Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:8][CH2:7][NH:6]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[S:32][CH:33]=[C:34]([C:36](O)=[O:37])[N:35]=2)[CH:26]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:8][CH2:7][N:6]1[C:36]([C:34]1[N:35]=[C:31]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[S:32][CH:33]=1)=[O:37]
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)c1csc(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxymethyl-4-(3,4,5trimethoxybenzoyl)piperazine hydrochloride obtained in Reference Example 6 (0.52 g), 2-(3-pyridyl)thiazol-4-carboxylic acid (0.3 g), triethylamine (0.46 g) and N,N-dimethylformamide (3 ml) is added dropwise, while stirring under icecooling, diethyl cyanophosphonate (0.47 g). The reaction mixture is stirred at 0° C. for one hour, and then poured into ice-water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:AcOEt-CH2Cl2 --CH3OH=10:9:1) to give 2-methoxymethyl-1-[2-(3-pyridyl) thiazol-4-ylcarbonyl]-4-(3,4,5-trimethoxybenzoyl) piperazine. Recrystallization from ethanol gives colorless needles m.p. 149-150° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:23])[CH3:22]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:21]([CH3:23])[CH3:22])[CH2:31][CH2:32]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: CC(C)c1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2ccccc2C(C)C)CC1
Yield: 73 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-isopropylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]=[CH:10][C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:14]S(C)=O>>[C:3]1([CH:9]2[CH2:14][CH:10]2[C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(C)=O
Reactant: CC(=O)C=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)C1CC1c1ccccc1
Yield: 97 %

Procedure:
To Me3SOI (2.2 g, 10 mmol) in DMSO (20 mL) was added NaH (50%, 480 mg, 10 mmol). 4-Phenyl-but-3-en-2-one (1.13 g, 7.7 mmol) was added after 10 min. The reaction mixture was quenched after 30 min with water, extracted with EtOAc, and washed with water (3×30 mL). The organic extract was dried over MgSO4 and concentrated to give 1-(2-Phenyl-cyclopropyl)-ethanone (1.5 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=1[NH:18][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(Cl)c(N)c1
Product: COc1ccc(Cl)c(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 2-chloro-5-methoxyaniline (47 mg, 0.243 mmol) similar to Example 13 and isolated as a tan oil (35 mg, 44%). 1H NMR (CDCl3): 8.82–8.80 (m, 1H), 8.47 (d, J=7.8 Hz, 1H), 7.86–7.81 (m, 1H), 7.77 (d, J=2.7 Hz, 1H), 7.41–7.36 (m, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 6.68 (s, 1H), 6.65 (dd, J=2.7, 8.7 Hz, 1H), 3.85 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: O[C:2]1([C:22]([F:25])([F:24])[F:23])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:22]([F:25])([F:24])[F:23])[N:3]=[C:4]2[C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2cccs2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccs2)cc1
Yield: 82 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (0.60 g, 1.54 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) in toluene (100 ml) was heated to reflux for 4.5 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (1.2 g) was chromatographed on silica gel using ethyl acetate/hexane 50/50 to give pure 2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl) -1H-imidazol-2-yl]thiophene (0.47 g, 82%) as a white solid: mp (DSC) 182° C. Anal. Calc'd. for C15H11N2S2O2F3C, 48.38, H, 2.98, N, 7.52, S, 17.22 Found C, 48.36, H, 3.02, N, 7.42, S, 17.47.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[C@@H:10]([NH2:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:19]2(=[O:34])=[O:33])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([NH:40][C@@H:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:42](O)=[O:43])(=[O:39])[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:36])[C@@H:10]([NH:35][C:42](=[O:43])[C@@H:41]([NH:40][C:37](=[O:39])[CH3:38])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:19]2(=[O:33])=[O:34])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](N)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Reaction time: 1 h

Procedure:
The title A compound, (S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester (79 mg, 0.155 mmol) and (S)-2-acetylamino-3-phenyl-propionic acid (33.7 mg, 0.162 mmol) are dissolved in CH2Cl2 (3.1 mL). HOBt (24.8 mg, 0.162 mmol) is added as a solid, followed by EDCl (31.0 mg, 0.162 mmol) and TEA (0.023 mL, 0.162 mmol) in a slurry of CH2Cl2 (1 mL). After 1 h, EtOAc (100 mL) is added and the mixture is washed three times with 2N aqueous HCl (50 mL) followed by saturated aqueous NaHCO3 (50 mL). The EtOAc layer is dried over anhydrous Na2SO4 and concentrated to yield (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:69]([NH:72][CH2:73][CH2:74][C:75]1[O:79][N:78]=[C:77]([NH2:80])[N:76]=1)([CH3:71])[CH3:70]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:14]([C:15](=[O:17])[N:72]([CH2:73][CH2:74][C:75]2[O:79][N:78]=[C:77]([NH2:80])[N:76]=2)[CH:69]([CH3:71])[CH3:70])[CH:13]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CC(C)NCCc1nc(N)no1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CCc1nc(N)no1)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 47.8 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.104 g), TBTU (0.128 g), and HOBt (0.061 g) in DMF (1 ml) was added DIPEA (0.139 ml) and 5-(2-isopropylamino-ethyl)-[1,2,4]oxadiazol-3-ylamine (0.05 g). The reaction mixture was stirred at room temperature for 10 days, then silica was added and the solvent removed by evaporation at reduced pressure. The resulting silica was loaded onto the top of a column of silica which was then eluted with a gradient [cyclohexane:ethyl acetate (1:1 v/v) to neat ethyl acetate to ethyl acetate:methanol (9:1 v/v)]. Concentration of the required fraction at reduced pressure furnished the title compound as a yellow glass (0.069 g).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:3].[C:9](OC(=O)C)(=[O:11])[CH3:10].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:9]([O:8][C:2]([CH3:3])([CH2:4][CH2:5][CH2:6][CH3:7])[CH3:1])(=[O:11])[CH3:10]
Reactant: CCCCC(C)(C)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCCC(C)(C)OC(C)=O
Temperature: 70 °C

Procedure:
2-Methylhexan-2-ol (30.0 g, 0.258 mol) was treated with acetic anhydride (36.6 mL, 0.387 mol). Pyridine (30.0 mL, excess) was added dropwise over a 3 min period at 23° C. Then 4-(N,N-dimethylamino)-pyridine (1.27 g, 10.0 mmol) was added. The reaction was heated to 70° C. for 16 h. The reaction was cooled to 23° C. and poured onto 300 mL of crushed ice. After 15 min of stirring, most of the ice had melted. Solid NaHCO3 was added in portions (bubbling) until the pH was 9. The system was extracted with two portions of diethyl ether (100 mL, then 50 mL). The combined extracts were washed with 1.0 M aq. CuSO4 monohydrate (4×50 mL), dried over MgSO4, and filtered. The filtrate was distilled at ambient pressure at a bath temperature of 80-100° C. to remove most of the diethyl ether. The resulting oil left in the pot was fractionally distilled through a Snyder column with 3 chambers under reduced pressure (6-8 mmHg). A small-volume forerun was collected and discarded (bp<45° C.). The main fraction contained 2-methylhexan-2-yl acetate (bp 45-48° C.). 1H NMR (400 MHz, CDCl3) δ 1.94 (s, 3H), 1.74-1.68 (m, 2H), 1.40 (s, 6H), 1.33-1.22 (m, 4H), 0.88 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]1([O:25][CH2:24]1)[CH3:23]>C(#N)C>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][N:12]1[CH2:13][CH2:14][N:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:10][CH2:11]1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(O)CN1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.63 mmol) 1-benzoylpiperazine and 1.10 g (7.96 mmol, 3.0 eq.) potassium carbonate were suspended to 20 ml acetonitrile at room temperature. After adding 570 mg (7.90 mmol, 3.0 eq.) isobutylene oxide, it was heated at reflux and stirred overnight. After cooling to room temperature and adding 30 ml purified water, it was extracted twice with 30 ml ethylacetate. After collecting organic layer and drying with anhydrous magnesium sulfate, it was concentrated with decompression. The obtained residue was purified by chromatography using silicagel (mobile phase: dichloromethane/methanol=20:1) and 276 mg (40%) target compound as light-yellow solid was yielded.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][OH:5].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCOCC>N1C=CC=CC=1>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC[C@H](C)CCC[C@H](C)CCCC(C)C)cc1
Reaction time: 40 h
Yield: 94.7 %

Procedure:
A solution of 10.44 g (45.8 mmol) of (3R,7R)-3,7,11-trimethyldodecan-1-ol in 150 mL of anhydrous pyridine was stirred in an acetone-ice bath while 17.4 g (91.3 mmol) of p-toluenesulfonyl chloride was added in one portion. The mixture was stirred in the acetone-ice bath for 2 hr then kept at 0° C. for 40 hr before being quenched by the addition of 300 mL of ice-water. The product was isolated by extraction with 3×300 mL of ether. The ether extracts were combined, washed with 400 mL of cold 3N HCl and saturated brine, then dried (MgSO4), filtered and concentrated in vacuo. There was obtained 16.6 g (94.9%) of (3R,7R)-3,7,11-trimethyldodecyl p-toluenesulfonate.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:18]2[O:19][CH:20]=[CH:21][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C(=Cc1ccoc1)CC(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(OC(C)=O)c2occc2c1
Yield: 60.4 %

Procedure:
Sodium acetate (10 g, 120 mmol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(furan-3-yl)but-3-enoic acid (12.3 g, 48 mmol) in 100 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 250 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 5.2 g (29 mmol, 61%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:29][CH2:30]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1ccc2nc(NC(=O)N3CCN(c4cccc(C)c4)CC3)c(OC)nc2c1
Yield: 86 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 2.33 (s, 3H), 3.26-3.29 (m, 4H), 3.73-3.77 (m, 4H), 3.90 (s, 3H), 4.13 (s, 3H), 6.73-6.77 (m, 3H), 7.13-7.22 (m, 4H), 7.74 (d, J=9.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH:12]([CH2:18][NH2:19])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[C:33]([C:35]3[N:39]([CH3:40])[N:38]=[N:37][N:36]=3)[CH:32]=[C:31]([CH2:41][CH3:42])[CH:30]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH2:41]([C:31]1[CH:30]=[C:29]([NH:28][C:27]([NH:19][CH2:18][CH:12]2[CH:13]([CH2:16][CH3:17])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:11]2)=[O:26])[CH:34]=[C:33]([C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH:32]=1)[CH3:42]
Reactant: CCC1CCN(CCc2ccc(F)cc2)CC1CN
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)NCC2CN(CCc3ccc(F)cc3)CCC2CC)cc(-c2nnnn2C)c1
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A solution of 1-[2-(4-fluorophenyl)ethyl]-4-ethyl-piperidin-3-ylmethylamine (52 mg, 199 μmol) and [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (50 mg, 199 μmol) in N,N-dimethylformamide (1.0 mL) was treated with triethylamine (55 μL, 398 μmol). After 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonium hydroxide, provided an amorphous solid (50 mg, 51%). 1H NMR (300 MHz, CDCl3) δ8.37 (s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.11 (m, 2H), 7.03 (s, 1H), 6.92 (t, J=9 Hz, 2H), 6.11 (m, 1H), 4.12 (s, 3H), 3.53 (m, 1H), 3.18 (m, 2H), 3.00 (m, 1H), 2.80 (m, 2H), 2.63 (m, 4H), 2.2-2.0 (m, 2H), 1.82 (m, 1H), 1.66 (m, 2H), 1.40 (m, 1H), 1.3-1.1 (m, 2H), 1.20 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 494.4 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:10]=2[N:11]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][CH:15]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:13]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][N:9]([S:18]([C:14]3[CH:13]=[C:12]([CH3:22])[CH:17]=[CH:16][CH:15]=3)(=[O:20])=[O:19])[C:10]=2[N:11]=1
Reactant: Brc1ccc2c(n1)NCCO2
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: Cc1cccc(S(=O)(=O)N2CCOc3ccc(Br)nc32)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-Bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (1.0 g, 4.65 mmol) and m-tolylsulfonyl chloride were dissolved in pyridine (10 mL). The resulting mixture was stirred at 80° C. for one hour. An additional portion of m-tolylsulfonyl chloride (0.98 g, 5.12 mmol) was added and the reaction mixture was stirred at 80° C. for 16 hours. Next, excess solvent was removed under vacuum, and the resulting oil was triturated with water to obtain a tan solid, which was collected by vacuum filtration and washed with water and diethyl ether to give 6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. Yield 1.3 g (76%). LCMS (ESI): calc. C14H13BrN2O3S=368, 370; obs. M+H=369, 371.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[C:28]4[C:23](=[CH:24][N:25]=[CH:26][CH:27]=4)[C:22]([NH2:29])=[N:21][CH:20]=3)=[C:11]2[CH3:30])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C(O)C(F)(F)F>[CH3:30][C:11]1[NH:10][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]=1[C:19]1[C:28]2[C:23](=[CH:24][N:25]=[CH:26][CH:27]=2)[C:22]([NH2:29])=[N:21][CH:20]=1
Reactant: Cc1c(-c2cnc(N)c3cnccc23)c2cccnc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: OCC(F)(F)F
Solvent: C1CCOC1
Product: Cc1[nH]c2ncccc2c1-c1cnc(N)c2cnccc12
Yield: 80 %

Procedure:
A mixture of 23 g of 4-(1-benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine and 26 g of caesium carbonate in 400 ml of THF/trifluoroethanol (1:1 vol) is heated under reflux for 20 h. The mixture is cooled, the solvent is removed, and the product is purified by means of flash chromatography over 220 g of silica with a methanol gradient in ethyl acetate with 150 ml/min with UV detection at 254 nm, giving 12.2 g of 4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine, M˜275.31, M+H found 276.2;
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.[OH-].[Li+].OO>CO.O>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3.5 h
Yield: 90.5 %

Procedure:
To a stirred solution of N-Cbz-L-Leu-L-Leu-OCH3 (6.0 g, 14.6 mmol) in MeOH/H2O (3:1) (60 mL) at R. T. was added lithium hydroxide monohydrate (LiOH.H2O) (1.0 g, 43.9 mmol) and hydrogen peroxide (H2O2) (30% weight in H2O) (4.5 mL, 43.9 mmol). The reaction mixture was stirred for 3.5 h and then quenched with 10% HCl. The resulting mixture was extracted with EA (3×20 mL). The combined organic extracts were washed with sat. NaCl (2×10 mL), dried (MgSO4) and concentrated in vacuo to afford N-Cbz-L-Leu-L-Leu-OH as a white solid (5.0 g, 90.5%): 1H NMR (CDCl3, 300 MHz) δ 0.89-0.92 (t, 12H, J=3.0 Hz), 1.48-1.71 (m, 6H), 4.11-4.13 (m, 1H), 4.55-4.62 (m, 1H), 5.09 (s, 2H), 5.64 (d, 1H, J=9.0 Hz), 6.83 (d, 1H, J=9.0 Hz), 7.33-7.40 (m, 5H) ppm.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(C(=O)O)cc32)n1)c1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc2ncn(-c3ccnc(N[C@@H](C)c4ccccc4)n3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-[6-carboxy-benzimidazol-1-yl]pyrimidine in 0.2 mL of benzene and 0.1 mL of methanol was added 0.015 mL of (trimethylsilyl)diazomethane (2 M in hexanes). The solution was stirred for 30 min at room temperature then concentrated. The product was purified by chromatography to afford the title compound. Partial 1H NMR (500 MHz CD3OD): δ 8.9 (s, 1H); 8.63 (br, 1H); 8.42 (d J=5.0 Hz, 1H); 8.09 (d J=11 Hz, 1H); 7.87 (d J=11 Hz, 1H); 6.83 (d J=5.0 Hz, 1H); 5.29 m, 1H); 3.98 (s, 3H); 1.64 (d J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([N+:11]([O-:13])=[O:12])[C:4]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].S(N)(=O)(=O)[OH:21].C(O)(C)C.Cl([O-])=O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([OH:21])=[O:8])=[C:5]([N+:11]([O-:13])=[O:12])[C:4]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCOc1c(OC)ccc(C=O)c1[N+](=O)[O-]
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCCCCOc1c(OC)ccc(C(=O)O)c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
4-Methoxy-2-nitro-3-pentyloxybenzaldehyde (70 g, 261.9 mmol), amidosulfuric acid (76.3 g, 785.7 mmol) and isopropanol (210 ml) were mixed, an aqueous sodium chlorite (38.5 g, 340.5 mmol) solution (350 ml) was added dropwise to this solution while cooling in a water bath. After stirring for 20 minutes, ethyl acetate (300 ml) was added to separate the organic layer. The aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with saturated brine (150 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration to give 4-methoxy-2-nitro-3-pentyloxybenzoic acid (59.02 g, 80%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:20]([C:19]2[CH:18]=[N:17][C:16]([Cl:15])=[CH:24][CH:23]=2)=[O:21])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2ccc(Cl)nc2)C1

Procedure:
63.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 6-chloro-nicotinic acid to give (R)-3-{[(6-chloro-pyridine-3-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Yellow oil. MS 340.1 ([M+H]+)