Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[S:20][C:19]([Cl:21])=[N:18][C:17]=2[Cl:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH:27](=O)[CH:28]([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC1SC(CO)=C(Cl)N=1>CC(OC)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[S:20][C:19]([Cl:21])=[N:18][C:17]=2[Cl:22])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2sc(Cl)nc2Cl)CC1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: OCc1sc(Cl)nc1Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: CC(C)CN(Cc1sc(Cl)nc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid t-butyl ester (330 g, 0.9 mol, 1 equiv. mol) in 3.5 L MTBE is added acetic acid (57.2 g, 0.95 mol, 1.06 equiv. mol), isobutyraldehyde (97.3 g, 1.35 mol, 1.5 equiv. mol) and sodium triacetoxy borohydride (305 g, 1.44 mol, 1.6 equiv. mol) suspension in 0.5 L of MTBE. A slight exotherm takes place temperature increases from 24 to 26° C. After 5 h at room temperature the reaction mixture is quenched with 1.3 L water and 30% sodium hydroxide (500 ml). The yellow organic upper phase is washed with 2 L water, then with 2 L of brine. The organic layer is then concentrated under vacuum. The crude product is isolated as yellow powder, 395 g (HPLC 92% area), contaminated by ˜7% of (2,4-dichloro-thiazol-5-yl)-methanol. Purification is done by dissolution of the crude in 900 ml isopropanol/water 8/2 v/v, stirring at 80° C. until complete dissolution, then cool down to room temperature. Filtered at 0° C., the solid is washed with 150 ml of cold isopropanol. The cake is then dried under vacuum at 50° C., to afford 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl ester as a white crystalline powder, 293 g (78% yield for the two first steps). Mass spectrum (ion spray): m/z=422 (M+1); 1H NMR (250 MHz, CDCl3): δ=4.35 (2H, brd), 3.87 (2H, s), 2.80 (3H, m), 2.42 (2H,d), 1.86 (3H, m), 1.61 (11H, m), 1.06 (6H, d); 13C NMR (62 MHz, CDCl3): δ=155.02, 150.71, 137.29, 132.52, 79.95, 58.81, 58.44, 47.64, 43.93, 28.82, 28.03, 27.48, 21.03.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:36])([F:24])[F:35])=[CH:31][N:30]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C(F)(F)F)cn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 5-trifluoromethyl-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:21]([OH:23])=O)[N:15]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:16]=2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:56]1([CH2:62][CH2:63][CH2:64][NH2:65])[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:21]([NH:65][CH2:64][CH2:63][CH2:62][N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:23])[N:15]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:16]=2)=[O:10])=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(CC2CC2)c(C(=O)O)n1
Reactant: NCCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(CC2CC2)c(C(=O)NCCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
34.8 mg (0.1 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-(cyclopropylmethyl)-1H-imidazole-2-carboxylic acid (Example 4A) are dissolved in 0.3 ml of DMF and, after addition of 39.7 mg (0.1 mmol) of HBTU and 10.12 mg (14 μl; 0.1 mmol) of triethylamine, stirred at room temperature for 30 minutes. This solution is added to a solution of 28.8 mg (0.2 mmol) of (3-morpholin-4-ylpropyl)amine in 0.1 ml of DMF and shaken overnight. After filtration, the reaction mixture is purified by preparative HPLC (column: Macherey-Nagel VP 50/21 Nucleodur C18 gravity, 5 μm; flow rate: 25 ml/min; eluent A: acetonitrile, eluent B: water+0.1% conc. aqueous ammonia solution, gradient: 0 min 10% A, 2.00 min 10% A, 6.00 min 90% A, 7.00 min 90% A, 7.10 min 10% A, 8 min 10% A; running time: ca. 10 min per separation; wave length: 220 nm). The correct fractions are evaporated in vacuo.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:45]=[CH:44][CH:43]=[CH:42][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH:31]4[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]4)[CH:30]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[NH:33]1[CH2:32][CH:31]([N:29]2[CH:30]=[C:26]([NH:25][C:20]3[N:19]=[C:18]([CH2:17][CH2:16][C:15]4[CH:42]=[CH:43][CH:44]=[CH:45][C:14]=4[C:11]4([C:8]([NH2:9])=[O:10])[CH2:12][CH2:13]4)[C:23]([Cl:24])=[CH:22][N:21]=3)[CH:27]=[N:28]2)[CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(C4CNC4)c3)ncc2Cl)CC1
Reaction time: 16 h
Yield: 68 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 3-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate A18 (0.110 g, 0.204 mmol) in DCM (5 mL) and the reaction was stirred for 16 hours. The volatiles were removed in vacuo and the resultant residue loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH (100 mL) and then with 5% NH4OH in MeOH (100 mL). The basic fractions were combined and the solvent was removed in vacuo to give the title compound 14 as a tan solid (61 mg, 68%). 1H NMR (400 MHz, d4-MeOD) δ 8.27 (s, 1H), 8.09 (s, 1H), 7.65 (s, 1H), 7.44-7.37 (m, 2H), 7.34 (m, 1H), 7.27 (m, 1H), 5.36-5.18 (m, 1H), 4.15 (m, 2H), 3.96 (m, 2H), 3.20 (m, 4H), 1.63 (m, 2H), 1.20-1.05 (m, 2H). LCMS-C: rt 4.30 min; m/z 438.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:8][C:7]1[C:2]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([O:18][CH2:19][CH3:20])=[O:17])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of 4.56 g 2,3,5-trichloropyridine, 8.80 g of diethyl malonate, 30 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred for 8 hours at 110° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 7.45 g of the resultant residue was subjected to silica gel column chromatography, to obtain 7.08 g of diethyl (3,5-dichloro-2-pyridyl)malonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[F:13].[CH2:14]([O:16][C:17](=[O:22])[CH:18](Cl)[S:19][CH3:20])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:22])[CH:18]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([F:13])[CH:7]=1)[N:4]=[CH:3][C:2]([Br:1])=[CH:11]2)[S:19][CH3:20])[CH3:15]
Reactant: Oc1cc(F)c2ncc(Br)cc2c1
Reactant: CCOC(=O)C(Cl)SC
Product: CCOC(=O)C(Oc1cc(F)c2ncc(Br)cc2c1)SC

Procedure:
In a similar procedure to Stage 2, Step 1 of Example 5, 3-bromo-8-fluoro-quinolin-6-ol was reacted with chloro-methylsulfanyl-acetic acid ethyl ester to give (3-Bromo-8-fluoro-quinolin-6-yloxy)-methylsulfanyl-acetic acid ethyl ester.
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:21]([N:23]1[CH2:32][CH2:31][CH2:30][C@H:24]1[C:25]([N-:27][CH2:28][CH3:29])=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=O)C1C=CC=CC=1.CO.[H][H]>[Pd].O>[ClH:1].[NH2:12][C@H:13]([C:21]([N:23]1[CH2:32][CH2:31][CH2:30][C@H:24]1[C:25]([N-:27][CH2:28][CH3:29])=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20]
Reactant: CC[N-]C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC[N-]C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N

Procedure:
L-Arginyl-L-prolyl-N-ethylamide, hydrochloride is prepared by the following procedure. A solution of 8.7 g. of Nα -benzyloxycarbonyl-L-arginyl-L-prolyl-N-ethylamide hydrochloride in 100 ml. of methanol is stirred with 500 mg. of 20% palladium-on-carbon under one inch water pressure of hydrogen for three hours. The catalyst is removed by filtration and the filtrate evaporated under reduced pressure and at 35°-40° C. The residual foam is used without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH2:19][CH2:18]1.N.[H][H]>[Ni].CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:21][CH2:22]1
Reactant: N#CCCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Yield: 99 %

Procedure:
A mixture of 7.4 parts of 4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinebutanenitrile and 240 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 7.33 parts (99%) of 4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinebutanamine (302).
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[CH:8]=[CH:9][CH:10]=1)#[N:2]>C(OCC)(=O)C.[C].[Pd]>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]2[O:12][CH2:13][CH2:14][O:15]2)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#CC=Cc1cccc(C2OCCO2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CCCc1cccc(C2OCCO2)c1

Procedure:
To a solution of 4.48 g of a cis-trans isomer mixture of 2-[3-(2-cyanoethenyl)phenyl]-[1,3]dioxolane in 100 ml of ethyl acetate was added 0.60 g of 5% palladium carbon to perform hydrogenation. The catalyst was filtered by filtration with Celite, and the filtrate was concentrated under reduced pressure to obtain 3.52 g of 2-[3-(2-cyanoethyl)phenyl]-[1,3]dioxolane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3[C:24]4[CH2:32][CH2:31][C:30]5[C:26](=[CH:27][N:28]([CH2:33][C:34](O)=[O:35])[N:29]=5)[C:25]=4[S:37][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:38][N:39]([CH3:48])[CH2:40][CH2:41][CH2:42][N:43]=[C:44]=NCC.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:37][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH2:33][C:34]([N:43]2[CH2:42][CH2:41][C@H:40]([N:39]([CH3:48])[CH3:38])[CH2:44]2)=[O:35])[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)Cn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 36.9 %

Procedure:
To DMF (3 mL) were sequentially added [6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]acetic acid (80 mg, 0.15 mmol), 3(R)-(−)-3(Dimethylamino)pyrrolidine (23 mg, 0.20 mmol), (3-Dimethylamino-propyl)-ethyl-carbodiimide (50 mg, 0.26 mmol), 4-methylmorpholine (0.03 ml, 0.29 mmol), and 1-Hydroxybenzotriazole (39 mg, 0.29 mmol). The mixture was stirred at rt for 14 h after which time the reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined organic layers were concentrated in vacuo and purified by prep HPLC. The combined fractions were treated with saturated Na2CO3 and dried to afford free base product (35 mg, 42%) as a white solid. 1H-NMR (CD2Cl2) δ 8.38 (s, 1H), 7.81 (d, 1H), 7.53 (s, 1H), 7.45 (dd, 1H), 7.38 (dd, 1H), 7.28-7.22 (m, 2H), 6.97-7.08 (m, 3H), 5.15 (s, 2H), 4.84 (s, 2H), 3.64-3.80 (m, 2H), 3.15-3.53 (m, 3H), 3.07 (t, 2H), 2.61-2.81 (m, 1), 2.25 (s, 3H), 2.23 (s, 3H), 1.69-2.20 (m, 3H); LCMS RT=3.80 min, [M+H]+=632.2
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(S(O[CH2:15][C:16]#[N:17])(=O)=O)C=CC=CC=1.[C:18]1([CH3:26])[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=1>>[CH3:26][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[CH2:15][C:16]#[N:17]
Reactant: Cc1cc(C)cc(C)c1
Reactant: N#CCOS(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C)c(CC#N)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
8.0 g (0.06 mol) of aluminum chloride are first introduced into 40 ml of mesitylene at 0° C. 4.1 g (0.02 mol) of phenylsulfonyloxyacetonitrile are then added, and the reaction mixture is stirred at room temperature overnight. The crude product obtained after hydrolysis is chromatographed on silica gel using dichloromethane. 2.3 g (72.3% of theory) of 2,4,6-trimethylbenzyl cyanide are isolated.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C:4](=O)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:39](O)(=[S:41])[CH3:40]>O1CCCC1>[C:2]([C@@H:3]1[CH2:4][NH:5][C:39](=[S:41])[CH2:40]1)(=[O:1])[CH3:6]
Reactant: O=C1C[C@@H](O)CN1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1CNC(=S)C1
Reaction time: 0.17 h

Procedure:
(4R)-4-Hydroxy-2-pyrrolidone (4.5 g) is suspended in tetrahydrofuran (300 ml), and thereto is added triphenylphosphine (23.4 g). After stirring the mixture for 10 minutes, diethyl azodicarboxylate (14 ml) is added dropwise to the mixture below -10° C., and the mixture is stirred at the same temperature for 10 minutes. Thioacetic acid (6.3 ml) is added dropwise to the reaction mixture below -10° C., and the mixture is stirred at the same temperature for 2 hours, and the solvent is evaporated under reduced pressure. The residue is crystallized from diisopropyl ether, and the precipitate is removed by filtration. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent, chloroform : ethanol =98:2) to give (4S)-4-acetylthio-2-pyrrolidone (3.8 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[N+:22]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.CO>CO.[Pd]>[NH2:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccc(F)cc1N)C(=O)O
Yield: 52.4 %

Procedure:
4.35 g (S)-2-tert-Butoxycarbonylamino-3-(4-fluoro-2-nitro-phenoxy)-propionic acid in 80 ml methanol were hydrogenated with 0.14 g Pd(10%)/C. Chromatography on silicagel with dichloromethane/methanol 9:1 yielded 2.08 g (52%) (S)-3-(2-amino-4-fluoro-phenoxy)-2-tert-butoxycarbonylamino-propionic acid as light brown solid, MS m/e (%): 313.0 (M−H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:14])[C@H:5]2[C:10]([OH:13])([CH3:12])[CH3:11].[CH2:16]([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.COS(OC)(=O)=O>O1CCCC1.C(O)(=O)C>[CH3:1][C:2]1([CH3:15])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:14])[C@H:5]2[C:10]([O:13][CH3:16])([CH3:11])[CH3:12]
Reactant: CC(C)(O)[C@@H]1C(=O)N2[C@@H]1CCOC2(C)C
Reactant: [Li]CCCC
Solvent: CC(=O)O
Solvent: COS(=O)(=O)OC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(C)(C)[C@@H]1C(=O)N2[C@@H]1CCOC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (6R, 7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]octan-8-one (43.0 mg) in tetrahydrofuran (1.29 ml) was added dropwise a solution of n-butyl lithium (0.128 ml of 1.74M solution in hexane) at -78° C. After stirring for 10 minutes at the same temperature, hexamethylphosphoric triamide (38.6 μl) was added to the mixture. The resultant solution was stirred for 10 minutes at -78° C. and a solution of dimethylsulfate (38.2 μl) in tetrahydrofuran (0.344 ml) was added to the mixture. The resultant mixture was allowed to warm to ambient temperature over a period of an hour and stirred at ambient temperature overnight. After acetic acid (12.7 μl) was added, the solvent was distilled off, and the residue was dissolved in ethyl acetate (10 ml) and washed with a mixture of 10% aqueous solution of sodium bicarbonate (0.3 ml) and a saturated aqueous sodium chloride (3 ml). The aqueous washings were extracted with ethyl acetate (10 ml) and the combined ethyl acetate extracts were washed with a saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate solution was filtered and evaporated in vacuo. The residue was chromatographed on silica gel (2.2 g) eluting with a mixture of ethyl acetate and methylene chloride (1:100 to 1:1) to give (6R, 7R)-2,2-dimethyl-7-(1-methoxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]octan-8-one (24.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2][CH3:3].[CH3:19]OC(C1C=NC(Cl)=C(Br)N=1)=O.N1CCCC1.[OH-].[K+]>C(O)CCC>[CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2][CH2:3][CH3:19]
Reactant: COC(=O)c1cnc(Cl)c(Br)n1
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNC1
Solvent: CCCCO
Product: CCCCOc1nc(C(=O)O)cnc1N1CCCC1
Yield: 8 %

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (example 10, step c), the title compound was synthesized from 6-Bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester, butanol (commercially available), pyrrolidine (commercially available) and subsequent saponification with KOH in 8% yield. m/z (ES+): 266.0 (M+H).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[OH:67][CH:68]1[CH2:73][CH2:72][N:71]([C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([N:71]4[CH2:72][CH2:73][CH:68]([OH:67])[CH2:69][CH2:70]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: OC1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 26.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(4-hydroxypiperidin-1-yl)benzaldehyde (1.2 eq, 0.091 mmol, 19 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (11 mg, 26%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.41-1.49 (m, 2H, 2× piperidine CHAHB), 1.81-1.84 (m, 2H, 2× piperidine CHAHB), 2.62 (s, br, 4H, piperazine N(CH2)2), 2.97-3.02 (m, 2H, 2× piperidine CHAHB), 3.62 (s, 2H, NCH2), 3.64 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 3.66-3.70 (m, 2H, 2× piperidine CHAHB), 4.68 (d, J=4.2 Hz, 1H, CHOH), 7.04 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 7.39 (dd, J=7.6, 4.7 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.8 Hz, 1H, pyridine H-4), 7.99 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 8.16 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (d, br, J=4.5 Hz, 1H, pyridine H-6), 8.56 (s, br, 1H, pyridine H-2), 13.17 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][C:17]1([CH3:20])[CH2:19][O:18]1>CO>[CH:7]([N:8]1[CH2:19][C:17]([CH3:20])([OH:18])[CH2:16]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC1(CCl)CO1
Solvent: CO
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.2 %

Procedure:
Diphenylmethanamine (68.8 mL, 375 mmol) was added dropwise into a solution of 2-(chloromethyl)-2-methyloxirane (40 g, 375 mmol) in methanol (160 mL) and the reaction was stirred at rt for 72 h and then at reflux for 20 h. The reaction was cooled to ambient temperature, evaporated in vacuo and suspended in acetone (200 mL). The solid was collected by filtration to give 1-benzhydryl-3-methyl-azetidin-3-ol (60 g, 63%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ7.61 (m, 4H), 7.31 (m, 6H), 6.43 (m, 1H), 6.00 (m, 1H), 3.80-4.00 (m, 4H), 1.45 (m, 3H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([O:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[C:10](=[N+]=[N-])[C:11](=[O:13])[CH3:12])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)=[O:25].CC1(C)OO1>CC(C)=O>[C:1]([O:7][CH2:8][CH:9]([O:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[C:10](=[O:25])[C:11](=[O:13])[CH3:12])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(C)=O
Reactant: CCCCC(=O)OCC(OC(=O)CCCC)C(=[N+]=[N-])C(C)=O
Agent: CC1(C)OO1
Product: CCCCC(=O)OCC(OC(=O)CCCC)C(=O)C(C)=O
Reaction time: 1 h

Procedure:
To a solution of methyl diazo dipentanoate 9 (27 mg, 0.086 mmol) in acetone (1 mL) was added dimethyldioxirane acetone solution (2.5 mL, ca. 0.07-0.09 M). The resulting mixture was stirred for 1 h and solvent and excess reagents were removed under reduced pressure to obtain 21 as bright yellow oil (yield=26 mg, quantitative).