Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[P:28](=[O:32])([OH:31])([OH:30])[OH:29]>O>[P:28]([OH:32])([OH:31])([OH:30])=[O:29].[S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: c1cc2ccsc2cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: O
Product: OB(O)c1cc2ccncc2s1
Temperature: -44 °C
Reaction time: 1.25 h
Yield: 113.3 %

Procedure:
A three neck flask fitted with an internal thermometer containing the material from Step iii (4.12 g, 30.5 mmol) was evacuated and then filled with nitrogen atmosphere, THF (50 mL) was added and the solution cooled to −44° C. (CH3CN/dry ice). n-Butyllithium (1.6M/hexane, 21 mL, 34 mmol) was added over 10 minutes, while maintaining the internal temperature at or below −35° C. The reaction was stirred at −33 to −45° C. for 75 minutes. Triisopropyl borate (8.4 mL, 36.6 mmol) was added and the cooling bath removed. The reaction was stirred for one hour then phosphoric acid (85% aqueous, 2.5 mL, 33.5 mmol) was added. The reaction was diluted with 10 mL water resulting in a precipitate. The reaction was stirred vigorously for 15 minutes. A yellow solid was collected by filtration, rinsing with EtOAc (about 50 mL) to provide a white powdery solid (9.57 g). Approximately half of the material was washed with 50 mL water to isolate 3.16 g of a pale pink solid. Both crops of material are the same as determined by spectral data. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.87 (1H, d, J=5.5 Hz), 7.95 (1H, s), 8.41 (1H, d, J=5.7 Hz), 9.11 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[N:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH2:32][C:3]1=2.[ClH:40]>ClCCl>[ClH:40].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=4)=[N:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)nc4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)nc4=O)cc31)CCNCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 94 %

Procedure:
To a solution of tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (36 mg, 0.067 mmol) in dichloromethane (1.0 mL) was added HCl (2M in diethyl ether, 5.0 mL). The resulting slurry was stirred at room temperature for 14 h and then concentrated under reduced pressure. The resulting residue was purified by semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.20 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA). The clean fractions were combined, concentrated under reduced pressure and lypholized overnight. The trifluroacetate salt was dissolved in a 1:2 mixture of acetonitrile and water (10 mL) and passed through a plug of SAX column. The column was further washed with a 1:2 mixture of acetonitrile and water (10 mL). The combined filtrate was lypholized to give the title compound (30.1 mg, 94%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.48 (s, 1H), 8.80 (d, J=8.5 Hz, 1H), 8.38 (d, J=6.5 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.0 Hz, 1H), 7.36 (d, J=7.0 Hz, 1H), 7.18 (dd, J=8.5, 1.5 Hz, 1H), 3.78 (s, 3H), 3.56 (t, J=5.5 Hz, 2H), 3.50 (t, J=5.5 Hz, 2H), 3.37 (t, J=5.5 Hz, 2H), 3.26 (t, J=5.5 Hz, 2H); ESI MS m/z 440 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@@H:17]([O:19][CH3:20])[C@H:16]([OH:21])[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:22]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[C:13]([I:22])=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@@H:17]([O:19][CH3:20])[C@H:16]([OH:21])[CH2:15]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Yield: 93.4 %

Procedure:
To a mixture of 3.11 g of 2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine and 10 ml of N,N-dimethylformamide, while stirring in an ice bath, was added dropwise 2.5 g of N-iodosuccinimide, and the resultant mixture was stirred overnight as it was. To this was added sodium sulfite and the reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give 4.19 g of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1.[I-:14].[Na+].II.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[I:14][C:4]1[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][NH:7][C:3]=1[S:2][CH3:1]
Reactant: [I-]
Reactant: CSc1cc(-c2ccccc2)n[nH]1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1[nH]nc(-c2ccccc2)c1I
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of 5-(methylthio)-3-phenyl-1H-pyrazole (1.5 g, 7.88 mmol) in THF (20 mL) and water (20 mL), were added sodium iodide (1.182 g, 7.88 mmol), iodine (3.00 g, 11.83 mmol), and K2CO3 (1.634 g, 11.83 mmol) at room temperature. The reaction was warmed to 100° C. and stirred for 2 h. The reaction was quenched with 2.0 M aqueous sodium thiosulfite and concentrated under reduced pressure. The mixture was extracted with ethyl acetate and washed with NaHCO3 solution. The organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.35 g). LCMS m/z=317.02 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3H), 7.43-7.79 (m, 5H), 13.5 (s, 1H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[O:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=3)[CH:21]=2)[NH:16][N:15]=1.[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36].O>CN(C=O)C>[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:28]([C:26]1[O:27][C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[NH2:13])=[CH:24][CH:25]=1)=[O:30]
Reactant: Nc1n[nH]c2ccc(-c3ccc(C(=O)O)o3)cc12
Reactant: NCc1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1n[nH]c2ccc(-c3ccc(C(=O)NCc4cccc(O)c4)o3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
144 mg (0.75 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 146 mg (0.60 mmol) of 5-(3-amino-1H-indazol-5-yl)furan-2-carboxylic acid and 73.9 mg (0.60 mmol) of 3-hydroxybenzylamine in 1 ml of DMF, and the mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture, which is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated, and the residue is purified by preparative HPLC, giving N-3-hydroxybenzyl-5-(3-amino-1H-indazol-5-yl)furan-2-carboxamide (“62”) as yellowish solid, ESI 349.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[CH:28])[C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]>C(O)=O>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[CH:28])[C:19]([OH:21])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Solvent: O=CO
Product: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)O

Procedure:
The title compound was prepared by hydrolysis of the compound from Step A using formic acid as described in Example 43, Step D.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:23]C)=[C:5]([O:21]C)[CH:6]=[C:7]([CH:20]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:9])#[N:2].B(Br)(Br)Br.CO>C(Cl)Cl>[C:1]([C:3]1[C:4]([OH:23])=[C:5]([OH:21])[CH:6]=[C:7]([CH:20]=1)[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)=[O:9])#[N:2]
Reactant: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)cc(C#N)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc(C(=O)c2ccc(C(F)(F)F)cc2)cc(O)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.5 g 5-cyano-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone (dissolved in 75 ml of methylene chloride) are treated at 5° with 2.18 ml of boron tribromide, whereupon the mixture is stirred at room temperature for 18 hours. The reaction mixture is subsequently diluted with 50 ml of methylene chloride. The mixture is heated under reflux for an additional 4 hours, treated at -70° with 15 ml of methanol, stirred at room temperature for 2 hours, evaporated, the residue is dried in vacuo and partitioned between ethyl acetate and ice-water. The aqueous phase is extracted twice more with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate and evaporated. The thus-obtained material is stirred at 130° for 6 hours with 10 ml of acetic anhydride and 1 ml of pyridine. The mixture is evaporated and the residue is partitioned between ice-water and methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated, and the residue is chromatographed on 30 g of silica gel with methylene chloride. The thus-obtained diacetate is dissolved in 10 ml of methanol. The solution is treated with 4.2 ml of 1N sodium hydroxide solution, stirred at 0° for 1 hour, neutralized with acetic acid, evaporated and partitioned between ethyl acetate and saturated sodium chloride solution. The ethyl acetate phases are dried over sodium sulfate and evaporated, and the residue is recrystallized from methylene chloride. There is obtained 5-cyano-3,4-dihydroxy-4'-(trifluoromethyl)benzophenone of melting point 204°-206°.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:6]=[C:7]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=[CH:9][CH:10]=1)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[O:24]=[C:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[NH:23][CH:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[CH:4]=[O:3])[CH:12]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:13]([C:22]=23)=[N:14][NH:15]1
Reactant: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
A mixture of 8-(3-(diethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (90 mg, 0.21 mmol) in 3N hydrochloric acid (10 mL) was stirred at room temperature for 3 hr. Then the mixture was neutralized with potassium carbonate. The resulting suspension was filtered to give 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (40 mg, yield 50%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.24 (d, J=7.6 Hz, 1H), 4.77 (d, J=7.6 Hz, 1H), 4.85 (brs, 1H), 7.01-7.03 (m, 2H), 7.08-7.10 (m, 1H), 7.21-7.24 (m, 3H), 7.37-7.39 (m, 2H), 7.61-7.65 (m, 1H), 7.74-7.75 (m, 2H), 7.79-7.81 (m, 1H), 9.59 (brs, 1H), 9.92 (s, 1H). LC-MS (ESI) m/z: 368 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:5]2[NH:6][CH:7]=[CH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[N+:12]([C:8]1[C:9](=[O:10])[C:4]2[CH:3]=[C:2]([CH3:1])[S:11][C:5]=2[NH:6][CH:7]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2c(=O)cc[nH]c2s1
Solvent: CC(=O)O
Product: Cc1cc2c(=O)c([N+](=O)[O-])c[nH]c2s1
Reaction time: 0.17 h
Yield: 51 %

Procedure:
To a solution of 1.65 g of 2-methylthieno[2,3-b]pyridin-4(7H)-one 1 in 45 ml of acetic acid is added dropwise a solution of 1.24 g of concentrated nitric acid (d=1.38) in 5 ml of acetic acid at 110° C. The mixture is heated with stirring at the same temperature for 10 minutes and left on cooling. The resulting crystals are collected by filtration and washed with ethyl acetate to give 1.07 g (51%) of Compound 2 as pale yellow crystals melting at 280°-282° C. (dec.).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[F:5][CH:6]([F:14])[C:7]1[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=1.OP([O-])(O)=O.[Na+]>O1CCCC1>[F:5][CH:6]([F:14])[C:7]1[O:11][C:10]([CH:12]([OH:13])[C:1]#[CH:2])=[CH:9][CH:8]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1ccc(C(F)F)o1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(C(F)F)o1
Temperature: 0 °C

Procedure:
43 cm3 of a 0.5M solution of ethynyl magnesium bromide in tetrahydrofuran is added at 0° C. over one hour to a solution containing 2.5 g of the product prepared in Stage A and 30 cm3 of tetrahydrofuran. The reaction mixture is maintained under agitation at 0° C. for 1 hour. It is poured into a saturated aqueous solution of sodium acid phosphate. 3 g of product is obtained which is chromatographed on silica eluting with a hexane--ethyl acetate mixture (7-3). 2.5 g of desired product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1([Mg]Br)[CH2:12][CH2:11]1.O.C(OCC)(=O)C>C(OCC)C.O1CCCC1>[CH:10]1([CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:7])[CH2:12][CH2:11]1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Br[Mg]C1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.50 g (10.67 mmol) of 4-chlorobenzaldehyde were dissolved in 20 ml of diethyl ether at 0° C., and 32.0 ml (16.00 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, addition of water and ethyl acetate to the reaction solution, and separation of the phases. The organic phase was dried over sodium sulfate, the solid was filtered off, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 1.21 g (62% of theory) of the title compound.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.O[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[N:25][CH:26]=[N:27]2)=[CH:22][C:21]=1[O:30][CH3:31].C(P(CCCC)CCCC)CCC.O=S1(=O)CCNCC1>C(Cl)Cl.CCOCC>[CH3:31][O:30][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:20]=1)[N:27]=[CH:26][N:25]=[CH:24]2
Reactant: COc1cc2cncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: O=S1(=O)CCNCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2ncncc2c1
Reaction time: 18 h
Yield: 10.7 %

Procedure:
1,1′-(Azodicabonyl)dipiperidine (525 mg, 2.1 mmol) was added in portions to a mixture of 44-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0 mmol), (prepared as described for the starting material in Example 2), tributylphosphine (420 mg, 2.11 mmol) and 42-hydroxyethyl)-1,1-dioxothiomorpholine (140 mg, 7.8 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the resulting precipitate was removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride (14 ml of a 1M solution, 14 mmol) and the precipitate was collected by filtration. The residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product was triturated with ether/methylene chloride collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(241,1-dioxothiomorpholino)ethoxy)6-methoxyquinazoline (120 mg, 36%).
Reaction SMILES: C[O:2][C:3](=[O:15])[C@@H:4]([OH:14])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Li+]>>[CH2:7]([S:6][CH2:5][C@H:4]([OH:14])[C:3]([OH:15])=[O:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H](O)CSCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H](O)CSCc1ccccc1
Yield: 46 %

Procedure:
This reaction was performed as previously described by Deechongkit, S.; You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 497, using (R)-3-Benzylsulfanyl-2-hydroxy-propionic acid methyl ester 110b and lithium hydroxide. (R)-3-Benzylsulfanyl-2-hydroxy-propionic acid 110c (3.08 g, 14.51 mmol, 46%) was isolated as a viscous oil: MS calcd. for C10H12O3S (M+Na+) 235.1, found 235.3.
Reaction SMILES: [O:1]=[C:2]1[NH:12][C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]#[N:11])[C:4]=2[CH2:3]1.[ClH:13]>CCO.[Pd]>[ClH:13].[NH2:11][CH2:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:12][C:2](=[O:1])[CH2:3][C:4]=12
Reactant: N#Cc1ccnc2c1CC(=O)N2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccnc2c1CC(=O)N2

Procedure:
Hydrogenation of 2-Oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (100 mg) was done using Pd/C (20 mg), HCl (37%, 0.3 mL) in EtOH (3 mL) to give 4-aminomethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7](=[O:30])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:29])[C:16]([C:18]2[C:19]([C:24]([O:26]CC)=[O:25])=[N:20][O:21][C:22]=2[CH3:23])=[O:17])[N:13]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7](=[O:30])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:29])[C:16]([C:18]2[C:19]([C:24]([OH:26])=[O:25])=[N:20][O:21][C:22]=2[CH3:23])=[O:17])[N:13]=1
Reactant: CCOC(=O)c1noc(C)c1C(=O)N(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(C(=O)O)c1C(=O)N(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 2 h

Procedure:
Example: Ethyl 4-(((2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)methyl)(methyl)-carbamoyl)-5-methylisoxazole-3-carboxylate (105 mg) was dissolved in ethanol (5 ml) and 1 N sodium hydroxide (5.0 eq) was added and stirred for 2 hours. The reaction was acidified to pH=2 and concentrated. The precipitate was filtered, washed with water and dried to give 4-(((2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)methyl)(methyl)carbamoyl)-5-methylisoxazole-3-carboxylic acid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH2:5][C:4]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:3]1.[OH-:14].[Na+].Cl>>[C:4]1([CH2:3][C:2]([OH:1])=[O:14])([CH2:5][C:6]([NH2:7])=[O:8])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [OH-]
Reactant: O=C1CC2(CCCCC2)CC(=O)N1
Agent: Cl
Agent: [Na+]
Product: NC(=O)CC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
9 g of 2,4-dioxo-3-azaspiro[5,5]undecane and 30 g of 10% NaOH are placed in a 250 ml flask equipped with mechanical agitator, thermometer and condenser. The mixture is heated under reflux for 1 hour, cooled to 25° C. and acidified with 36% HCl to pH 5. The precipitate formed is filtered off, washed with water and dried under vacuum. 6.4 g of cyclohexanediacetic acid monoamide are obtained.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([CH2:8][C:9](OCC)=[O:10])[CH2:4][CH2:3]1.[BH4-].[Li+].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.CO.CS(C)=O.O>[Cl:17][C:18]1[C:19]([O:10][CH2:9][CH2:8][CH:5]2[CH2:6][CH2:7][C:2]([F:1])([F:14])[CH2:3][CH2:4]2)=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: CCOC(=O)CC1CCC(F)(F)CC1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCCC2CCC(F)(F)CC2)cc1F
Temperature: 0 °C
Yield: 26.3 %

Procedure:
To a of solution ethyl 2-(4,4-difluorocyclohexyl)acetate (1.44 g, 7.00 mmol) in anhydrous tetrahydrofuran (23 mL) and anhydrous methanol (0.6 mL) was added lithium borohydride (4 M in tetrahydrofuran, 3.5 mL, 16.00 mmol) at 0° C. and the mixture was heated to reflux for 2 hours. The mixture was then cooled to 0° C. and quenched with methanol until gas evolution ceased. The solution was warmed to ambient temperature then poured into water (50 mL). The aqueous layer was separated and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude alcohol (0.98 g), which was dissolved in anhydrous dimethylsulfoxide (6 mL), tert-butyl 5-chloro-2,4-difluorobenzoate (1.64 g, 6.60 mmol) and cesium carbonate (4.11 g, 12.6 mmol) was added. The reaction mixture was heated at 70° C. for 2 hours and then cooled to ambient temperature and diluted with water (60 mL) and extracted with ethyl acetate (4×20 mL). The combined organic layers were washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes) to afford the title compound (0.681 g, 29%): 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.7 Hz, 1H), 6.63 (d, J=12.1 Hz, 1H), 4.08 (t, J=6.6 Hz, 2H), 2.17-2.07 (m, 2H), 1.77-1.62 (m, 5H), 1.57 (s, 9H), 1.42-1.29 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH:3]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)[C:4]([NH2:6])=O.B>C1COCC1>[CH3:1][CH:2]([CH3:18])[CH:3]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)[CH2:4][NH2:6]
Reactant: CC(C)C(Nc1ccnc2ccccc12)C(N)=O
Agent: B
Solvent: C1CCOC1
Product: CC(C)C(CN)Nc1ccnc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Methyl-2-(4-quinolylamino)butanamide (460 mg, 1.9 mmol) was dissolved in anhydrous THF (30 ml) under argon, the mixture was cooled to 0° C. and a 1M solution of borane in anhydrous THF (8 ml, 8 mmol) was added with stirring. Stirring was continued for 1 hour at 0° C., the cooling bath was removed and the mixture was allowed to warm to room temperature overnight with stirring. The mixture was quenched with 1M NaOH and extracted with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (pre-packed silica column, gradient of ethyl acetate/methanol containing 1% ammonia). 220 mg was obtained (0.96 mmol, 51%). MS (APCI) m/z=229.8 [M+H]+.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N([O-])=O.[Na+].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>Cl.O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: c1ccncc1
Reactant: Nc1ccccc1CO
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: OCc1ccccc1-c1ccccn1

Procedure:
2-Aminobenzylalcohol (10 g) was dissolved in concentrated hydrochloric acid (25 ml) and the solution diluted with water (20 ml). The solution was stirred at 0° and a solution of sodium nitrite (5.9 g) in water (20 ml) added dropwise. The mixture was stirred at 0° for 40 minutes. The solution was added dropwise to pyridine (92 ml) stirred at 80°. After stirring at 80° for 90 minutes the mixture was concentrated in vacuo and the residue heated with 880 ammonia (100 ml). The mixture was concentrated in vacuo and the residue slurried with water and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried and evaporated. Flash chromatography produced the sub-title compound as a red oil (3.8 g). M.S. m/e 185 Base Peak 80.