Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([F:44])[CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.O.CO>[F:44][C:42]1[CH:41]=[C:4]([CH:3]=[C:2]([F:1])[CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)cc(F)c5)c4)c3c2)c1
Yield: 8.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfonamide (300 mg, 0.473 mmol) was hydrolyzed with lithium hydroxide (40 mg, 0.946 mmol) in THF/water/methanol (15/10/5 ml) mixture to afford 20 mg (8.8% yield) of the desired compound. 1H NMR (DMSO-d6, 400 MHz): δ 11.82 (s, 1H), 9.82 (s, 1H), 8.48-8.47 (d, 1H), 8.43 (s, 1H), 8.355-8.350 (d, 1H), 8.00 (s, 1H), 7.71-7.80 (d, 1H), 7.53-7.46 (m, 3H), 7.25-7.23 (m, 2H), 6.98-6.97 (d, 2H), 5.42 (s, 2H), 3.05 (s, 3H). MS: m/z=479.8 (M+1), HPLC: 94.78% (Method-B).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][CH2:16][C:17](=[O:26])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1>C(#N)C>[CH2:8]([O:15][CH2:16][C:17](=[O:26])[C:18](=[N+:36]=[N-:37])[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
5.54 ml (40 mmol - 2 equivalents) of triethylamine were added dropwise to a solution, which had been cooled to 0° C., of 5.29 g (20 mmol) of tert.-butyl 4-benzyloxyacetoacetate and 4.34 g (22 mmol) of p-toluenesulphonyl azide in 40 ml of anhydrous acetonitrile. The mixture was stirred at 0° C. for 30 min, 8 g of kieselguhr were added, and evaporation in vacuo and chromatography on 100 g of silica gel (toluene:ethyl acetate 95:5) were carried out. 3.98 g (69%) of the title compound were obtained as colorless crystals, melting point: 68° C., Rf: 0.31 (toluene:ethyl acetate 95:5).
Reaction SMILES: Cl.C(OC1C=CC=CC=1N1C=CN=C1)C=C.C(OC(=O)C)(=O)C.[N+]([O-])(O)=O.C[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1>>[N:39]1([C:31]2[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:30]=2[OH:29])[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: COc1ccc([N+](=O)[O-])cc1-n1ccnc1
Agent: C=CCOc1ccccc1-n1ccnc1
Agent: Cl
Solvent: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(O)c(-n2ccnc2)c1

Procedure:
2.15 g. of 1-(2-methoxyphenyl)-imidazole (literature citation in Example 56) is nitrated in a mixture of 60 ml. of acetic anhydride and 20 ml. of 65% nitric acid for 2 hours at 10°. By ether splitting (literature citation in Example 56) of the thus-formed 1-(2-methoxy-5-nitrophenyl)-imidazole (1.8 g.; m.p. 139°-140° from methylene chloride/ether), 420 mg. of 2-(1-imidazolyl)-4-nitrophenol is obtained according to the literature citation in Example 56. This product is etherified analogously to Example 56 with the use of 400 mg. of 2,4 -dichlorobenzyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18](I)=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[B:28](OC)([O:31]C)[O:29]C>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]([B:28]([OH:31])[OH:29])=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(I)c2C1
Reactant: COB(OC)OC
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(B(O)O)c2C1
Temperature: -78 °C
Reaction time: 0.02 h
Yield: 126.5 %

Procedure:
A 1.3M solution of isopropylmagnesium chloride lithium chloride complex solution (39 mL, 0.5 mmol) was added to a stirred solution of (4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (0.2 g, 0.42 mmol) in THF (4 mL) at −78° C. and under N2. The mixture was stirred at −78° C. for 1 minute and then trimethyl borate (0.093 mL, 0.84 mmol) was added. The mixture was stirred−78° C. for 30 minutes and at room temperature for 1 hour. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield {5-[(4-fluorophenyl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl}boronic acid (0.21 g, 56% yield) as a yellow oil that was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)[CH2:4][C@@H:3]1[CH2:15]O.S(Cl)(Cl)=O.CN1CCCC1=O.[OH-].[Na+]>COCCOC>[Cl:13][C:11]1[CH:12]=[C:7]([N:5]2[CH2:6][C@@H:2]3[C@@H:3]([CH2:15][NH:1]3)[CH2:4]2)[CH:8]=[N:9][C:10]=1[Cl:14]
Reactant: N[C@@H]1CN(c2cnc(Cl)c(Cl)c2)C[C@@H]1CO
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: COCCOC
Solvent: O=S(Cl)Cl
Product: Clc1cc(N2C[C@@H]3CN[C@@H]3C2)cnc1Cl

Procedure:
The treatment of Compound 5D with an acid such as hydrochloric acid under cooling conditions provides (allyl-5,6-dichloro-pyridin-3-yl)-amino)-acetaldehyde which when treated with 2-(S)-hydroxyamino-2-phenyl-ethanol and magnesium bromide in a solvent such as isopropyl alcohol provides (3S,4S)-2-[5-(5,6-dichloro-pyridin-3-yl)-hexahydro-pyrrolo[3,4-c]isoxazol-1-yl]-2-(2′S)-phenyl-ethanol (Compound 5G). Compound 5G when treated with methanesulfonyl chloride to generate the mesylate which is then treated with sodium tert-butoxide followed by an acidic workup provides (3S,4S)-5-(5,6-dichloro-pyridin-3-yl)-hexahydro-pyrrolo[3,4-c]isoxazole (Compound 5H). The treatment of Compound 5H with Raney-nickel and 40 PSI of hydrogen in a mixture of tetrahydrofuran, ethanol and water provides (3S,4S)-[4-amino-1-(5,6-dichloro-pyridin-3-yl)-pyrrolidin-3-yl]-methanol (Compound 51). The treatment of Compound 51 with thionyl chloride and N-methylpyrrolidinone under heated conditions in 1,2-dimethoxyethane followed by treatment with sodium hydroxide or another similar base provides (1S,5S)-3-(5,6-dichloropyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane (Compound 5J).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:4]3\[C:5](=[O:11])[NH:6][C:7]4[C:3]\3=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=4)[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: O=C1Cc2c(Br)cccc2N1
Product: O=C1Nc2cccc(Br)c2/C1=C/c1ccc2cn[nH]c2c1
Reaction time: 8 h
Yield: 38.3 %

Procedure:
The title compound was synthesized according to the method of Example A19, utilizing 4-bromoindolin-2-one (50 mg, 0.23 mmol) and 1H-indazole-6-carbaldehyde (34.5 mg, 0.23 mmol). On completion the reaction mixture was stored at rt overnight. Filtration and rinsing with xs EtOH provided the title compound as an orange solid (30 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.36 (br. s., 1H), 10.91 (br. s., 1H), 8.78 (s, 1H), 8.73 (s, 1H), 8.13 (s, 1H), 7.80 (d, J=8.28 Hz, 1H), 7.65 (d, J=8.28 Hz, 1H), 7.22 (d, J=8.28 Hz, 1H), 7.16 (t, J=7.78 Hz, 1H), 6.88 (d, J=7.78 Hz, 1H); MS ESI [M+H]+ 340.1/341.9, calcd for [C16H10BrN3O+H]+ 340.0/342.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
The compound 34-3 (60 mg) prepared according to the same procedure as described in Step 2 was dissolved in 50% aqueous tetrahydrofuran solution (10 ml) and to the solution was added lithium hydroxide (24 mg). The mixture was stirred at room temperature for 5 hours to hydrolyze the compound 34-3 and the solvent was removed therefrom. The residue was dissolved in ethyl acetate and extracted to the obtain the compound 34-4 (43 mg, 81%). The compound 34-4 was dissolved in benzene (2 ml) and to the solution was added dropwise oxalyl chloride (100 μl), followed by refluxing for 2 hours. The reaction mixture obtained by concentrating the resultant under reduced pressure and hydrochloride compound 3-4 (67 mg) prepared in Example 13 were added to dichloromethane (6 ml), and to the mixture was added triethylamine (60 μl), followed by stirring at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and the obtained residue was purified by column-chromatography (ethyl acetate/hexane=1/1) to yield the compound 34-5 (34 mg, 38%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCOCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: ClCc1cccc(I)c1
Solvent: C1COCCO1
Product: Ic1cccc(CN2CCCC2)c1
Yield: 96.7 %

Procedure:
A solution of 3-iodobenzyl chloride (100 mg, 0.396 mmol) in 1,4-dioxane (3 ml) was treated with pyrrolidine (0.5 ml, 6.02 mmol) and heated to reflux for 5 h. The cooled mixture was evaporated to dryness and treated with EtOAc and water. The organics were separated, dried over MgSO4, filtered and evaporated to afford 1-(3-iodo-benzyl)-pyrrolidine as a clear syrup (110 mg, 97%).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([NH2:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].S(=O)(=O)(O)O.[N+](C1C=CC=CC=1)([O-])=O.[CH3:31][C:32]([CH:34](OC(C)=O)OC(C)=O)=[CH2:33]>C(O)(=O)C.O>[CH3:34][C:32]1[CH:33]=[C:5]2[C:4]([C:3]3[CH:2]=[CH:1][CH:10]=[C:9]4[C:11](=[O:12])[O:13][C:14](=[O:15])[C:7](=[CH:6]2)[C:8]=34)=[N:16][CH:31]=1
Reactant: Nc1ccc2c3c(cccc13)C(=O)OC2=O
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cnc2c(c1)cc1c3c(cccc32)C(=O)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of 4-amino-1,8-naphthalic anhydride (Okazaki, M.; Ishikawa, N. Yuki Gosei Kagaku Kyokai Shi 1956, 14, 398; Chem. Abstr. 1957, 51, 8051c) (28.0 g, 131 mmol), ferrous sulfate heptahydrate (7.20 g, 25.8 mmol), concentrated sulfuric acid (13 mL, 234 mmol), and nitrobenzene (27.0 mL, 262 mmol) in acetic acid (260 mL) was heated to reflux. Methallylidene diacetate (43.5 mL, 262 mmol) was added dropwise over a period of 2.5 h using an addition funnel. After the addition was complete, the reaction mixture was heated for 1.5 h and poured into a beaker of ice/water (500 mL). The aqueous solution was further diluted to 800 mL with water, stirred for 1 h and filtered by suction. The residue was washed with water and dried in vacuo to obtain 32.3 g of a dark brown solid. The crude solid was heated at reflux in acetic acid (80 mL) and filtered hot to obtain 15.63 g (44%) of a light brown solid: mp >290° C.; MS m/e 264 (M+H+); 1H NMR (DMSO-d6, 300 MHz) δ 2.60 (s, 3H), 8.10 (t, 1H), 8.60 (s, 1H), 8.62 (s, 1H), 9.01 (s, 1H), 9.12 (d, 1H), 9.45 (d, 1H).
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([NH:14][C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3C(OC(C)(C)C)=O)[CH:19]=2)=[O:13])[CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:22]1[CH2:23][CH2:24][CH2:25][CH:21]1[CH2:20][N:18]1[CH:19]=[C:15]([NH:14][C:12]([C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:3]2[CH:2]=[C:1]([CH3:33])[CH:6]=[CH:5][CH:4]=2)=[O:13])[CH:16]=[N:17]1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC3CCCN3C(=O)OC(C)(C)C)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC3CCCN3)c2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of rac-tert-butyl 2-((4-(5-(m-tolyl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate (100 mg, 0.22 mmol) in DCM (2.3 mL), TFA (0.170 mL, 2.215 mmol) was added at 0° C. After stirring for 5 h at rt, the solvent and the remaining TFA was removed under reduced pressure. The residue was dissolved in DCM and 1 N aq. NaOH-solution was added until basic. The layers were separated and the aq. layer was extracted with DCM (1×). The combined organic layers were washed with brine, dired (MgSO4), filterd and the solvent was removed under reduced pressure to yield rac-N-(1-(pyrrolidin-2-ylmethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide a yellow oil which was used in the next step without further purification. LC-MS conditions A: tR=0.62 min, [M+H]+=352.07.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH3:20])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:23]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]12[CH2:10][CH2:11][C:12]([C:17]([O:19][CH3:20])=[O:18])([CH2:15][CH2:16]1)[CH2:13][CH2:14]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C12CCC(NC(=O)OC(C)(C)C)(CC1)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)C12CCC(N(Cc3ccccc3)C(=O)OC(C)(C)C)(CC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of methyl 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate (2.50 g, 8.82 mmol) in DMF (42 mL) at about 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.706 g, 17.6 mmol). The reaction mixture was stirred for about 30 min at about 0° C. and TBAI (0.652 g, 1.76 mmol) and benzyl bromide (2.10 mL, 17.7 mmol) were added. The reaction was warmed to ambient temperature and continued to stir for about 5 h. The solvent was removed under reduced pressure and the residue was taken up in DCM (50 mL) and water (30 mL). The layers were separated and the organic phase was washed with brine (30 mL), dried over anhydrous MgSO4, filtered and concd under reduced pressure. The resulting oil was purified by silica gel chromatography eluting with a gradient of 0-30% EtOAc in heptane to give methyl 4-(benzyl(tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylate (2.71 g, 82%) as a clear colorless oil: LC/MS (Table 1, Method b) Rt=3.09 min; MS m/z: 374 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:23][CH2:24]Cl)[CH2:21][CH3:22]>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@H:3]([N:2]1[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: CCN(CCCl)CCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN([C@@H](CNC(=O)OC(C)(C)C)C(=O)OC)CC1
Yield: 40.4 %

Procedure:
A solution of 5.0 g (19.6 mmol) of commercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 3.3 g (19.6 mmol) of bis(2-chloroethyl)ethylamine in 50 ml of N,N-diisopropylethylamine is heated at 127° C. for 5 h. After evaporation of a maximum amount of diisopropylethylamine, the reaction medium is diluted with ethyl acetate and washed with an aqueous solution of sodium hydroxide having a concentration of 1N. The organic phase obtained is then washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography on silica gel, elution being carried out with a 30/70 heptane/ethyl acetate mixture. 2.5 g (40%) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate are obtained in the form of an oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[N:27]=[CH:26][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=1)[N:11]=3.[NH3:29]>CO>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[N:27][C:6]([O:5][CH2:4][C:3]([NH2:29])=[O:2])=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:25])[CH3:24]
Reactant: N
Reactant: COC(=O)COc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OCC(N)=O)cc1OCC2
Temperature: 50 °C
Yield: 50 %

Procedure:
[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-acetic acid methyl ester (88 mg, 0.23 mmol) was dissolved in a solution of ammonia in methanol (7N, 5 mL) and the reaction mixture heated at 50° C. for 2 h, during which a white precipitate formed. The reaction mixture was concentrated in vacuo and the residue subjected to reverse phase preparative HPLC (C-18, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) to yield 427 as a white solid (42 mg, 50%). LCMS: RT=2.85 min, [M+H]+=370; 1H NMR (400 MHz, d6-DMSO) 9.07 (1H, s), 7.88 (1H, s), 7.86 (1H, s), 7.41 (1H, s), 7.18 (1H, s), 6.45 (1H, s), 5.87 (1H, sept, J=6.7 Hz), 4.66 (2H, s), 4.60-4.44 (4H, m), 1.44 (6H, d, J=6.7 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10](N(OC)C)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]([CH:10]=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1nc(SC)ncc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncc(Br)c(C=O)n1
Reaction time: 0.17 h

Procedure:
A solution of 5-bromo-N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (11A, 8.2 g, 28 mmol) in THF (120 mL) was added dropwise to a suspension of lithium aluminum hydride (1.06 G, 28 mmol) and THF (120 mL) at −78° C. The mixture was stirred for 10 minutes after addition finish. H2O (1.06 mL), 15% aqueous NaOH solution (1.06 mL) and H2O (3.18 mL) were successively added to the mixture at 0° C. very slowly. The resulting precipitate was filtered and washed with THF. The filtrate was concentrated in vacuo to afford crude of the title compound. MS (m/z): 233.14, [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1([CH:26]([NH2:28])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:11][C:4]1[CH:5]=[C:6]([C:8]([NH:28][C@@H:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:27])=[O:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(Cl)cc(C(=O)[O-])cc1Cl
Reactant: CC(N)c1cccc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(Cl)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Yield: 96 %

Procedure:
A solution of 2,6-dichlorobenzene-1,4-dicarboxylic acid, 1-methyl ester (Example 4; 3.00 g, 12.0 mmol), ®-(+)-1-(1-naphthyl)ethylamine (2.00 g, 11.7 mmol), HBTU (5.68 g, 15.0 mmol), HOBT (2.04 g, 15.1 mmol), and diisopropylethylamine (6.20 g, 48.0 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature over the weekend. The solvent was evaporated and ethyl acetate (150 mL) was added. The solution was washed with 1 M HCl (100 mL) and the aqueous layer was back-extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine (200 mL each), then dried (MgSO4), filtered, evaporated and chromatographed (30% ethyl acetate/hexanes) to give 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid, methyl ester (4.52 g, 96%) as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:14])[CH:8]=[C:9]([C:12]#[N:13])[C:10]=1[I:11])=[O:5])[CH3:2].[B-](F)(F)(F)[F:16].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O.C(Cl)Cl>C(#N)C>[C:12]([C:9]1[C:10]([I:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]([CH3:14])[C:8]=1[F:16])#[N:13]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1c(I)c(C#N)cn1C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(I)c(C#N)c(F)n1C
Temperature: 80 °C

Procedure:
Dissolve 4-cyano-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.69 mmol, prepared in preparation 34) and SELECTFLUOR® (4.04 mmol, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate)) in acetonitrile (27 mL). Heat the mixture at 80° C. for 16 h. Add H2O (30 mL) and methylene chloride (30 mL) into the reaction mixture. Extract with methylene chloride (3×30 mL). Combine the organic layers, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography to provide the title compound. Mass spectrum (m/e): 318.9 (M−1). Rf=0.5 (50% Et2O in hexanes).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[CH2:10][C@@H:9]([NH2:11])[CH2:8]1)=[O:6])[CH3:3].[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[O:24][N:23]=2)=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([CH2:31][NH:11][C@@H:9]4[CH2:10][C@H:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8]4)=[CH:33][CH:34]=3)[O:24][N:23]=2)=[CH:20][CH:21]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)[C@H]1C[C@@H](N)C1
Reactant: CC(C)Cc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1C[C@@H](NCc2ccc(-c3nc(-c4ccc(CC(C)C)cc4)no3)cc2)C1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
cis-3-Amino-cyclobutanecarboxylic acid ethyl ester hydrochloride (0.193 g, 1.35 mmol) was added to a solution of 4-[3-(4-isobutylphenyl)-1,2,4-oxadiazol-5-yl]benzaldehyde (0.333 g, 1.08 mmol), acetic acid (2 mL) and THF (18 mL) and stirred for 30 minutes. Sodium triacetoxyborohydride (0.500 g, 2.36 mmol) was added to the reaction mixture, stirred at room temperature for 16 hours, and concentrated in vacuo to give a white solid. The solid was triturated with water, filtered and dried to give the title compound (0.260 g, 55% yield) as a white solid.