Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].C([O-])([O-])=O.[K+].[K+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[CH2:39][CH2:40]O>CN(C=O)C>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]2[N:6]3[N:5]=[C:4]([C:7]4[CH:8]=[CH:9][C:10]([O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[CH:11][CH:12]=4)[C:3]([C:20]([NH2:22])=[O:21])=[C:2]3[NH:1][CH2:40][CH2:39][C:31]=2[CH:32]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1ccc(F)c(CCO)c1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCc1cc([N+](=O)[O-])ccc1-2
Temperature: 80 °C
Reaction time: 16 h
Yield: 11.3 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (30 mg, 0.10 mmol) in DMF (5.0 mL) was added K2CO3 (28 mg, 0.20 mmol), followed by 2-(2-fluoro-5-nitrophenyl)ethanol (37 mg, 0.20 mmol). The mixture was warmed to 80° C. stirred for about 16 hr. After cooling down to RT, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (15 mL) and water (15 mL), the aqueous was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by Pre-TLC (DCM/CH3OH=20/1) to afford the product about 5.0 mg (11.1%). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (t, J=4.0 Hz, 1 H), 8.28 (d, J=2.8 Hz, 1 H), 8.22 (dd, J=2.8, 9.2 Hz, 1 H), 8.12 (d, J=9.2 Hz, 1 H), 7.64-7.60 (m, 2 H), 7.45-7.41 (m, 2 H), 7.22-7.17 (m, 1 H), 7.14-7.09 (m, 4 H), 3.72-3.65 (m, 2 H), 3.29-3.24 (m, 2 H). MS (ESI) m/e [M+1]+ 442.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:34])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc2c1cnn2CCN1CCCC1
Reactant: O=C(O)CCc1ccc(Oc2ccccc2)cc1
Product: O=C(CCc1ccc(Oc2ccccc2)cc1)Nc1cccc2c1cnn2CCN1CCCC1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine and 3-(4-phenoxy-phenyl)-propionic acid were processed according as described in Example 3 to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.84 (m, 2 H), 2.00 (m, 2 H), 2.64 (t, J=7.64 Hz, 2 H), 2.93 (t, J=7.64 Hz, 2 H), 3.06 (m, 2 H), 3.52 (m, 2 H), 3.71 (m, 2 H), 4.74 (t, J=6.08 Hz, 2 H), 6.95 (m, 4 H), 7.11 (m, 1 H), 7.28 (m, 2 H), 7.36 (m, 2 H), 7.49 (m, 1 H), 7.67 (m, 1 H), 8.13 (m, 2 H), 9.95 (s, 1 H); MS (DCI/NH3) m/z 455 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[N:27]1.N1CCCCC1>CO>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](/[CH:35]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:27]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
The synthesis was performed with reference to the known literature (Tetrahedron, Vol. 29, p. 359, 1973). A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) in methanol (1.2 mL) was added with 1H-indazole-3-carboxaldehyde (0.0419 g, 0.287 mmol), and piperidine (0.00244 g, 0.0287 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.125 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([C:23]([OH:26])([CH3:25])[CH3:24])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C@@H:28]([CH2:31][CH3:32])[CH2:29][NH2:30]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:23]([OH:26])([CH3:25])[CH3:24])[C:20]([NH:30][CH2:29][C@@H:28]([CH3:27])[CH2:31][CH3:32])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](C(C)(C)O)C(=O)O1
Reactant: CC[C@H](C)CN
Product: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Yield: 92.5 %

Procedure:
A solution of 500 mg (1.35 mmoles) of (3S, 5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]-3-(1-hydroxy-1-methylethyl)dihydrofuran-2(3H)-one (prepared as described in Preparation 6) in 1.00 g (11.5 mmoles) of 2(S)-methylbutylamine was stirred at 100° C. for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), to give 570 mg (yield 92%) of the title compound as white crystals, melting at 64°-67° C.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[C:11]([Mg]Br)#[CH:12]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[C:11]#[CH:12]
Reactant: C#C[Mg]Br
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(C#N)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-Formyl-benzonitrile (1.5 grams, 10.0 mmole) in tetrahydrofuran (20 ml) at −78° C. was added 0.5 M ethynyl magnesium bromide (26 ml, 13.0 mmole) dropwise. The mixture was stirred at −78° C. for 30 minutes and allowed to warm to room temperature over one hour. The reaction was cooled to 0° C., quenched with 10 ml methanol, poured into 200 ml water, acidified with oxalic acid and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a solid. (1.6 g). MW 157.18; MS (m/e) 157 (M+).
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]1[CH2:15][N:14]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]1=[O:25])=[O:10])C1C=CC=CC=1.[NH2:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:36]/[O:37][CH3:38])/C(O)=O)[N:31]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.[Pd]>[NH2:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:36][O:37][CH3:38])[C:9]([NH:11][CH:12]2[CH2:15][N:14]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:13]2=[O:25])=[O:10])[N:31]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)CON1C[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)NC1CN(OCC(=O)OC(C)(C)C)C1=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-[[3-[(Benzyloxycarbonyl)amino]-2-oxo1-azetidinyl]oxy]acetic acid. 1,1-dimethylethyl ester (1.4 g, 4.0 mmol) was dissolved in 25 ml of dry dimethylformamide and hydrogenated with 1 g of 10% palladium on charcoal as catalyst. After 20 minutes the catalyst was filtered and a mixture of (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetic acid (4.4 mmol). 1-hydroxybenzotriazole hydrate (0.15 g, 1.0 mmol). dicyclohexylcarbodiimide (0.81g. 4.4 mmol) and 30 ml of dry dimethylformamide was added. The mixture was stirred overnight at room temperature. The precipitated dicyclohexyl urea was filtered off and the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed with 5% NaHCO3 and dried over MgSO4. Filtration and evaporation in vacuo gave the title compound which solidified by stirring with ether/petroleum ether; melting point 120° C. dec.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].Cl>O.CN(C=O)C>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:3]2[CH2:7][CH2:6][NH:5][C:4]2=[O:8])=[CH:19][CH:20]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1NCCN1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN2CCNC2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride (approximately 60% strength suspension in oil, 1.2 g, approximately 30 mmol) was added portionwise to a solution of imidazolidin-2-one (2.58 g, 30 mmol) in abs. DMF (40 mL) under a blanket of argon within 10 min. The reaction mixture was stirred for 90 min at RT and a solution of 4-tert-butylbenzyl bromide (3.7 mL, 20.1 mmol) in abs. DMF (3 mL) was then added. The reaction mixture was stirred at RT over a period of 3 h and then added to a mixture of H2O (100 mL) and 2N hydrochloric acid solution in H2O (10 mL). The resulting mixture was stirred for 30 min, and the resulting crystals were separated with the aid of a frit and washed with H2O (3×30 mL). The isolated solid matter was recrystallized from a mixture of H2O (100 mL) and EtOH (120 mL). The substance formed (1.4 g, mp: 122-127° C.) is compound D.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:13][CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11]1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: c1ccc2c(c1)CCNC2
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1Cl)N1CCc2ccccc2C1

Procedure:
26.08 g of 2-chlorobenzoyl chloride were reacted with 44.33 g (0.6 mol) of 1,2,3,4-tetrahydroisoquinoline in chloroform overnight, whilst stirring. After the chloroform had been driven off, the resulting solid was recrystallised from isopropyl alcohol.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:13])[CH2:9][CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][CH2:8][OH:13])[CH:3]=1
Reactant: C#CCCCO
Reactant: Brc1cccnc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCCC#Cc1cccnc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
3-Bromopyridine (5.4 g, 34.2 mmol) was dissolved in triethylamine (10 ml) and degassed under nitrogen. 4-Pentyn-1-ol (3.50 ml, 37.6 mmol) was added followed by bis(triphenylphosphine)palladium (II) chloride (0.245 g, 0.349 mmol) and copper(I)iodide (0.136 g, 0.714 mmol) and the resulting mixture was stirred and heated under reflux for 20 mins. when a dark brown sludge was obtained. The mixture was cooled to rt and partitioned between EtOAc (200 ml) and water (50 ml). The aqueous phase was extracted further with EtOAc (2×100 ml); the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The material was purified by column chromatography. The sample was loaded in dichloromethane and purified on silica (Si) 100 g using a gradient of 0-100% ethyl acetate in cyclohexane over 60 mins on the Flashmaster II. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (4.99 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:12]=[C:13]2[NH:17][C@@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:15][S:14]2)[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:12]=[C:13]2[N:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:15][S:14]2)[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)CBr
Reactant: Cc1cc(N=C2N[C@@H](CC(C)C)CS2)cc(C)c1[N+](=O)[O-]
Product: Cc1cc(N=C2SC[C@H](CC(C)C)N2CC(C)C)cc(C)c1[N+](=O)[O-]

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 3,5-Dimethyl-4-nitroaniline was converted to 3,5-Dimethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 3,5-Dimethyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(3,5-dimethyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(3,5-dimethyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: CO[O:3][P:4]([O:9][CH2:10][CH2:11][O:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)/[C:17](=[CH:24]/[C:25]2[NH:26][C:27]([CH3:31])=[CH:28][C:29]=2[CH3:30])/[C:16]1=[O:32])=[O:14])([O:6]OC)=[O:5].Br[Si](C)(C)C>C(#N)C>[P:4]([O:9][CH2:10][CH2:11][O:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)/[C:17](=[CH:24]/[C:25]2[NH:26][C:27]([CH3:31])=[CH:28][C:29]=2[CH3:30])/[C:16]1=[O:32])=[O:14])([OH:6])([OH:5])=[O:3]
Reactant: COOP(=O)(OCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCOP(=O)(O)O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 42 h
Yield: 46.1 %

Procedure:
To the suspension of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(dimethoxy-phosphonooxy)-ethyl ester (180 mg,0.4 mmol) in 12 mL of acetonitrile was added bromotrimethylsilane (120 mL, 0.91 mmol) and N,O-bis-(trimethylsily)acetamide (225 mL, 0.91 mmol) sequentially. The reaction mixture was then stirred at room temperature for 42 h and concentrated. The residue was then washed with ethyl acetate, water, and 0.1 N HClaq and dried in a vacuum oven to yield 75 mg (37%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-phosphonooxy-ethyl ester as a red solid. 1H NMR (400 MHz, CDCl3) δ 12.40 (s, br, 1H, NH-1′), 7.84-7.86 (m, 1H, H-4), 7.76-7.79 (m, 1H, H-7), 7.63 (s, 1H, H-vinyl), 7.19-7.22 (m, 2H, H-5, 6), 6.11 (d, J=1.95 Hz, 1H, H-4′), 4.52-4.56 (m, 2H, NCOOCH2CH2OPO(OCH3)2-1), 4.15-4.19 (m, 2H, NCOOCH2CH2OPO(OCH3)2-1), 2.37 (s, 3H, CH3), and 2.33 (s, 3H, CH3).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([O:11][C:12](=[O:34])[CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:31][CH2:32][CH3:33])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:7]([O:11][C:12](=[O:34])[CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][C:21]([N:23]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:31][CH2:32][CH3:33])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C(C)C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isobutyryl chloride (38 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C27H35N3O3+H: 450, observed: 450.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7]C)=[O:6].N([O-])=[O:14].[Na+]>O.OS(O)(=O)=O>[Br:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([OH:14])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(N)cc(Br)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromobenzoate (5.2 g, 23 mmol) in water (80 mL) and H2SO4 (60 mL) was added dropwise a solution of NaNO2 (1.9 g, 28 mmol) in water (10 mL) at 0° C. The reaction mixture was added to a mixture of water (180 mL) and H2SO4 (240 mL). The mixture was heated at reflux for 30 minutes before being cooled to room temperature. The resulting mixture was poured into crushed ice and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford 3-bromo-5-hydroxybenzoic acid (3.8 g, 78% yield), which was directly used in next step. 1H NMR (400 MHz, d-DMSO) δ 10.27 (s, 1H), 7.43 (t, J=1.6 Hz, 1H), 7.28 (dd, J=1.2, 2.0 Hz, 1H), 7.15 (t, J=2.0 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C(O)CCC>[F:18][C:17]1[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ncccc2F)CC1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNC(=O)[C@H]1CC[C@H](Oc2ncccc2F)CC1
Temperature: 125 °C

Procedure:
A mixture of trans-4-(3-fluoro-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.60 g, 2.4 mmol) and hydrazine hydrate (0.53 ml, 11 mmol) in n-butanol (1 ml) was heated at 125° C. for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.45 g, 83%) as white solid, which was used in the next step without further purification. MS m/e: 254 (M+H+)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[O:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH2:10][C:13]([OH:12])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CC(=O)c1cccc(F)c1F
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)(CC(=O)c1cccc(F)c1F)C(=O)OCC

Procedure:
2′,3′-Difluoroacetophenone (10.23 g, 65.6 mmol) and diethyl ketomalonate (15 mL, 98.4 mmol) were stirred at 140° C. for 48 hours. The crude mixture was diluted with toluene and purified by chromatography on silica gel, eluting with 20% v/v ethyl acetate in hexane to afford the title compound as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:10]=[C:9]1[C:22]([O:24]C(C)(C)C)=[O:23])=O)(C)(C)C>Cl.O1CCOCC1>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10]1
Reactant: CC(C)(C)OC(=O)C1=CC(COc2cccc(F)c2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@H](COc2cccc(F)c2)CN1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-(3-fluoro-phenoxymethyl)-pyrroline-1,2-dicarboxylic acid di-tert-butyl ester (Preparation 5, 475 mg, 1.2 mmol) was dissolved in a solution of anhydrous hydrogen chloride in dioxane (4M, 15 ml) and stirred at 50° C. under a nitrogen atmosphere for 1 hour. The solvent was removed under reduced pressure and the resulting semi-solid triturated with ethyl acetate to give a white solid which was recrystallised from ethyl acetate/isopropyl alcohol to give the title compound as a mixture of diastereomers (˜5:1 2S,4S:2S,4R) as a white solid hydrochloride salt (90 mg, 35%)
Reaction SMILES: [CH:1]1[C:6]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=[C:3]([F:12])[CH:2]=1.S(Cl)(Cl)=O.[CH3:17]O>>[NH2:11][C@H:7]([C:6]1[CH:5]=[CH:4][C:3]([F:12])=[CH:2][CH:1]=1)[C:8]([O:10][CH3:17])=[O:9]
Reactant: N[C@@H](C(=O)O)c1ccc(F)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4 g (R)-4-fluorophenylglycine are suspended in 80 ml of methanol. While cooling with the ice bath 3.28 ml of thionyl chloride are slowly added dropwise, so that the temperature is maintained between 15° C. and 20° C. The reaction mixture is stirred for 12 hours at ambient temperature and then evaporated to dryness. 5.1 g of the product are obtained as the hydrochloride. Analytical HPLC-MS (method A): RT=0.8 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:30]([O:29][C:27]([NH:26][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2[N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2N)c1)NC(=O)OC(C)(C)C
Yield: 66.9 %

Procedure:
A suspension of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-nitropyridin-2-yl)phenyl)guanidine (520 mg) in ethanol (15 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 500 mg) under a hydrogen atmosphere for 24 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was triturated with ethanol, filtered, and dried to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-aminopyridin-2-yl)phenyl)guanidine (325 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][C@@H:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CCCCO1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To a solution of 2.18 g (18.75 mmol) of (2S)-oxan-2-ylmethanol in pyridine (25 mL) are added 7.15 g (37.5 mmol) of p-toluenesulfonylchloride portionwise at 10° C. After complete addition the reaction is allowed to warm to room temperature and stirred for 18 h. The reaction is poured onto a stirred mixture of 6M aqueous HCl/ice. The mixture is extracted with DCM (3×25 mL). The organic layer is dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to give 3.91 g of (2S)-oxan-2-ylmethyl 4-methylbenzene-1-sulfonate. Yield: 76%, ES-MS: m/z: 293 [M+Na]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.21-1.32 (1H, m), 1.41-1.60 (4H, m), 1.80-1.90 (1H, m), 2.45 (3H, s), 3.37 (1H, td, J=11.41, 2.82 Hz), 3.48-3.58 (1H, m), 3.89-3.98 (3H, m), 7.34 (2H, d, J=8.09 Hz), 7.80 (2H, d, J=8.24 Hz).