Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[N:9]=1)[C:5]#[N:6].[NH:11]([CH3:13])[CH3:12]>C1COCC1.CC(=O)OCC>[Cl:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([N:11]([CH3:13])[CH3:12])[N:9]=1)[C:5]#[N:6]
Reactant: CNC
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1cc(C#N)cc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 2,6-dichloroisonicotinonitrile (2.50 g, 14.5 mmol) in 2 N Me2NH in THF (20 mL) is stirred in a sealed vessel at 105° C. for 24 h. The dark suspension is cooled to rt, diluted with EA (200 mL), washed with water (2×50 mL) followed by sat. aq. NaHCO3-solution (50 mL), dried over Na2SO4, filtered and concentrated to give crude 2-chloro-6-dimethylamino-isonicotinonitrile; LC-MS: tR=0.96 min, [M+1]+=182.00. This material is dissolved in dioxane (100 mL) and Pd(dppf) (120 mg, 0.147 mmol) is added. To this solution, MeZnCl (5.02 g, 43.4 mmol, 2 M solution in THF) is slowly added. The mixture is stirred at rt for 30 min, then at 75° C. for 16 h. The orange suspension is cooled to rt, diluted with EA (150 mL) and washed with water (2×50 mL). The aq. washings are basified by adding NaOH and the precipitate that forms is filtered off. The filtrate is extracted with DCM (3×70 mL). The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with EA containing methanol to give 2-dimethylamino-6-methyl-isonicotinonitrile (699 mg) as a brownish oil which slowly solidifies; LC-MS: tR=0.50 min, [M+1]+=162.05.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CC2C=CC=CC=2)C=CC=CC=1.[PH2](O)=O.[C:24](Cl)(Cl)=[O:25].[C:28](Cl)([Cl:30])=[O:29].[C:32]1([OH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:24](=[O:25])([O:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([O:7][C:28]([Cl:30])=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cl
Agent: O=[PH2]O
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: Oc1ccccc1
Product: O=C(Cl)Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1
Temperature: 120 °C

Procedure:
The reactor of Example 1 is charged with phenol (319.0 g, 3.390 mol), diphenylmethane as an internal GC standard (3.0723 g), and 50 weight percent hypophosphorous acid (7.046 g). Phosgene (64.6 g, 0.65 mol) is passed into the reactor for 90 min. Phosgene/phenol molar ratio is 0.19. After heating at 120° C. an additional 4 hr the reactor is cooled to ambient temperature. Analysis by GC yields diphenyl carbonate (29.1 mmol), phenylchloroformate (156.7 mmol) and phenol (2.96 mol). Selectivity to phenylchloroformate is 36 mole percent based on phenol, 24 mole percent based on phosgene. Part of the phenol is consumed in a reaction with hypophosphorous acid to yield triphenyl phosphate.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].C(O[CH:12](OCC)[N:13]([CH3:15])[CH3:14])C.C(O)C.C>C(OCC)C>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:4][C:2](=[O:3])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=O
Reactant: CCOC(OCC)N(C)C
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)C=CN(C)C
Temperature: 5 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
Ethyl pyruvate (1,500 g) is added in the course of 2 hours, while the temperature is maintained at approximately 5° C., to N,N-dimethylformamide diethyl acetal (2,100 g) cooled to a temperature in the region of 5° C. The mixture is then stirred for 3 hours at a temperature in the region of 20° C. The reaction ethanol is evaporated off to dryness and the residue obtained is pounded with diethyl ether (12 litres) and charcoal 3S (30 g) and then filtered on supercel. The filtrate is taken up with water (500 cc), and the organic phase is decanted and the aqueous phase is extracted with dichloromethane (3×2000 cc). The organic phases are mixed, dried over sodium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The oil obtained is purified by distillation (b.p.0.1 mm Hg 146°-149° C.). Ethyl 4-dimethylamino-2-oxo-3-butenoate (695 g) is thereby obtained and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)CCCCCO.[C:19]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]O)(=[O:27])[CH2:20][CH2:21]CCCCC>>[C:19]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:9][C:1](=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:27])[CH:20]=[CH2:21]
Reactant: CCCCCCCC(=O)OCCCCCCO
Reactant: CCCCCCCC(=O)O
Agent: OCCCCCCO
Product: C=CC(=O)OCCCCCCOC(=O)CCCCCCC
Reaction time: 5 h

Procedure:
A mixture of caprylic acid (110.5 g; 0.7662 mol) and 1,6-hexandiol (600 g; 5.077 mol) was heated to max. temperature 200° C. for 5 hours, while 25 g of organic volatile compounds and water was removed by distillation. The excess of 1,6-hexandiol was distilled off in vacuum and the residue was cooled and diluted with benzene (750 ml). The benzene solution was extracted with water (3×250 ml), the solvent was evaporated, and the product was distilled through a short empty column (100×25 mm). 6-Hydroxyhexyl caprylate (HHC) had b.p. 120° C./8 Pa. The main fraction containing 98.6% HHC was obtained in the yield of 157.2 g (84%). Elemental analysis for C14H28O3 theory: 68.81% C; 11.55% H; found: 68.65% C, 11.72% H. Infrared and 13C--NMR spectra proved the structure of HHC.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[O:9])=[N:6][CH:7]=1.Cl.[CH3:18][C:19]1([CH3:38])[C:23]([CH3:25])([CH3:24])[O:22][B:21]([C:26]2[CH:27]=[N:28][N:29]([C:31]3([CH2:35][C:36]#[N:37])[CH2:34][NH:33][CH2:32]3)[CH:30]=2)[O:20]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:36]([CH2:35][C:31]1([N:29]2[CH:30]=[C:26]([B:21]3[O:22][C:23]([CH3:25])([CH3:24])[C:19]([CH3:38])([CH3:18])[O:20]3)[CH:27]=[N:28]2)[CH2:34][N:33]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[O:9])=[N:6][CH:7]=2)[CH2:32]1)#[N:37]
Reactant: C[C@H](NC(=O)c1cnc(Cl)cn1)C(F)(F)F
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CNC3)c2)OC1(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1)C(F)(F)F
Temperature: 100 °C
Yield: 97 %

Procedure:
A mixture of 5-chloro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide (254 mg, 1.00 mmol), {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (325 mg, 1.00 mmol) and N,N-diisopropylethylamine (401 μL, 2.30 mmol) in 1,4-dioxane (5.0 mL) was heated at 100° C. for 2 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (gradient: 20-80%) to afford the desired product (0.49 g, 97%). LCMS cacld. for C22H28BF3N7O3 (M+1)+: m/z=506.2. Found: 506.1.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:7]([Cl:16])[CH:6]=1)C.C([BH-](CC)CC)C.[Li+].O>O1CCCC1>[Cl:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([Cl:16])[C:8]=1[S:12]([CH3:15])(=[O:14])=[O:13])[CH2:4][OH:3]
Reactant: CCOC(=O)c1cc(Cl)c(S(C)(=O)=O)c(Cl)c1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1c(Cl)cc(CO)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dichloro-4-(methylsulfonyl)benzoic acid ethyl ester (2.6 g) in tetrahydrofuran (50 mL) was added lithium triethylborohydride (1 M in tetrahydrofuran, 24 mL) at 0-5° C. under nitrogen. The mixture was stirred for 30 min and then water (2 mL) was added and the tetrahydrofuran was evaporated under vacuum. Toluene (100 mL) and water (30 mL) w ere added and then hydrogen peroxide (30% in water, 20 mL) was added at 10-20° C. After 30 min, the separated solid was dissolved by adding ethyl acetate (100 mL). The organic phase was separated and washed with saturated sodium pyrosulfite solution (25 mL) and then with potassium bicarbonate solution (1 M, 25 mL) and then dried with sodium sulphate and evaporated to dryness (yield 1.8 g). 1H-NMR (400 MHz, DMSO-d6) d=3.43 (s, 3H), 4.57 (s, 2H), 5.6 (b, 1H), 7.59 (s, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]([O:9]C)=O.O.[NH2:12][NH2:13]>CC(O)C>[OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: NN
Reactant: COC(=O)[C@H]1CCC[C@@H]1O
Solvent: O
Solvent: CC(C)O
Product: NNC(=O)[C@H]1CCC[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a 50-mL four-necked flask were added 2.33 g (16.2 mmol) of methyl (S,S)-2-hydroxycyclopentanecarboxylate and 9.3 ml of 2-propanol and stirring was started. Hydrazine monohydrate (1.62 g; (32.3 mmol) was dropped thereinto at 23° C. taking 30 minutes. After the dropping, the mixture was stirred at 85° C. for 15 hours. Followed by, heating was stopped and the mixture was cooled down to room temperature to precipitate the crystals. The crystals were filtered and washed with a small amount of 2-propanol. The resulting crystals were dried to give 1.50 g of the title compound. The yield was 63%. Ratio of anti-form to syn-form of the compound was measured by the same manner as in Example 4 and found that the anti/syn ratio was more than 99/1.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC=C(Oc1ccccc1C)C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(Oc1ccccc1CBr)C(=O)OC

Procedure:
A mixture of 2.2 g of methyl 2-(2-methylphenoxy)-3-methoxyacrylate, 1.78 g of N-bromosuccinimide, and a catalytic amount of azobisisobutyronitrile was heated at reflux in carbon tetrachloride for 4 hours. The solid was filtered, and the solvent evaporated to give crude methyl 2-(2-bromomethylphenoxy)-3-methoxyacrylate. A mixture of this crude material, 2.0 g of N-benzyloxy propionamide, and 3.9 g of caesium carbonate was heated at reflux in acetonitrile for 20 hours. The solid was filtered, the solvent evaporated, and the residue purified by silica gel chromatography to give methyl 2-{2-[(1-benzyloxyiminopropyl)oxymethyl]phenoxy}-3-methoxyacrylate (isomer Z) (0.75 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8].C(N(CC)CC)C>C(#N)C>[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8]
Reactant: C1CNCCN1
Reactant: CCn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 91.9 %

Procedure:
Piperazine (0.06 g, 0.74 mmol) was added to a solution of 1-ethyl-6,7-difluoro-3-hydroxy-1H-quinazoline-2,4-dione (Example D, 0.15 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 20 mL of acetonitrile. The solution was heated to reflux for 23 hours, cooled, and filtered to give 0.17 g of the title compound as a solid, mp 206-208° C.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33])=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>C(Cl)Cl.Cl>[CH3:2][N:3]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:23][CH:22]=1)[OH:4]
Reactant: CNO
Reactant: CCCCCCOc1ccc(CCCCCCCCC(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCOc1ccc(CCCCCCCCC(=O)N(C)O)cc1
Yield: 48.5 %

Procedure:
To a cold, stirring suspension of 0.6 gm of N-methyl hydroxylamine hydrochloride and 0.7 gms sodium carbonate in 15 ml CH2Cl2 was added dropwise 2 gms 9(4-hexyloxyphenyl)nonanoyl chloride. The resulting mixture was stirred in the cold for 1/2 hr, then 0.9 ml water was added and the reaction stirred at room temperature for 22 hr. 100 ml CH2Cl2 and 40 ml water was added, and the pH of the aqueous layer was adjusted to 3-4 with a few drops of conc. HCl. The organic layers were separated and the aqueous layer was 3×20 ml CH2Cl2 extracted. The combined organic extracts were washed with water and NaCl solution, and dried over MgSO4. The drying agent was filtered off, the solvent was evaporated in vacuo, and the residue was purified by column chromatography on silica gel in chloroform. The major component had R=0.2. The fractions containing product (as determined by thin layer chromatography) were combined, evaporated in vacuo and the resulting solid recrystallized from hexanes to give 1.0 gm product of m.p. 59°-61°. Elemental analysis calculated C 72.69, H 10.26, N 3.85, O 13.2% found C 72.54, N 10.46, N 3.98%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl.O>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:17][C:16]2([CH3:18])[CH3:19])#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(C)(=O)=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (100 mg, 0.36 mmol) and pyridine (0.12 mL, 1.44 mmol) in anhydrous dichloromethane was added methanesulfonyl chloride (41.3 mg, 0.36 mmol) at ice-bath. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by prepared HPLC to give N-[2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide as white solid. LC/MS m/e obsd. (ESI+) [(M+H)+] 356.20.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H](CO)[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1N.[OH2:13]>>[C:7]([OH:8])(=[O:13])[CH:5]([CH2:3][C:2]([OH:1])=[O:10])[OH:6]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O
Product: O=C(O)CC(O)C(=O)O

Procedure:
In this connection, it was found that the highest glucosamine content was observed when the raw material was treated with pure water and then treated in an autoclave.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH2:3][CH2:2]1.C(Cl)(=O)O[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.NC1C=CC([NH:35][C:36](=O)[O:37]C(C)(C)C)=CC=1.O>C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([NH:11][C:36]([NH:35][C:17]3[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=3)=[O:37])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: Nc1cccc(CN2CCOCC2)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3-(morpholinomethyl)aniline (0.46 g), TEA (0.37 mL) and 4-nitrophenyl carbonochloridate (530 mg) in THF (18 mL) was stirred at ambient temperature for 2 hours, treated with tert-butyl 4-aminophenylcarbamate (500 mg) and an additional 0.37 mL of TEA. the resulting mixture was stirred at ambient temperature for 48 hours, poured into water and extracted 3× with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel with 2% methanol/dichloromethane to provide 1-(3-(morpholinomethyl)phenyl)-3-(4-nitrophenyl)urea which was dissolved in dichloromethane (30 mL), cooled in an ice bath, and treated with TFA (1.8 mL). The reaction mixture was stirred for 30 minutes at 0° C. and for 12 hours at ambient temperature, and concentrated three times from methanol/toluene.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)cc1
Yield: 34 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 34% of theory, C37H46N6O5 (654.8); Rf value: 0.15 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=655; (M+H+Na)++=339; (M+Na)+=677.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:16][C@@H:17]([CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:18][NH:19]C(=O)OCC[Si](C)(C)C)=[O:15])[CH2:9]1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].C(Cl)Cl>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:16][C@@H:17]([CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:18][NH2:19])=[O:15])[CH2:9]1
Reactant: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CNC(=O)OCC[Si](C)(C)C)CC2CCCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN)CC2CCCCC2)C1
Reaction time: 0.5 h

Procedure:
2-(Trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropylcarbamate (85.3 mg, 0.14 mmol) was dissolved in 6 mL 1:1 TFA/CH2Cl2 (6 mL) and stirred for 30 min. LC-MS showed the reaction was complete. After concentration, (3R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)-N—((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide trifluoroacetic acid salt was isolated by prep HPLC. LC-MS (3 min) tR=1.56 min, m/z 446 (M+1). 1H NMR (CD3OD) δ 7.37-7.25 (m, 5H), 4.30 (d, 1H), 4.03 (m, 1H), 4.97-4.90 (m, 2H), 3.50-3.39 (m, 2H), 3.27 (s, 3H), 3.00 (dd, 1H), 2.85-2.75 (m, 3H), 1.81-0.82 (m, 22H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:30][C:29]1[CH:28]=[C:27]([CH3:31])[NH:26][C:25](=[O:32])[C:24]=1[CH2:23][NH:22][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:11]=1)=[O:15]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (60 mg, 0.213 mmol), DMSO(2 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (60.1 mg, 0.319 mmol) HCl salt, N-methylmorpholine (0.093 mL, 0.850 mmol), 1-hydroxy-7-azabenzotriazole (57.9 mg, 0.425 mmol), and EDC (81 mg, 0.425 mmol). The final product was collected as 66 mg (74%). LCMS E-S (M+H)=446.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.0 Hz, 6 H), 2.13 (br. s., 3 H), 2.23 (br. s., 3 H), 4.43 (m, 2 H), 5.37 (m, 1 H), 5.91 (br. s., 1 H), 8.15-8.34 (m, 3 H), 8.44 (s, 1 H), 8.78 (br. s., 2 H), 9.00 (br. s., 1 H), 11.58 (br. s., 1 H).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)[O:5][C:4]([CH3:28])([CH3:27])[CH2:3]1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:27][C:4]1([CH3:28])[CH2:3][CH:2]([O:1][S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)[O:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(CC(=O)c2ccc3c(c2)C(O)CC(C)(C)O3)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(CC(=O)c2ccc3c(c2)C(OS(=O)(=O)c2ccc(C)cc2)CC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 1-(4-hydroxy-2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone (3.5 mg, 0.009 mmol) dissolved in anhydrous dichloromethane (1.0 mL) is added TsCl (1.94 mg, 0.011 mmol), DMAP (1.24 mg, 0.011 mmol) and TEA (21.3 μL, 0.015 mmole). The reaction mixture continues stirring at room temperature overnight. The next day, the reaction mixture is diluted with water. The aqueous layer is separated and extracted with ethyl acetate (3×). All combined organic layers are dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material is purified using silica gel chromatography to yield the desired product.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[O-2].[Mg+2].[Cl:9][C:10]1[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]>O.C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:15]([C:13]1[S:14][C:10]([Cl:9])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=1)(=[O:17])=[O:16])[CH2:5][OH:6]
Reactant: NC(CO)CO
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)NC(CO)CO)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (0.5 g, 5.49 mmol) in water (2 ml) was added at room temperature magnesium oxide (1.11 g, 27.5 mmol) and THF (6 ml). The suspension was stirred at room temperature for 30 min and a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (2.88 g, 10.9 mmol) in THF (2 ml) was added. The light yellow suspension was stirred at room temperature for 1 h and, after filtration on Dicalit, evaporated. Water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) and subsequent crystallization from ethyl acetate/hexane to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (0.76 g, 44%) as a light yellow solid. MS (ISP) 314.9 [(M−H)−], mp 142° C.