Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:2].[C:18]([NH:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C(O)(=O)C>C(O)C>[C:18](=[N:26][NH2:27])([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.[CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:2]
Reactant: NNC(=O)c1cccnc1
Agent: CCOP(=O)(Cc1ccccc1C=O)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: NN=C(O)c1cccnc1

Procedure:
2.0 g (8 mmol) of the compound A and 1.07 g (8 mmol) of nicotinic acid hydrazide were dissolved in 30 ml of absolute ethanol. After adding 1 ml of acetic acid, the mixture was boiled under reflux for 8 h. The solvent was removed by rotary evaporation and the residue was chromatographed on silica gel (eluent CH2Cl2 /EtOH 9.5/0.5; Rf =0.45). The product E was obtained in crystalline form. Yield: 2.2 g (73%); m.p.: 136° to 140° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)[CH:7]=1.[CH3:16][N:17]([CH:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26](O)=[O:27])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C)C=O.O.CCOC(C)=O>[C:21]([O:20][C:18](=[O:19])[N:17]([C@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26]([N:11]1[CH2:12][CH2:13][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:14][CH3:15])=[CH:9][CH2:10]1)=[O:27])[CH3:16])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)C(Cc1ccccc1)C(=O)O
Reactant: COc1ccc(F)cc1C1=CCNCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(F)cc1C1=CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
The crude product of 4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridine (0.49 g, 2.4 mmole) (Intermediate 9) was dissolved in N,N-dimethylformamide (10 mL) at 0° C., and the resulting solution treated with 2-[N-methyl-N-(tert-butoxycarbonyl)-amino]-3-phenyl-propionic acid (0.73 g, 2.6 mmole) in a minimal amount of DMF, DAEC (0.50 g, 2.6 mmole), HOBT (0.42 g, 3.1 mmole) and NMM (0.40 mL, 3.6 mmole). The mixture was stirred overnight, and was diluted with water (50 mL) and EtOAc (50 mL). The layers were separated and the organic layer was washed with HCl (1N), saturated NaHCO3, and the combined aqueous washings were extracted three times with EtOAc (3×25 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford (R)-{1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridin-1-yl]-2-oxo-ethyl}-methyl-carbamic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:14].[CH2:24](I)[CH:25]=[CH2:26]>>[CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:26][CH:25]=[CH2:24])[CH:16]=1)=[O:14]
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Reactant: C=CCI
Product: C=CCn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-Quinolizidin-2-ylmethylindole-3-carboxylate (E9b) was alkylated with allyl iodide using the method in Example 18. The product was chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E19) as a colourless oil. This was converted to its hydrochloride salt mp 190°-192° C. (acetone)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([C:17]2[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cc(C)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Temperature: 100 °C

Procedure:
A mixture of methyl 2-bromo-5-methylbenzoate (1.01 g, 4.41 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 5.28 mmol), Pd(PPh3)4 (0.764 g, 0.66 mmol), K2CO3 (1.83 g, 13.23 mmol) and dioxane/H2O (4:1, 15 mL) was degassed for 10 min and then heated overnight at 100° C. The mixture was cooled, diluted with brine, and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 and dried over Na2SO4. The solvent was removed in vacuo to obtain the crude material, which was purified by silica gel chromatography to obtain the title compound. ESI-MS (m/z): 231 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([CH3:14])[C:6]=1[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[K+]>O.CO>[CH2:18]([O:17][C:15]([C:4]1[NH:3][C:2]([CH3:1])=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:5]=1[CH3:14])=[O:16])[CH3:19]
Reactant: CCOC(=O)CCc1c(C)[nH]c(C(=O)OCC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1[nH]c(C)c(CCC(=O)O)c1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To a suspension of 10 g (38.9 mmol) ethyl 2,4-dimethyl-5-(ethoxycarbonyl)-3-pyrrolepropionate (commercially available) in a mixture of water (250 mL) and methanol (MeOH) (50 mL) was added 3.0 g of KOH in 50 mL of water. The mixture was stirred at 70° C. for 4 hr. The reaction mixture was cooled and the methanol was stripped from the mixture under vacuum. The remaining solution was filtered and the filtrate was then acidified with 6N hydrochloric acid to pH 3. The precipitate which formed was collected by filtration, washed with a 2:1 mixture of water and ethanol and dried under vacuum to give 7.5 g of 4-(2-carboxy-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: O=[O+][O-].[C:4]([O:7][CH:8]1[N:11](C(=C(C)C)C(O)=O)[C:10](=[O:19])[C@@H:9]1[C@H:20]([F:22])[CH3:21])(=[O:6])[CH3:5].CSC>>[C:4]([O:7][CH:8]1[NH:11][C:10](=[O:19])[C@@H:9]1[C@H:20]([F:22])[CH3:21])(=[O:6])[CH3:5]
Reactant: CC(=O)OC1[C@@H]([C@@H](C)F)C(=O)N1C(C(=O)O)=C(C)C
Agent: O=[O+][O-]
Solvent: CSC
Product: CC(=O)OC1NC(=O)[C@@H]1[C@@H](C)F
Reaction time: 2 h

Procedure:
Ozone is passed through a solution of 6.2 g of 2-[4-acetoxy-(3R)-3-[1(R)-fluorethyl]-2-oxoazetidine-1-yl]-3-methyl-2-butenoic acid.benzhydrylester at -78° until a permanent blue colour is achieved. The excess ozone is drive out with nitrogen and 1.75 g of dimethylsulphide added. The reaction mixture is allowed to rise to room temperature. The solvent is evaporated on a rotary evaporator, the residue taken up in 100 ml of methanol and after addition of 2 drops of triethylamine stirred for 2 hours. After renewed concentration the residue is chromatographed on silica gel (dichloromethane/ethylacetate=10/3) to obtain the oily title compound.
Reaction SMILES: O1CCCC1.CN(OC)[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C([Li])CCC>C(OC(=O)C)C.O.CCCCCC>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]([C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:27][NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH:33]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: CON(C)C(=O)c1ccccc1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)c2ccccc2N)c1

Procedure:
A tetrahydrofuran (30 ml) solution of N-methyl-N-methyloxy-2-aminobenzamide (2.70 g) and N-tert-butoxycarbonyl-3-bromobenzylamine (2.86 g) was cooled to −78° C. To the solution was gradually added dropwise a hexane solution of n-butyl lithium (1.6 mol/L) (31 ml). To the mixture were then added water (70 ml) and acetic acid ethyl ester (70 ml). The organic layer was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off. The residual oily compound was purified by means of a silica gel column chromatography to give 2-amino-3′-(tert-butoxycarbonylaminomethyl)benzophenone as a yellow oily product (1.2 g).
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:31][C:32](=O)[CH2:33][C:34]1[NH:38][CH:37]=[N:36][N:35]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:32](=[O:31])[CH2:33][C:34]1[NH:38][CH:37]=[N:36][N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCNC(Cc4ccccc4)C3)ccc12
Reactant: CCOC(=O)Cc1nnc[nH]1
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4nnc[nH]4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 27 %

Procedure:
Prepared using the same procedure described in Example 275 from 6-(3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 5 days to afford the title compound as a colorless solid (72 mg, 27%). LC/MS (Method B) 3.52 min, [M+1]+ 484.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]([O:20][CH3:21])=[O:19])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:22][OH:23])[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]([O:20][CH3:21])=[O:19])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1CS[C@H]2C[C@@](CO[Si](C)(C)C(C)(C)C)(NC(=O)OC(C)(C)C)C(=O)N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CS[C@H]2C[C@@](CO)(NC(=O)OC(C)(C)C)C(=O)N21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
337 mg of methyl (3R,6S,7aS)-6-tert-butoxycarbonylamino-6-(tert-butyldimethylsilanyloxymethyl)-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylate were dissolved in 10 ml of THF and cooled to 0° C. A 1 M solution of tetrabutylammonium fluoride was added dropwise, and the mixture was allowed to reach room temperature within 2 h. It was then partitioned between 120 ml of saturated ammonium chloride solution and 120 ml of ethyl acetate. The aqueous phase was extracted twice with 40 ml of ethyl acetate each time. The combined organic phases were washed once with 80 ml of saturated sodium chloride solution and dried with MgSO4. The solvents were removed in vacuo, and the residue was purified by chromatography on silica gel.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][C:11]([N:13]([S:20]([C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[C:32]=4[N:31]=[CH:30][CH:29]=[CH:28]5)(=[O:22])=[O:21])[CH2:14][C:15]([O:17]CC)=[O:16])=[CH:12][C:7]=3[N:6]=[C:5]2[CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[NH:43])[NH2:42])=[CH:37][CH:36]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][C:11]([N:13]([S:20]([C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[C:32]=4[N:31]=[CH:30][CH:29]=[CH:28]5)(=[O:21])=[O:22])[CH2:14][C:15]([OH:17])=[O:16])=[CH:12][C:7]=3[N:6]=[C:5]2[CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[NH:42])[NH2:43])=[CH:37][CH:36]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C1CC1)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)c1ccc(CCc2nc3cc(N(CC(=O)O)S(=O)(=O)c4cccc5cccnc45)ccc3n2C2CC2)cc1

Procedure:
Prepared analogously to Example 3 from 1-cyclopropyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=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.C[N:39]1[CH2:44][CH2:43][O:42]C[CH2:40]1.Cl.N1CC(O)C1>C(Cl)Cl.CN(C=O)C>[OH:42][CH:43]1[CH2:44][N:39]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:40]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (30.00 g, 138.08 mmol), which is commercially available, and TBTU (48.8 g, 151.9 mmol) was mixed in DCM (400 mL). The mixture was cooled to 0° C. and NMM (45.5 mL, 414.2 mmol) and DMF (100 mL) was added. After 30 min at rt was azetidin-3-ol hydrochloride (18.15 g, 165.7 mmol) added. The resultant mixture was stirred at rt over night. The mixture was washed with NaHCO3 (saturated, 2×300 mL) and brine (300 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (35 g, 93%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CD3OD) δ 0.74-1.10, 1.45, 1.67-2.14, 3.58-3.91, 3.92-4.34, 4.37-4.52, 4.52-4.72. Total no of protons: 23. LCMS (M+H)+: 273.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH2:6][CH2:5][N:4]([C:8]2[CH:34]=[CH:33][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=5)[N:17]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:3][N:4]([C:8]2[CH:34]=[CH:33][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=5)[N:17]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:5][CH2:6][O:7]1
Reactant: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc([N+](=O)[O-])cc45)nc3c2)CCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(N)cc45)nc3c2)CCO1
Yield: 71.1 %

Procedure:
2-Methyl-4-(2-(5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-benzo[d]imida-zol-5-yl)morpholine (60 mg, 0.130 mmol) was added to 10% Pd/C (10 mg) in ethanol (25 mL) and then hydrogen gas (60 psi) was applied for 8 h at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (40 mg). 1H NMR: (400 MHz, CD3OD): δ 7.66 (d, 1H, J=2.0 Hz), 7.52 (m, 2H), 7.13 (s, 1H), 7.04-7.00 (m, 2H), 5.79 (dd, 1H, J=2.4 and 9.2 Hz), 3.97 (m, 2H), 3.79 (m, 3H), 3.49 (m, 1H), 3.41 (m, 1H), 2.76 (m, 1H), 2.62 (m, 1H), 2.44 (m, 1H), 2.13 (m, 1H), 2.05 (m, 1H), 1.80 (m, 1H), 1.68 (m, 2H), 1.22 (d, 3H, J=6.4 Hz); ESI-MS [M+H]+: 433.2.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[NH:26][C:27]([O:29][CH:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])[CH3:31])=[O:28])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].Cl>CO>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH:30]([O:29][C:27]([NH:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:39])=[O:3])=[CH:13][CH:12]=2)=[CH:15][CH:16]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(C(C)(C)C(=O)O)cc3)cc2)c1NC(=O)OC(C)c1ccccc1F
Temperature: 25 °C

Procedure:
2-(4′-{4-[1-(2-Fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-2-methyl-propionic acid ethyl ester (0.51 mmol) in Methanol (50 mL) was treated with lithium hydroxide (excess) as well as 1N aqueous LiOH (excess, and the reaction was stirred at room temperature. Analytical LCMS indicated that starting material was still present, so the reaction was stirred at 80° C. overnight. The mixture was neutralized with 1N HCl (20 mL) and extracted with EtOAc. The combined organic layers were washed with water, dried, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: C(O)C.Cl.C(OC([NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([Cl:31])=[CH:26][CH:25]=2)=[O:21])=O)(C)(C)C>ClCCl>[ClH:31].[Cl:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:20]([NH:19][C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]1[NH2:12])=[O:21])=[CH:30]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: N[C@@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 48 h
Yield: 198.2 %

Procedure:
A saturated ethanol solution (100 ml) of hydrochloric acid was added to a solution of (±)-trans-N1-(tert-butoxycarbonyl)-N2-[(5-chloroindol-2-yl)-carbonyl]-1,2-cyclohexanediamine (5.18 g) in dichloromethane (100 ml) at room temperature. After stirring for 2 days, the reaction mixture was concentrated under reduced pressure, diethyl ether (300 ml) was added to the resultant residue, and colorless precipitate formed was collected by filtration and dried to obtain the title compound (4.30 g) as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[C:7]([CH2:24][CH2:25][CH3:26])[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:8]2[C:7]([CH2:24][CH2:25][CH3:26])=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[N:10][CH:9]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCc1cc(C(=O)OC)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(C(=O)O)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 124.9 %

Procedure:
To a solution of tert-butyl 4-[6-(methoxycarbonyl)-4-propylpyridin-3-yl]piperazine-1-carboxylate (111 mg, 0.307 mmol) in methanol (3.0 mL), 4N aqueous solution of sodium hydroxide (383 μL, 1.53 mmol) was added under ice-cold conditions, and the mixture was stirred at room temperature overnight. The reaction solution was added 4N aqueous solution of hydrochloric acid under ice-cold conditions, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform), and the title compound (134 mg (yield >99%)) was obtained as a yellow crystal.
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]([CH2:22][CH3:23])[C:16]=2[CH:15]=[CH:14][C:13]=1[C:24]([OH:26])=[O:25])=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+].Cl>O>[CH2:22]([N:17]1[C:16]2[CH:15]=[CH:14][C:13]([C:24]([OH:26])=[O:25])=[C:12]([C:10]3[NH:2][C:1](=[O:3])[C:4]([CH:5]([CH3:7])[CH3:6])([CH3:8])[N:9]=3)[C:20]=2[N:19]=[C:18]1[CH3:21])[CH3:23]
Reactant: CCn1c(C)nc2c(C(=O)NC(C)(C(N)=O)C(C)C)c(C(=O)O)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1c(C)nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc21
Reaction time: 2 h
Yield: 28.2 %

Procedure:
A mixture of 4-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-1-ethyl-2-methyl-5-benzimidazolecarboxylic acid (4.09 g, 11.4 mmol), 10N sodium hydroxide (6.8 mL, 68.0 mmol) and water is stirred for 2 hours at reflux temperature, cooled, acidified to pH 4 with hydrochloric acid and filtered. The filter cake is recrystallized from acetonitrile to yield the title product as a white powder (1.10 g, 28.2%), mp 250°-256° C. (dec).
Reaction SMILES: Br[C:2]1C=NC=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH:7]=1.[Br:18][C:19]1[N:24]=C(CP(=O)(OCC)OCC)C=C[N:20]=1>>[Br:18][C:19]1[N:24]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH:7]=[CH:2][N:20]=1
Reactant: Fc1ccc(F)c(/C=C/c2cncc(Br)c2)c1
Reactant: CCOP(=O)(Cc1ccnc(Br)n1)OCC
Product: Fc1ccc(F)c(/C=C/c2ccnc(Br)n2)c1

Procedure:
Prepared according to the same procedure as (E)-3-bromo-5-(2,5-difluorostyryl)pyridine, starting with diethyl (2-bromopyrimidin-4-yl)methylphosphonate. 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=5.2 Hz, 1H), 7.93 (d, J=16.2 Hz, 1H), 7.83 (ddd, J=9.3, 5.8, 3.2 Hz, 1H), 7.72 (d, J=5.2 Hz, 1H), 7.46 (d, J=16.2 Hz, 1H), 7.43-7.30 (m, 2H), Mass spec.: 299.1 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8](=O)[CH2:9][CH3:10])[CH2:3]1.Cl.[C:13]1([CH2:19][O:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:19][O:20][N:21]=[C:8]([C:4]2[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][CH:5]=2)[CH2:9][CH3:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(=O)C1=CCCN(C)C1
Reactant: NOCc1ccccc1
Agent: Cl
Product: CCC(=NOCc1ccccc1)C1=CCCN(C)C1
Yield: 82 %

Procedure:
Examploying the general method of Example 5 above, but starting with 1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-propanone and O-(phenylmethyl)hydroxylamine hydrochloride, the title compound was prepared in 82% yield and isolated as the ethanedioate salt, mp 137°-139° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=O)=[CH:4][C:3]=1[O:13][CH3:14].P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:17])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2cc[nH]c(=O)c2cc1Br
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ccnc(Cl)c2cc1Br
Temperature: 25 °C

Procedure:
A mixture of the product from Step 2 (7-bromo-6-methoxyisoquinolin-1(2H)-one) (4.7 g, 18.5 mmol) in phosphorus oxychloride (30 mL) was heated to reflux for 2 h, cooled to RT, the volatiles evaporated and the residue partitioned between 3M NaOH and DCM. The organic phase was dried over Na2SO4, solvent evaporated and the solid triturated with Et2O (20 mL) and filtered to give a solid (3.75 g). LRMS ESI+ (M+H)+ 274.0.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[C:19]([CH2:20][NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]([Br:28])=[CH:16][N:15]=1>O1CCOCC1>[Br:28][C:17]1[CH:16]=[N:15][C:14]2[NH:13][C:6](=[O:7])[N:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][C:19]=2[CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CNCc1cc(Br)cnc1N
Solvent: C1COCCO1
Product: CCOC(=O)CN1Cc2cc(Br)cnc2NC1=O
Yield: 5.6 %

Procedure:
CDI (1.8 g, 114 mmol) was added to a solution of ethyl 2-((2-amino-5-bromopyridin-3-yl)methylamino)acetate (1.1 g, 38.17 mmol) in dioxane (36 mL). The reaction mixture was stirred at reflux for 5 hours and then concentrated to dryness. The residue was partitioned between dichloromethane (40 mL) and water (30 mL). The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The isolated compound was finally precipitated from a mixture dichloromethane/pentane to give the title product as a yellow solid (670 mg, 56%).