[C@:4]1([O:24]C=O)[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C(=O)(O)[O-].[K+]>CO.O.C(OCC)(=O)C>[Br:1][CH2:2][C:3](=[O:27])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(OC=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Under argon, 4.0 g of 21-bromo-17-formyloxy-1,4-pregnadiene-3,20-dione is agitated in a mixture of 150 ml of methanol and 24 ml of water with 1.3 g of potassium bicarbonate at room temperature. After one hour, the reaction mixture is introduced into ice water, the precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, and dried over sodium sulfate, yielding 3.2 g of 21-bromo-17-hydroxy-1,4-pregnadiene-3,20-dione, mp 189.9° C. (decomposition).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[C:23]1([C:29](O)=[O:30])([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:29]([C:23]3([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]3)=[O:30])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(O)C1(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1

Procedure:
5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (30.0 mg, 0.1 mmol) and 1,1-cyclopropanedicarboxylic acid (0.1 mmol) was dissolved in DCM (3 mL), added in HOBt (1.0 eq, 14.0 mg), EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was purified by Gilson to yield 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-cyclopropanecarboxylic acid. 1-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-cyclopropanecarboxylic acid was dissolved in 3 mL DCM with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol), added in HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight and then was purified by reverse phase hplc using a Gilson (0.1% TFA conditions) to yield 1,1-dimethylethyl (2S)-4-[(5′-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)-amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[F:12][CH:13]([F:17])[C:14]([CH3:16])=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:10])[CH2:9][C:14]([CH:13]([F:17])[F:12])([CH3:16])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)C(F)F
Reactant: CC(=O)c1ccc(Cl)cc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C(F)F)CC(=O)c2ccc(Cl)cc2O1
Reaction time: 3 h
Yield: 83.9 %

Procedure:
1-(4-Chloro-2-hydroxyphenyl)ethanone (8.07 g, 47.3 mmol), MeOH (81 mL), 1,1-difluoroacetone (4.89 g, 52.0 mmol), and pyrrolidine (4.30 ml, 52.0 mmol) were stirred at ambient temperature for 45 hours, at 35° C. for 7 hours, then at 50° C. for 3 hours. The reaction mixture was concentrated, diluted with MTBE (75 mL), then washed with water (40 mL), 2N HCl (2×25 mL), brine (20 mL), 2N NaOH (2×20 mL), and brine (2×20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (9.78 g, 39.7 mmol, 84%) as a brown oil. MS (DCI/NH3) m/z 264 (M+NH4)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:35])[N:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=[O:34])N(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]>C1COCC1.CCCCCC>[CH3:13][O:14][C:15]([N:16]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30](=[O:34])[CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]1=2)=[O:35]
Reactant: COC(=O)N(c1ccccc1C)c1ccccc1C(=O)N(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Diisopropylamine (11.66 g, 0.115 mol, 1.2 eq.) is dissolved in THF (150 mL) and the solution is cooled down to −10° C. A solution of n-Butyllithium in hexane (72 mL of a 1.6 M solution, 1.2 eq.) is added slowly in order to keep the temperature below 0° C. (40 min). A solution of (2-dimethylcarbamoyl-phenyl)-o-tolyl-carbamic acid methyl ester (30.2 g, 0.096 mol, 1 eq.) in THF (80 mL) is added in 45 min. to the obtained solution. The reaction mixture is stirred for 1 hour at −5° C. before quenching by addition of water (30 mL). The mixture is concentrated in vacuum and water (220 mL) and ethylacetate (220 mL) are added to the oily residue. The phases are stirred rapidly before letting them separate. The organic phase is washed with aqueous sulfuric acid (300 mL of 1-M solution) and twice with water (300 mL). The organic phase is evaporated to dryness and delivers 23.0 g (89.5% yield) of the title compound as an orange oil that solidifies on standing.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:12])[CH2:10][Cl:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[OH:1][N:2]=[C:3]([C:9]1([O:15][CH2:14][CH2:13][O:12]1)[CH2:10][Cl:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: OCCO
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)C1(CCl)OCCO1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxo-4-chlorobutyrate (syn isomer, 10 g), ethylene glycol (16 g), p-toluenesulfonic acid (0.3 g) and dried benzene (100 ml) was heated for 19 hours under reflux while removing water azeotropically. After the reaction mixture was cooled to ambient temperature, water (30 ml) and benzene (20 ml) were added thereto. The mixture was saturated with sodium chloride and the benzene layer was separated, and the remaining aqueous layer was further extracted with benzene (20 ml). The benzene layer and extract were combined together, washed with a saturated aqueous solution of sodium chloride (30 ml×2), dried over magnesium sulfate and then filtered. The filtrate was evaporated to give an oil of ethyl 2-hydroxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer, 7.23 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][N:17]3[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:24]=4)=[CH:21][N:22]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[C:29]1([C:25]2[CH:24]=[C:23]([C:20]3[N:17]4[CH:18]=[CH:19][C:14]([C:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=5)=[CH:15][C:16]4=[N:22][CH:21]=3)[CH:28]=[CH:27][N:26]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C1=C(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CCNC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Ex. 1.103) (1.0 eq, 0.2 mmol, 90 mg) is dissolved in dioxane/MeOH (1 ml, 1 ml) and HCl (4M in dioxane, 10.0 eq, 2.0 mmol, 0.5 ml) is added. The reaction is stirred at room temperature for 16 h. The solvent is removed in vacuo to yield 3-(2-phenyl-pyridin-4-yl)-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=353
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[CH3:7][C:8]([CH3:13])([CH2:11]O)[CH2:9][OH:10]>C1C=CC=CC=1>[C:2]([CH:3]1[O:10][CH2:9][C:8]([CH3:13])([CH3:11])[CH2:7][O:4]1)([OH:6])=[O:5]
Reactant: O=CC(=O)O
Reactant: CC(C)(CO)CO
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)COC(C(=O)O)OC1
Yield: 73.4 %

Procedure:
Following a general procedure,23 a mixture of glyoxylic acid monohydrate (5.0 g, 54 mmol), 2,2-dimethyl 1,3-propanediol (8.5 g, 81 mmol) and Amberlyst-15 ion-exchange resin (100 mg) in benzene (140 mL) was refluxed for 15 h in a flask fitted with a Dean-Stark apparatus. The reaction mixture was filtered. The filtrate was concentrated and then refluxed with 20% aqueous NaOH (50 mL) for 30 min. The resulting alkaline solution was extracted with ether and neutralized in the cold with dilute HCl. At the end the pH was brought to ˜1.0 using H3PO4. The acidified aqueous layer was extracted with ether. The extracts were combined, dried (Na2SO4) and concentrated to afford a white solid (6.349 g, 73%): mp 58-60° C.; 1H NMR δ 0.80 (s, 3H), 1.22 (s, 3H), 3.57 (d, J=12.0 Hz, 2H), 3.79 (d, J=12.0 Hz, 2H), 4.97 (s, 1H); 13C NMR δ 169.1, 124.7, 95.8, 77.5, 30.6, 23.0, 21.9; FAB-MS obsd 161.0806, calcd 161.0814 (C7H12O4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>O.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)c1cccc(Br)c1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1cccc(-c2cccc(C(N)=O)c2)c1
Yield: 74.1 %

Procedure:
To a stirred mixture 3-bromobenzoic acid amide (0.76 g; 3.8 mmol) and toluene (25 mL), Pd(PPh3)4 (0.180 g; 0.16 mmol), a solution of Na2CO3 (2.543 g; 24 mmol) in H2O (10 mL), and one of 3-methoxyphenylboronic acid (1.132 g; 7.45 mmol) in EtOH (10 mL) were added. The mixture was refluxed for 1 h under vigorous stirring, cooled, and the acqueous phase extracted with AcOEt. The combined organic layers were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography (cyclohexane/EtOAc 1:1 then 4:6) and recrystallization gave the desired product (0.64 g) as white solid. Yield 74%. Mp: 138–40° C. (EtOH). MS (EI): m/z 227 (M+, 100%). 1H NMR (CDCl3): δ 3.88 (s, 3H); 5.71 (br s, 1H); 6.11 (br s, 1H); 6.94 (m, 1H); 7.18 (m, 2H); 7.39 (t, 1H); 7.53 (t, 1H); 7.77 (m, 2H); 8.05 (t, 1H) ppm. IR (Nujol): 3327, 3148, 1676, 1640, 1613, 1584 cm−1.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=O)[CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCCNC2C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CC3CCCNC3C2)cc1

Procedure:
44 g (about 0.18 mol) of crude or pure 6-benzyl-5,7-dioxo-octahydropyrrolo[3,4-b]pyridine are reduced with 15.2 g (0.40 mol) of lithium aluminum hydride in 390 ml of absolute tetrahydrofuran in the course of 10 hours in accordance with the working instructions of Example Ic. 24.4 g of a colorless oil having a boiling point of 93°-95° C./0.06 mbar are obtained on distillation.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=1[NH:20]C(=O)C.CO.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH3:6][O:7][C:8](=[O:24])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=1[NH2:20]
Reactant: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1NC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1N
Temperature: 70 °C
Yield: 79.1 %

Procedure:
0.12 ml of sulfuric acid 98% are added dropwise at 0° C. (exothermic) to a suspension of 69 mg (0.257 mmol) of 2-acetylamino-5-methoxy-4-nitro-benzoic acid methyl ester, 0.69 ml of methanol and 0.12 ml of water. The mixture is then heated to 70° C. for 30 minutes, cooled to room temperature, poured onto a mixture of ice, water and ethyl acetate and the pH adjusted to 6 with concentrated potassium bicarbonate solution. The organic phase is separated, washed with brine, dried over sodium sulfate, filtered and evaporated, giving 46 mg (79%) of 2-amino-5-methoxy-4-nitro-benzoic acid methyl ester as red-brown crystals, m.p. 127-129° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][N:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18]2)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.C(Cl)Cl.C(N(CC)CC)C.[CH3:39][O:40][C:41](Cl)=[O:42]>O>[CH2:22]([N:17]1[CH2:18][CH:19]2[N:14]([CH2:13][C@H:2]([NH:1][C:41](=[O:42])[O:40][CH3:39])[CH2:3][O:4][C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=3)[CH:15]([CH2:21][CH2:20]2)[CH2:16]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc(OC[C@@H](N)CN2C3CCC2CN(Cc2ccccc2)C3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)N[C@H](COc1ccc(C#N)cc1)CN1C2CCC1CN(Cc1ccccc1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
4-{[(2S)-2-Amino-3-(3-benzyl-3,8-diazabicyclo[3.2.1]oct-8-yl)propyl]oxy}benzonitrile (3.7 g, 9.8 mmol; from step (f) above) was mixed with DCM (50 mL) and triethylamine (2.1 g, 21.5 mmol). The mixture was cooled to 0° C. and methylchloroformate (0.8 mL, 10.7 mmol) was added dropwise. The reaction was performed under an argon atmosphere. After 2 h, the temperature was allowed to reach r.t, at which temperature it was then stirred overnight. Water was added, the organic layer was separated, dried and evaporated. Purification by chromatography (CHCl3:MeOH (95:5)) gave 2.9 g (68%) of the sub-title compound.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:21])[CH2:11][C@@H:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(OB(O)O)C=CC=CC=1.O.C1C([N+]([O-])=O)=CC=C([O:42][C:43]([O:45][CH2:46][C:47]2[O:51][N:50]=[CH:49][CH:48]=2)=O)C=1>C1(C)C=CC=CC=1.C1COCC1>[NH2:20][C@@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][C@H:10]([OH:21])[C@@H:2]([NH:1][C:43]([O:45][CH2:46][C:47]1[O:51][N:50]=[CH:49][CH:48]=1)=[O:42])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccno1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: OB(O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A mixture of 1.54 g (5.41 mmol) of (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane and 0.673 g (5.41 mmol) of phenylboric acid in anhydrous toluene (130 mL) was heated at reflux under argon for 2 hrs with removal of H2O by a Dean-Stark trap. The resulting yellow solution was allowed to cool and the solvent was removed in vacuo to give an oil which solidified upon standing. The residue was taken up in 90 ml of THF, cooled to -40° C., and treated dropwise under Ar atmosphere over a period of 1 h with 1.11 g (3.78 mmol) of ((5-isoxazolyl)methyl)-(4-nitrophenyl)carbonate in 40 ml of THF. The solution was allowed to warm to -20° C. over the next 0.5 hr, then was stirred at 0° C. for 2.5 hrs and at room temperature for 1 hr. After removal of the solvent in vacuo, the residue was taken up in ethyl acetate (200 mL), washed sequentially with 5% aqueous K2CO3 (4×25 mL) and saturated brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Silica gel chromatography of the residue using a gradient of methanol in chloroform (2%, 4%, 6%) afforded a mixture of the desired product and its regioisomer. Purification of the mixture on two consecutive 250 g SiO2 columns (deactivated with 1% isopropylamine/CH2Cl2) with a gradient of isopropylamine/CH2Cl2 (0.5%, 1%) afforded the desired compound as a sticky solid (0.730 g, 1.78 mmol, 33%): 1H NMR (DMSO-d6) δ1.17-1.57 (m, 5H), 2.56-2.69 (m, 2H), 2.75-2.86 (m, 1H), 2.89-3.00 (m, 2H), 3.53-3.71 (m, 3H), 5.06 (s, 2H), 6.32 (d, J=2.4 Hz, 1H), 7.11-7.30 (m, 10H), 8.54 (d, J=2.4 Hz, 1H). Mass spectrum: (M+H)+ =410.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:10][CH:11]=2)[S:4]1(=[O:6])=[O:5].[Na].[C:24]1([N:30]2[C:34]([SH:35])=[N:33][N:32]=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClCCl.CC(C)=O>C(C(C)=O)C>[C:24]1([N:30]2[C:34]([S:35][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:10][CH:11]=4)[S:4]3(=[O:6])=[O:5])=[N:33][N:32]=[N:31]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [Na]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(CSc1nnnn1-c1ccccc1)C2=O
Yield: 84021.1 %

Procedure:
By a method similar to that of Example 44 condensation of 2-chloromethyl-6-[2-(2-methoxyethoxy)-ethoxy]saccharin (34 g.) and 1-phenyltetrazol-5-thiol sodium salt (0.19 g) in methyl ethyl ketone at 60° C. and purification of the product (470 mg) by column chromatography on silica gel first with dichloromethane and then with dichloromethane-acetone (up to 97:3) as eluant afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin as an oil (390 g, 82% yield).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17][C:18](N(C)C)=[N+](C)C)[C:12]2C=CC=CC=2N=N1.Cl.CONC.CN(C)C=O.[F:35][C:36]1[CH:37]=[C:38](/[CH:43]=[CH:44]/[C:45]([OH:47])=O)[CH:39]=[CH:40][C:41]=1[F:42]>O1CCCC1.C(OCC)(=O)C>[F:35][C:36]1[CH:37]=[C:38](/[CH:43]=[CH:44]/[C:45]([N:8]([O:17][CH3:18])[CH3:12])=[O:47])[CH:39]=[CH:40][C:41]=1[F:42]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)/C=C/c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
2-(1H-Benzotriazole-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (2.060 g, 5.43 mmol), O,N-dimethylhydroxylamine hydrochloride (0.583 g, 5.97 mmol) and a catalytic amount of dimethylformamide are added to a suspension of (E)-3-(3,4-difluorophenyl)prop-2-enoic acid (1 g, 5.43 mmol) in tetrahydrofuran (20 mL). The resulting solution is stirred at room temperature for 3 h. The solution is diluted with ethyl acetate (20 mL) and is washed with sequentially with aqueous saturated ammonium chloride (10 mL), water (10 mL), aqueous saturated sodium hydrogen carbonate (10 mL) and with brine (10 mL). The organic layer is then dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product isolated is purified by flash column chromatography on silica gel (heptane/ethyl acetate 0 to 60% as eluent) to afford the desired product as a white solid (478 mg, 2.104 mmol, 39% yield).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CC(C)=O.[N+:10]([C:13]1[CH:22]=[C:21]2[C:16]([NH:17][C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:15][C:14]=1[S:25](Cl)(=[O:27])=[O:26])([O-:12])=[O:11].C(O)(=O)C>O>[CH2:1]([N:3]([CH2:4][CH3:5])[S:25]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[N+:10]([O-:12])=[O:11])[NH:20][C:19](=[O:23])[C:18](=[O:24])[NH:17]2)(=[O:26])=[O:27])[CH3:2]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: CCNCC
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCN(CC)S(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 59 %

Procedure:
To a solution of 10.97 g (0.015 mole) of diethylamine in 20 ml of acetone 4.58 g (0.015 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added a temperature between 5° C. and 10° C., under stirring, the mixture is stirred at the same temperature for 3 hours and allowed to stand for 16 hours. Then 6 ml of acetic acid and 40 ml of water are added to the mixture, the separated crystals are filtered off, washed with water and acetone, dried and recrystallized from acetonitrile. Thus 3.50 g (59%) of N,N-diethyl-1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: >360° C.