Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([CH3:23])=[CH:25][CH:26]=2)=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-methyl-1-naphthalenecarboxylic acid (268 mg, 1.44 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1) and recrystallized from ethyl acetate-hexane to give the title compound (487 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23](O)[CH2:24][CH3:25])=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:37])CCOC>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([F:37])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 15 h
Yield: 77 %

Procedure:
To a stirred suspension of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (82.1 mg, 0.200 mmol) in acetonitrile (1.0 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride at room temperature. After 15 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (63.8 mg, 0.155 mmol, 77%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27](O)=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[CH3:1])=[CH:20][CH:19]=2)=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1
Reactant: COC(=O)Cc1cc(Cl)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(Cl)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 15 h
Yield: 42 %

Procedure:
To a mixture of [4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (1.0 g), methyl 2-(5-chloro-2-hydroxyphenyl)acetate (0.74 g), triphenylphosphine (1.08 g) and tetrahydrofuran (50 mL) was dropwise added a solution (40%, 1.79 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give methyl 2-[5-chloro-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.68 g, 42%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([N:15]([CH2:29][CH3:30])[CH2:16][CH2:17][O:18][CH:19]1[C:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:23][CH2:22][NH:21][CH2:20]1)[CH3:14].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[CH2:29]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][O:18][CH:19]1[C:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH2:20]1)[CH3:30]
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: CCN(CC)CCOC1CNCCC1(OC)OC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCOC1CN(CCCOc2ccc(F)cc2)CCC1(OC)OC
Temperature: 60 °C
Reaction time: 17 h
Yield: 75 %

Procedure:
A mixture of 7.5 parts of 1-(3-chloropropoxy)-4-fluorobenzene, 10.5 parts of N,N-diethyl-2-[(4,4-dimethoxy-3-piperidinyl)oxy]ethanamine, 7 parts of N,N-diethylethanamine, 1 part of potassium iodide and 90 parts of N,N-dimethylformamide was stirred for 17 hours at 60° C. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol. The whole was evaporated and the residue was taken up in acetonitrile. The solution was evaporated, yielding 14 parts (75%) of N,N-diethyl-2-[[1-[3-(4-fluorophenoxy)propyl]-4,4-dimethoxy-3-piperidinyl]oxy]ethanamine as a residue (intermediate 115).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][NH:4][C:3]1=[O:14].[Cl-].[Cl-].[Ca+2].Cl.[OH-].[Na+]>[Cu](Cl)Cl.[Cu]Cl.C(#N)C>[CH3:1][C:2]1[C:3](=[O:14])[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CC1CC(c2ccccc2)=NNC1=O
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: Cl
Solvent: CC#N
Product: Cc1cc(-c2ccccc2)n[nH]c1=O
Temperature: 25 °C
Yield: 93.8 %

Procedure:
7.0 g (35 mmole) of 2 is placed in a 250 ml single-necked round bottom flask followed by 30 mL of acetonitrile. The mixture is stirred to allow 2 to dissolve. 11.3 g (84 mmole, 2.4 equiv.) of anhydrous copper (II) chloride is added to the solution to give a green-yellow suspension. A reflux condenser is connected to the flask and a dry tube filled with anhydrous CaCl2 is fitted to the top of the condenser. To control the HCl gas that forms during the course of the reaction, a NaOH solution is used to absorb the HCl that escapes from the dry tube. The reaction mixture is heated to reflux, and the color of the reaction suspension changes to dark green upon heating. When the reaction is complete (after refluxing for 2 h), the flask is removed from the oil bath and cooled to ambient temperature. The reaction is cooled in an ice-water bath and 150 mL of ice-water is added to quench the reaction. The mixture is stirred vigorously for 10 minutes to give a gray precipitate and blue liquid containing copper (I) chloride. The precipitate is collected by filtration (pH of the filtrate is 0-1) and washed with 100 mL of 1N HCl solution, then 100 mL of water 5 times. To remove remaining copper by-products that are trapped in the solid, the filter cake is stirred in 150 mL of 1N HCl solution for 0.5 h and filtered. The filter cake is subsequently washed with Milli-Q water until the filtrate is at pH 7 (approximately 7 washes). The solid is dried over a medium frit sintered glass funnel in vacuo to give 3 as a light gray powder in 93.8% yield. [See Eddy, S et al. Synthetic Communications, 2000, 30(1), 1-7.Csende, F et al. Synthesis, 1995, 1240-1242.]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].Cl.Cl.[NH2:27][CH2:28][CH:29]1[C:33](=[N:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][NH:31][CH2:30]1.N12CCCN=C1CCCCC2>C(#N)C>[NH2:27][CH2:28][CH:29]1[C:33](=[N:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:32][N:31]([C:11]2[N:10]=[C:9]3[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]3[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[CH:3][C:2]=2[F:1])[CH2:30]1
Reactant: CC(C)(C)ON=C1CNCC1CN
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)ON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)CC1CN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
168 mg (0.5 mmole) of 6,7-difluoro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acid and 143 mg (0.55 mmole ) of 3-aminomethyl-4-t-butyloxyiminopyrrolidine dihydrochloride were suspended in 3 ml of dry acetonitrile. Then, 230 mg (1.5 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene was added thereto, and the reaction mixture was stirred for 15 minutes at room temperature and then treated according to the same manner as Example 89 to obtain 203 mg (Yield: 81%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][N:9]=2)[C:5]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:4]=2[O:3]1.C(OCC)(=[O:29])C>>[C:24]([C:21]1[CH:22]=[CH:23][C:4]2[O:3][C:2]([CH3:26])([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:10][N+:9]=3[O-:29])[C:5]=2[CH:20]=1)#[N:25]
Reactant: CC1(C)C=C(c2ccc(-c3ccccc3)cn2)c2cc(C#N)ccc2O1
Reactant: CCOC(C)=O
Product: CC1(C)C=C(c2ccc(-c3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 6, from 2,2-dimethyl-4-(5-phenyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-phenylpyridine N-oxide of melting point 173°-175° C. (from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([CH2:31][N+:32]#[C-:33])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:33]=[N:32][CH:31]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3cnco3)c2[C@@H]2CCCN12

Procedure:
A mixture of 1.51 g (5 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde, 1.07 g (5.5 mmol) of toluene-4-sulphonylmethyl isocyanide, 1 g of powdered potassium carbonate and 20 ml of methanol is heated to boiling under reflux for 2 hours. The mixture is then evaporated to a volume of 5 ml and the material obtained is chromatographed on silica gel while eluting with ethyl acetate/methanol (9:1). After recrystallization from ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-(5-oxazolyl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 201°-202°.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][C:8]=1[CH3:16]>ClCCl.C(=O)([O-])O.[Na+]>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][C:8]=1[CH3:16]
Reactant: COc1ccc(CC#N)cc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(CC#N)ccc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Boron tribromide (1M in dichloromethane, 6.2 mL, 6.2 mmol) was added to a solution of 4-methoxy-3-methylphenylacetonitrile (0.2 g, 1.24 mmol) in dichloromethane (10 mL), cooled to −78° C. The reaction mixture was stirred at this temperature for 1 hour and then at room temperature for 2 hours. The mixture was then re-cooled to −78° C., diluted with sodium hydrogen carbonate solution and allowed to warm to room temperature. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid in 87% yield, 0.16 g. 1H NMR (400 MHz, CDCl3) δ:7.07 (1H, s), 7.00 (1H, d), 6.76 (1H, d), 3.65 (2H, s), 2.25 (3H, s) ppm; LRMS APCI m/z 146 [M−H]−.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49]C(=O)OC(C)(C)C)[CH2:44]2)=[C:34]2[CH2:40][CH2:39][C:38]([OH:42])([CH3:41])[C:35]2=[N:36][CH:37]=1)=[O:30])=O)(C)(C)C>C(Cl)Cl.CO.[NH4+].[OH-]>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH2:49])[CH2:44]2)=[C:34]2[CH2:40][CH2:39][C:38]([OH:42])([CH3:41])[C:35]2=[N:36][CH:37]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCC2(C)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1N)c2N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (0.02 mL, 0.2 mmol) was added to a solution of tert-butyl {(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (4.0 mg, 0.0044 mmol) in DCM (0.01 mL). The reaction mixture was stirred at room temperature for 30 min., and then diluted with MeOH and neutralized with NH4OH. After filtration, the crude was purified by preparative LC-MS (Waters SunFire™ preparative C18 5 μm 30×10 mm column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.1% TFA) to give the title compound tris-trifluoroacetate salt as two diastereoisomers.
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[N:14]([CH:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([O:32]CCC)=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N+:15]=[N-:16].[N-]=[N+]=[N-]>>[C:8]1([C:3]2([C:1]3[N:14]([CH:17]4[CH2:36][N:21]5[C:22]6[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]5[CH2:19][CH2:18]4)=[CH:26][CH:25]=[CH:24][CH:23]=6)[N:15]=[N:16][CH:2]=3)[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC1(c2ccccc2)CCCC1
Agent: [N-]=[N+]=[N-]
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C1(c3ccccc3)CCCC1)CC2

Procedure:
The title compound was prepared using analogous procedures described in EXAMPLE 3 from (1-ethynylcyclopentyl)benzene and enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate, prepared by resolution of the racemic azide on a 4.6×250 mm ChiralCel OD column eluting with 15% MeOH, 15% iPrOH, 69.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm. Retention times=10.3 and 11.5 min. EXAMPLE 6.1 and 6.2 were prepared from the chiral azide with the retention time of 10.3 and 11.5 min respectively. 1H NMR data of EXAMPLE 6.1: 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 7.93 (s, 1H), 7.42 (d, 1H), 7.36 (dd, 2H), 7.31-7.23 (m, 3H), 7.13 (d, 1H), 7.07-6.97 (m, 2H), 4.59 (s, 1H), 3.98-3.89 (m, 1H), 3.58-3.46 (m, 2H), 3.03-2.92 (m, 1H), 2.29-2.20 (m, 1H), 2.10-2.01 (m, 1H), 1.54-1.43 (m, 1H). MS (+ESI) m/z: 441.2.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[O:23]=[C:24](Cl)OC(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([O:8][N:9]1[C:24](=[O:23])[N:14]2[CH2:15][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 2 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate (1.154 g, 4.37 mmol) was added dehydrated acetonitrile (198 mL), followed by ice-cooling. Triethylamine (1.60 mL) and diphosgene (0.389 mL) were sequentially added dropwise at 5° C. or less, followed by stirring at 2° C. for 20 minutes. Then, to the reaction solution was added 4-dimethylaminopyridine (70.0 mg), followed by stirring at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, followed by substituting and concentrating with ethyl acetate three times, and the solution was concentrated to 30 mL. Ethyl acetate (20 mL) and water (40 mL) were added thereto, followed by liquid separation, and the separated aqueous layer was extracted with ethyl acetate (30 mL) twice. The combined organic layers were washed with 5% citric acid aqueous solution (40 mL), 6.5% sodium bicarbonate aqueous solution (30 mL), and 5% brine (30 mL), and dried over anhydrous sodium sulfate, followed by filtration and concentration under reduced pressure. 1.16 g of the resulting residue was diluted with ethyl acetate (5.5 mL), and n-hexane (11 mL) was added, and a seed crystal was inoculated for crystallization. Further, n-hexane (49 mL) was added, followed by stirring at 0° C. for 1 hour. Subsequently, crystals were filtered, washed with n-hexane (60 mL), and then dried under vacuum to afford 882.3 mg of the title compound as colorless crystalline powder (yield 71%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1ccc(Br)c(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cc(C)ccc1Br)C(=O)OCC
Temperature: 100 °C
Yield: 84.1 %

Procedure:
A mixture of 2-bromo-5-methyl-aniline (1.0 g, 5.34 mmol) and diethyl 2-(ethoxymethylene)propanedioate (1.23 g, 5.90 mmol) was heated at 100° C. for 4 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then purified via silica gel column chromatography using 1 to 60% EtOAc in hexanes to yield diethyl 2-[[(2-bromo-5-methyl-phenyl)amino]methylene]propanedioate (1.6 g, 84%). 1H NMR (300 MHz, CDCl3) δ 11.19 (d, J=13.2 Hz, 1H), 8.48 (d, J=13.2 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.08 (s, 1H), 6.81 (d, J=8.1 Hz, 1H), 4.37-4.23 (m, 4H), 2.35 (s, 3H), 1.42-1.25 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)=[O:4].[C:16](O)(=[O:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:16](=[O:18])[CH3:17])[NH2:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(NN)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Product: COC(=O)c1ccc(N(N)C(C)=O)c([N+](=O)[O-])c1
Yield: 97 %

Procedure:
After boiling 105.6 g of 4-methoxycarbonyl-2-nitrophenylhydrazine with 1 liter of glacial acetic acid for 1 hour, the clear orange-red solution was evaporated under reduced pressure. The residue was stirred with 1500 ml of water, the crystalline precipitate was filtered by suction, washed with water and dried at 80° C. to give 123 g (97%) of 4-methoxycarbonyl-2-nitro-N-acetylphenylhydrazine, in the form of yellow powder-like crystals, m.p.: 182°-185° C., which melted at 190°-192° C. after recrystallization from aqueous ethanol.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[C:15](Cl)=[O:16])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[C:15]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:16])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(OC)c(OC2CCCC2)c1
Yield: 93.8 %

Procedure:
Diethylamine (69.2 g, 0.672 moles) was added dropwise at 5-10° C. to a solution of 3-cyclopentyloxy-4-methoxy benzoyl chloride (57 g, 0.224 moles) obtained as described in example 2, in methylene chloride (250 ml). The mixture was evaporated to dryness, dissolved in ethyl acetate, washed with water, with 2% potassium bisulphate, again with water and sodium bicarbonate, dried on sodium sulphate and brought to dryness. The residue was taken up with petrolatum (250 ml) to give 61.2 g of the title compound (yield: 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH2:24])[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.O.[Br].[N:27]#[C:28]C#N>C(O)(=O)C>[NH2:27][C:28]1[NH:24][C:23]2[CH:22]=[CH:21][C:4]([O:5][CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:3][C:2]=2[N:1]=1
Reactant: N#CC#N
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(N)c(N)c2)CC1
Agent: [Br]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc3[nH]c(N)nc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
A 100 mL flasked was charged of tert-butyl 4-(2-(3,4-diaminophenoxy)ethyl)piperazine-1-carboxylate (1.53 g, 4.54 mmol), water (50 mL) and acetic acid (2 mL) and stirred at room temperature for 15 minutes. The reaction mixture was placed in an ice bath and then charged with cyanogen bromine (0.526 g, 5 mmol) and continued to stir at 0° C. The reaction temperature was allowed to warm to room temperature and it was stirred over night. The reaction was completed as determined by LCMS. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in acetone, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.7 g of tert-butyl 4-(2-(2-amino-1H-benzo[d]imidazol-5-yloxy)ethyl)piperazine-1-carboxylate as a di-acetate salt as black foam. MS (EI): 362 (MH+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1([C@@H:35]2[O:40][CH2:39][C@@:38]([NH:49][C:50]([NH:52][C:53](=[O:60])[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[S:51])([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=3[F:48])[C@H:37]([C@@H:61](O)[CH3:62])[CH2:36]2)[CH2:34][CH2:33]1>O1CCCC1>[CH:32]1([C@@H:35]2[O:40][CH2:39][C@:38]3([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=4[F:48])[N:49]=[C:50]([NH:52][C:53](=[O:60])[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[S:51][C@H:61]([CH3:62])[C@@H:37]3[CH2:36]2)[CH2:34][CH2:33]1
Reactant: C[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Diethyl azodicarboxylate (92 μL, 0.59 mmol) was added to a 0° C. solution of triphenylphosphine (153 mg, 0.583 mmol) in tetrahydrofuran (7 mL), and the mixture was stirred for 10 minutes in the ice bath. A solution of N-({(3S,4R,6R)-6-cyclopropyl-3-(2,4-difluorophenyl)-4-[(1S)-1-hydroxyethyl]tetrahydro-2H-pyran-3-yl}carbamothioyl)benzamide (C30) (90 mg, 0.20 mmol) in tetrahydrofuran (2 mL) was added drop-wise to the reaction mixture, which was then stirred for 1 hour under ice cooling. The reaction mixture was concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 80% ethyl acetate in heptane) afforded the product as a gum. Yield: 45 mg, 0.10 mmol, 50%. LCMS m/z 441.1 [M−H+].