Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(OCC)(=O)C>[CH3:7][N:6]1[C@H:5]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:11][C:2]([C:2]4[CH:11]=[CH:10][CH:9]=[C:8]5[C:3]=4[CH:4]=[CH:5][N:6]=[CH:7]5)=[CH:3][C:19]=3[CH2:20][CH2:4]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: O=C([O-])[O-]
Reactant: Brc1cccc2cnccc12
Reactant: C1CCOC1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc5cnccc45)cc3CC[C@@H]12
Yield: 42 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 5-bromoisoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (5% methanol/ethyl acetate eluent) to give 98 mg (42%) of the title compound as an amorphous solid. mp 182°-184°. FDMS: m/e=356. α[D]589 =+57.25 (c=0.49, chloroform).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[O:10][CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H-].[Na+].Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C(COC)OC>[CH2:9]([NH:8][CH2:12][CH:11]([OH:10])[CH2:13][O:14][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ncccn1
Reactant: OCC1CN(Cc2ccccc2)C(c2ccccc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: OC(CNCc1ccccc1)COc1ncccn1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A solution of 26.93 g of 3-benzyl-5-hydroxymethyl-2-phenyl-oxazolidine in 100 ml of dimethoxyethane is added dropwise to a suspension of 2.4 g of sodium hydride in 50 ml of dimethoxyethane, whilst keeping the temperature of the reaction mixture at 20° C. The mixture is then stirred for 7 hours, after which a solution of 11.45 g of 2-chloropyrimidine in 30 ml of dimethoxyethane is added dropwise at 20° C. After stirring for 20 hours and boiling under reflux, the solvent is distilled off under reduced pressure, the residue is warmed with 10 ml of concentrated hydrochloric acid and 30 ml of water to 60° C. and then cooled, and the mixture is extracted with ether. 15 ml of 10 N sodium hydroxide solution are added to the aqueous phase at 0° C., the mixture is then extracted with ethyl acetate and the organic phase is dried over sodium sulphate, filtered and evaporated in vacuo. The residue is dissolved in acetone and a solution of 9.0 g of oxalic acid in acetone is added. The hydrogen-oxalate of 1-benzylamino-3-(2-pyrimidinyloxy)-2-propanol, of melting point 188°-189° C., is obtained. From this, the free base is obtained as an oil by adding sodium hydroxide solution at 0° C., extracting with ethyl acetate, drying the organic phase over sodium sulphate, filtering and evaporating.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15]C(C)(C)C)=[O:14])[C:8](=[O:23])[C:7]3=[CH:24][NH:25][C:5]([C:6]=23)=[N:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:20]([CH3:21])[CH3:22])[C:13]([OH:15])=[O:14])[C:8](=[O:23])[C:7]3=[CH:24][NH:25][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)OC(C)(C)C)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 59.1 %

Procedure:
(R)-tert-Butyl 2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate was stirred in DCM/TFA (50%, 10 mL) for 1 h, concentrated and dried in vacuo to afford the title compound as a beige solid (0.32 g, 59.1%). 1H NMR (400 MHz, DMSO-d6) δ 0.84 (d, J=6.30 Hz, 3 H) 1.04 (d, J=6.32 Hz, 3 H) 2.39 (dt, J=10.61, 6.57 Hz, 1 H) 4.83 (d, J=10.61 Hz, 1 H) 5.04 (d, J=9.60 Hz, 2 H) 7.98 (s, 1 H) 8.26 (s, 1 H) 12.39 (br. s., 1 H). [M+H] calc'd for C14H14FN3O3, 292; found, 292.5.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:29])[CH3:28]>CC#N.C(Cl)(Cl)Cl>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][O:26][C:27]([CH3:29])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:28])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: CC(C)(OCCBr)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(C)(OCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2)c1ccccc1
Product: [Br-]
Temperature: 60 °C
Yield: 24 %

Procedure:
1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (41 mg, 0.14 mmol) was added to a solution of {1-[(2-bromoethyl)oxy]-1-methylethyl}benzene (34 mg, 0.14 mmol) in 2:3 CH3CN/CHCl3 (3 mL), and the reaction was heated at 60° C. for 3 days. The reaction was concentrated under reduced pressure, and the crude product was washed with EtOAc (3×1 mL). The residue was taken up in 2.5 mL of DMSO and purified by preparatory HPLC (without TFA) to give the title compound (18 mg, 24%). LC/MS ESI RT 2.09 min M+ 456
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:14]=[C:15]([NH:19][S:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][C:21]([F:20])([F:33])[F:34])[CH:24]=3)(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc([C@@H]2CCN(Cc3ccccc3)C2)c1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1cccc([C@@H]2CCN(Cc3ccccc3)C2)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
(S)-1-Benzyl-3-(3-amino-phenyl)-pyrrolidine (0.4 g, 1.59 mmol) and commercially available 3-trifluoromethoxy-benzene sulfonylchloride (0.39 g, 1.5 mmol) were dissolved in 30 ml tetrahydrofurane. 0.66 ml of triethylamine (3.75 mmol) were added and the mixture was stirred for 16 h at room temperature. The solvent was evaporated under reduced pressure and the residue was treated with water/diethylether. After adjusting the aqueous phase to alkaline pH with 1 N aqueous NaOH, the aqueous layer was extracted with diethylether and the combined organic layers dried over magnesium sulfate, filtered and evaporated. The product was purified via silica gel chromatography using an Isco Companion semi-automated chromatography system to yield 0.512 g of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][OH:17].[BH4-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:18][CH:15]([CH2:14][CH2:13][NH:12][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:16][OH:17]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(CO)CCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(CO)CCNCc1ccccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 96.2 %

Procedure:
2-Nitrobenzaldehyde (7.33 g, 48.5 mmol) and 4-amino-2-methylbutanol (5.00 g, 48.5 mmol) were dissolved in toluene (50 ml) and heated to reflux for two hours with Dean Stark dehydration apparatus. After allowed to cool, the solvent was evaporated under reduced pressure. The obtained concentrate was dissolved in methanol (100 ml), added with sodium borohydride (2.75 g, 72.8 mmol) under ice cooled condition and stirred at the same temperature for two hours. The reaction mixture was further stirred at room temperature for two hours, adjusted to pH 4 by adding 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. Water (30 ml) was added to dissolve the concentrate and after extracted with ethyl acetate, pH was adjusted to 8 by added a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 2-methyl-4-(2-nitrobenzylamino)butanol (11.12 g).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Cl.Cl[CH2:15][C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1.[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>>[F:11][C:5]1[CH:6]=[C:7]([O:10][CH2:15][C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[CH2:28][N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH3:22])=[O:12]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Product: Cc1nc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCC[C@H]3C)c(F)c2)cs1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures D and E using 2-fluoro-4-hydroxy-benzoic acid methyl ester [CAS 197507-22-5], 4-chloromethyl-2-methylthiazole hydrochloride [CAS 39238-07-8], and 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 418.2
Reaction SMILES: [N+]1([O-])C2CCCC(C(OC)=O)C=2C=CC=1.C(N)(C)(C)C.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.C([NH:46][C:47]1[CH:56]=[CH:55][C:54]2[CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52][CH2:51][CH2:50][C:49]=2[N:48]=1)(C)(C)C.FC(F)(F)C(O)=O>C1(C(F)(F)F)C=CC=CC=1>[NH2:46][C:47]1[CH:56]=[CH:55][C:54]2[CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52][CH2:51][CH2:50][C:49]=2[N:48]=1
Reactant: COC(=O)C1CCCc2nc(NC(C)(C)C)ccc21
Agent: COC(=O)C1CCCc2c1ccc[n+]2[O-]
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CC(C)(C)N
Solvent: FC(F)(F)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCCc2nc(N)ccc21
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Methyl 5,6,7,8-tetrahydroquinoline-5-carboxylate-1-oxide (2.05 g, 9.89 mmol) and t-butyl amine (5.22 ml, 49.5 mmol) were dissolved in benzotrifluoride (50 ml) and cooled with an ice bath. The p-toluenesulfonic anhydride (6.46 g, 19.79 mmol) was added portionwise keeping the reaction's internal temperature below 5° C. The reaction was monitored and after 10 mins. when the LC-MS showed M+1=263 and 207 (M-56) at 1.20 indicating formation of intermediate methyl 2-(tert-butylamino)-5,6,7,8-tetrahydroquinoline-5-carboxylate. Trifluoroacetic acid (10 ml) was then added to the reaction mixture and heated at 70° C. for 5 hrs. The reaction was cooled and evaporated to dryness. The residue was taken up with water and the pH was adjusted to pH ˜8 with 5N NaOH. The reaction was extraction with DCM 2×. The combined DCM layers were washed with brine and dried over Na2SO4, filtered and evaporated to dryness. The residue was chromatographed through a 80 g ISCO Redi-sep column and eluted with solvent system of 5%(10% NH4OH in MeOH)/DCM to yield methyl 2-amino-5,6,7,8-tetrahydroquinoline-5-carboxylate. 1H-NMR (600 MHz, CDCl3): δ ppm 7.27 (d, J=8.3 Hz, 1H), 6.35 (d, J=8.3 Hz, 1H), 4.40 (b, 2H), 3.73 (s, 3H), 3.70 (t, J=6.9 Hz, 1H), 2.68-2.82 (m, 2H) 2.12-2.17 (m, 1H), 1.93-2.12 (m, 2H), 1.81-1.86 (m, 1H); LC-MS: M+1=207;
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[C@@H:7]([CH2:16][CH2:17][S:18][CH3:19])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH-].[K+]>CO>[C:12]([O:11][C:9]([NH:8][C@@H:7]([C:6]([NH:5][CH2:4][C:3]([OH:21])=[O:2])=[O:20])[CH2:16][CH2:17][S:18][CH3:19])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
The title compound of Example 8 (32.0 g, 0.1 mole) was dissolved in 200 ml of methanol to which was added 200 ml of 2 M potassium hydroxide. After ca. 5 min. at room temperature the solution was concentrated to about half volume and diluted with ethyl acetate. The solution was neutralized by washing with two portions of 0.5 M potassium bisulfate, and then dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was recrystallized to give the title compound, which was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].[N:23]([O-])=[O:24].[Na+].CO.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 27.3 %

Procedure:
5.4 g of 1-(2-chloroethyl)-3-n-butyl-3-D-mannopyranosylurea are dissolved in 20 ml of formic acid, and 3.5 g of sodium nitrite are added gradually thereto for 2 hours under ice-cooling and stirring. 40 ml of methanol and 30 g of potassium carbonate anhydrate are added to said mixture. Then, said mixture is further stirred for 10 minutes under ice-cooling. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.6 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-mannopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C.Br[C:40]1[N:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=1>O>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:40]1[N:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=1)=[O:22]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Reactant: FC(F)(F)c1cnc(Br)nc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2ncc(C(F)(F)F)cn2)c1

Procedure:
To a mixture of N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 100 mg, 0.31 mmol) and NMP (1 ml) was added DIPEA (0.200 mg, 1.56 mmol) and 2-bromo-5-(trifluoromethyl)pyrimidine (70 mg, 0.31 mmol). The mixture was subjected to microwave irradiation at 150° C. for 1 hour. Upon cooling, the reaction mass was poured into water (5 ml) and extracted with ethyl acetate (2×10 ml). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:19])[CH:13]=2)[N:8]=1.CN([CH:23]=[O:24])C.Cl>C1COCC1.CC(=O)OCC.CC(O)=O>[Cl:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:13]([CH:23]=[O:24])=[C:12]([F:19])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CN(C)C=O
Reactant: COc1nc2cc(F)ccc2nc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc2c(C=O)c(F)ccc2nc1Cl
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a solution of DIPA (22.3 mL) in THF (150 mL) was added at −20° C., n-BuLi (2.3M, 63.7 mL, 159 mmol). The mixture was stirred at −20° C. for 10 min. After cooling to −78° C., a solution of 2-chloro-6-fluoro-3-methoxy-quinoxaline (27.1 g, 127.4 mmol) in THF (100 mL+10 mL rinse) was added over 40 min. The reddish mixture was stirred at −78° C. for 40 min. DMF (15 mL) was added keeping the internal temperature below −70° C. The reaction proceeded 20 min. AcOH (15 mL) was added. Once the mixture had warmed up to rt, 3M HCl (180 mL) and EA (500 mL) were added. The mixture was further diluted with EA (400 mL) until two clear layers were obtained. The two layers were separated and the aq. layer was extracted with EA (3×300 mL). The org. layer was washed twice with sat. aq. NaHCO3 (200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with an ether-EA mixture (1-1, 250 mL), washed with ether (2×100 mL), and dried under high vacuum to afford the title aldehyde as a beige solid (23 g, 76% yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH:23]1CC(=O)NC1=O>CO>[CH3:23][O:20][C:19](=[O:21])[C@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C1CC(O)C(=O)N1
Solvent: CO
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 24 h

Procedure:
N-Boc-O-benzylserine-hydroxysuccinimide (16.0 g, 40.8 mmol) was dissolved in methanol (300 ml) and stirred at 50° C. for 24 hours. The solvent was evaporated and the residue was taken up in ethyl acetate (120 ml), washed with aqueous saturated sodium bicarbonate (2×50 ml) and water (50 ml). The organic solution was dried with sodium sulphate and after evaporation of the solvent the N-Boc-O-benzylserine methyl ester was isolated as a colourless oil. Yield 9.9 g (83%). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:22])[CH3:21]>CN(C=O)C>[CH:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:25][CH2:24]1)([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C

Procedure:
To a vial was added 4-fluoronitrobenzene (1.41 g, 1.06 mL, 0.01 mol), DIEA (1.92 mL, 0.011 mmol), isopropylpiperazine (1.41 g, 0.011 mmol), and DMF (10 mL). Mixture was heated at 100° C. for 48 h in a sealed tube. The reaction mixture was cooled to RT and concentrated. The residue was purified via silica gel column chromatography (gradient elution with 0 to 10% MeOH in DCM) to afford 1-isopropyl-4-(4-nitrophenyl)piperazine.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO.[NH:22]1[CH2:25][CH2:24][CH2:23]1>C(O)(C)C.C(OCC)(=O)C.[Cu](I)I>[N:22]1([C:7]2[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: C1CNC1
Reactant: Nc1ccc(I)cc1F
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCC2)cc1F
Temperature: 80 °C
Yield: 80.7 %

Procedure:
To a mixture of 2-fluoro-4-iodoaniline (1 g, 4.14 mmol), copper iodide (304 mg, 0.21 mmol) and potassium phosphate (1.75 g, 8.27 mmol) in ethylene glycol (465 μl, 8.27 mmol) and isopropanol (4 mL) in a bomb flask was added azetidine (304 mg, 5.17 mmol). The flask was sealed and heated to 80° C. for 24 hours. The reaction mixture was dissolved in ethyl acetate (50 mL), washed with water (3×50 mL), brine (50 mL), and the brine layer back extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to a brown oil. The oil was purified by chromatography over silica gel eluted with 40% v/v ethyl acetate in hexanes. The product containing fractions were combined and concentrated to give 4-azetidin-1-yl-2-fluoro-phenylamine as an orange oil (555 mg, 81% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15](F)=[C:14](C)[C:13]=1[C:20]([F:23])([F:22])[F:21]>CCCCCC.CN(C)C=O>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)=[CH:14][C:13]=1[C:20]([F:21])([F:23])[F:22]
Reactant: Cc1cc[nH]n1
Reactant: COC(=O)c1ccc(F)c(C)c1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ccc(C)n2)cc1C(F)(F)F
Yield: 59.7 %

Procedure:
Sodium hydride (60% suspension in oil, 3.85 g, 96.3 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (150 mL). A solution of 3-methylpyrazole (7.75 mL, 96.3 mmol) in dimethylformamide (50 mL) was added dropwise at ambient temperature. Stirring was continued until the gas evolution subsided, and then a solution of methyl 4-fluoro-2-trifluoromethylbenzoic acid methyl ester of Step A (17.8 g, 80.1 mmol) in dimethylformamide (50 mL) was added dropwise to the clear solution. After stirring for 30 min at room temperature, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was dissolved in 1:1 mixture of dichloromethane and hexane and absorbed onto a silica Merck-60 flash column. Elution with a dichloromethane-hexane gradient (from 1:1 to 4:1) provided the title compound (13.6 g) as a white solid, m.p. 59-61° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:32])=[O:31]>>[ClH:1].[CH3:29][S:30]([CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH3:18])=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:39][CH:40]=1)(=[O:31])=[O:32]
Reactant: CS(=O)(=O)CCc1ccc(N)cc1
Reactant: CC(Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C)c1ccccc1
Product: CC(Nc1nc2cc(N(C)c3ccnc(Nc4ccc(CCS(C)(=O)=O)cc4)n3)ccc2n1C)c1ccccc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(1-phenyl-ethyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 4-(2-methanesulfonyl-ethyl)-phenylamine (50 mg, 0.25 mmol) as a white solid (81 mg, 55%). 1H NMR (300 MHz, d6-DMSO) δ 10.09 (s, 1H), 8.87 (s, 1H), 7.84 (d, J=6.9 Hz, 1H), 7.48-7.61 (m, 5H), 7.36-7.40 (m, 3H), 7.20-7.31 (m, 4H), 5.82 (d, J=5.7 Hz, 1H), 5.09 (m, 1H), 3.74 (s, 3H), 3.47 (s, 3H), 3.37-3.42 (M, 2H), 2.94-2.99 (M, 5H), 1.63 (d, J=6.6 Hz, 3H). MS (ESI) m/z=556 [M+H]+.