Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:37])[CH3:36])[CH2:30]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:29]3[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:37])[CH3:36])[CH2:30]3)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@H]1CCNC1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Product: CC(=O)N[C@H]1CCN(C2CCN(C(=O)c3c(C)nn(-c4cccc(C(F)(F)F)c4)c3C3CC3)CC2)C1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (S)—N-pyrrolidin-3-yl-acetamide in direct analogy to the general procedure used in example 129. MS: 504.3 (MH+).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([OH:17])[C:11]([O:13]C(C)C)=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO>[C:1]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([OH:17])[C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)OC(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Yield: 86.9 %

Procedure:
In 10 ml of methanol was dissolved 0.5 g of isopropyl (2S, 3S)-3-(N-Boc)amino-4-phenyl-2-hydroxybutyrate, followed by addition of 1.38 g of aqueous 3N sodium hydroxide solution, and the resulting mixture was washed at room temperature for 2 hours for the promotion of the hydrolysis reaction. After the termination of the reaction was confirmed, aqueous 1N hydrochloric acid solution was added to the resulting mixture to adjust the mixture to pH 3.0, followed by concentration under reduced pressure. The concentrate was diluted with ethyl acetate and water, followed by layer separation, and the resulting ethyl acetate layer was washed with saturated sodium chloride solution. Furthermore, the ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated, to obtain (2S, 3S)-3-(N-Boc)amino-4-phenyl-2-hydroxybutyric acid of 0.38 g in a yield of 86.9%. The NMR analysis is shown below.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH3:10])[C:8]([CH2:11][CH3:12])=[N:7][CH:6]=1.[CH3:13][N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[C:22](O)=[C:21]([CH3:27])[CH:20]=2)=[N:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:13][N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:20]=[C:21]([CH3:27])[C:22]([O:1][CH2:2][CH2:3][CH2:4][C:5]3[N:9]([CH3:10])[C:8]([CH2:11][CH3:12])=[N:7][CH:6]=3)=[C:23]([CH3:25])[CH:24]=2)=[N:15]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1O
Reactant: CCc1ncc(CCCO)n1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ncc(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)n1C
Temperature: 20 °C
Yield: 119.2 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-1-methyl-2-ethylimidazole (150 mg, 0.89 mmol), 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenol (200 mg, 0.98 mmol), and triphenylphosphine (257 mg, 0.98 mmol) was dissolved in 10 ml of THF under nitrogen at 0° C. To the above solution was added at 0° C. DEAD (170.5 mg, 0.98 mmol) and the mixture was stirred for 2 h allowing the mixture to warm to 20° C. The solvent was removed in vacuo, and the residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/1-3/1; methylene chloride/methanol 30/1-10/1) to afford 376 mg (quantitative) of 5-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1-methyl-2-ethyl-imidazole, as a white crystalline solid, m.p. 96°-98° C. (recrystallization from methylene chloride/hexane).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>>[I:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH:17]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(I)cc1
Product: O=C(C=Cc1ccccc1)c1ccc(I)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and p-iodoacetophenone, 1-(4-iodophenyl)-3-phenylprop-2-en-1-one was obtained as beige coloured solid.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[C:5]([S:14][C:15]#[N:16])=[CH:4][CH:3]=1.NC1C2C(=C([N+]([O-])=O)C=CC=2)C(SC#N)=CC=1>O>[C:12]([C:7]1[C:6]2[C:11](=[CH:2][CH:3]=[CH:4][C:5]=2[S:14][C:15]#[N:16])[CH:10]=[CH:9][CH:8]=1)#[N:13]
Reactant: N#CSc1ccc(N)c2cccc(C#N)c12
Agent: N#CSc1ccc(N)c2cccc([N+](=O)[O-])c12
Solvent: O
Product: N#CSc1cccc2cccc(C#N)c12

Procedure:
3.4 Parts of impure 1-amino-5-cyano-4-thiocyanatonaphthalene were then deaminated by the method described in Example 2 for deamination of 1-amino-5-nitro-4-thiocyanatonaphthalene. The crude product, after drowning out into water, was filtered off, washed well, dried and recrystallised from ethanol to yield 0.62 parts of pure 1-cyano-8-thiocyanatonaphthalene, m.pt 129.5°-130.5° C. The I.R. spectrum contained a band at 2220 cm-1 due to the cyano group and a band at 2160 cm-1 due to the thiocyanate group.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:16][C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[C:18]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH:17]=3)[N:11]=2)[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(C=O)cc(C)n1
Reactant: CN1CCN(Cc2ccc(N)c(C(N)=O)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc(CN4CCN(C)CC4)cc3c(=O)[nH]2)cc(C)n1
Temperature: 115 °C
Reaction time: 20 h

Procedure:
To a solution of 2,6-dimethylpyridine-4-carbaldehyde (0.14 g, 1.00 mmol) in N,N-dimethyl acetamide (8 mL) were added 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzamide (0.25 g, 1.00 mmol), sodium hydrogensulfite (0.18 g, 1.20 mmol), and p-toluenesulfonic acid (0.057 g, 0.30 mmol). The reaction mixture was stirred at 115° C. for 20 hours under nitrogen, then cooled to room temperature. Solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed with sat. NaHCO3, water, then brine, and dried over anhydrous sodium sulfate. Solvent was evaporated and the residue was purified by column chromatography (silica gel 230-400 mesh; 2-3% 7 M ammonia in methanol and dichloromethane as eluent) to give the title compound. Yield: 0.035 g (9.6%). MP 229-230° C. 1H NMR (400 MHz, CDCl3): δ 8.30 (br s, 1H), 7.88 (s, 2H), 7.84 (m, 2H), 3.66 (s, 2H), 2.72 (s, 6H), 2.50 (br s, 8H), 2.30 (s, 3H). MS (ES) m/z: 364.17 (M+1), 182.67 (100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc([C@H]2CC[C@H](O)CC2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1cccc(C2CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
The mixture of cis and trans 4-(3-cyanophenyl)-1-hydroxycyclohexane (1.8 g, 9 mmole) was dissolved in 100 ml methylene chloride and Dess-Martin reagent(4.2 g, 10 mmole) was added. The mixture was stirred at room temperature for five hours. The reaction solution was washed with water (3×100 mL) and dried over sodium sulfate. The product was purified by column chromatography using hexane/ethyl acetate (85/15) as the eluent to afford 4-(3-cyanophenyl)-cyclohexane-1-one (1,1 g, 63%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2)=[O:14])=O)(C)(C)C.[OH-].[Na+]>Cl.CO>[CH2:24]([C:9]1([C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)=[O:14])[CH2:10][CH2:11][CH2:12][NH:8]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1(Cc1ccccc1)C(=O)c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccc2[nH]ccc2c1)C1(Cc2ccccc2)CCCN1
Yield: 62.2 %

Procedure:
A solution of 2-benzyl-2-(1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.045 g, 0.111 mmol) in 1N HCl in MeOH (2.2 mL) was stirred for 14 hours at ambient temperature under nitrogen. Aqueous NaOH (4 N, 0.6 mL) was added and the reaction mixture was extracted into DCM. The combined extracts were washed with brine then dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by chromatography (silica, 0-10% of a 9:1 MeOH:NH4OH solution in DCM) gave (2-benzyl-pyrrolidin-2-yl)-(1H-indol-5-yl)-methanone (0.021 g, 0.069 mmol, 62%) as a colourless solid, MS=305 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[N:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:21]=[CH:20][C:5]4[N:6]5[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:7]5=[N:8][C:4]=4[CH:3]=3)[C:33](=[O:37])[CH:32]=2)=[N:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3cc(Br)ccc32)C1
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCn2c(nc3cc(-n4ccc(OCc5ccc(F)cn5)cc4=O)ccc32)C1
Yield: 49.2 %

Procedure:
tert-Butyl 8-bromo-3,4-dihydropyrazino[1,2-a]benzimidazole-2(1H)-carboxylate (150 mg, 0.426 mmol) and 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (103 mg, 0.468 mmol) were reacted according to Example 18 (step g) to provide the title compound (103 mg, 47%) as a white solid: ESI MS m/z 492 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([O:21][CH3:22])[CH:4]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:24][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([O:21][CH3:22])[CH:4]=1
Reactant: COC(=O)C(Oc1ccc(CO)cc1OC)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(Oc1ccc(CBr)cc1OC)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
To a cooled (0° C.) solution of 0.490 g (1.62 mmol) of the product of Step A dissolved in 8 mL of CH2Cl2 was added 0.673 g (2.03 mmol) of carbon tetrabromide and 0.531 g (2.03 mmol) of triphenylphosphine. The reaction mixture was stirred for 1.5 hours and was allowed to slowly warm to room temperature. The reaction mixture was then concentrated in vacuo, and purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.478 g (81%) of the title compound.
Reaction SMILES: C([CH:3]1[CH2:26][NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1)C.Cl[C:28]1N=C(N)C(N)=C[CH:29]=1>>[CH2:28]([CH:26]1[NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1)[CH3:29]
Reactant: CCC1CNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C1
Reactant: Nc1ccc(Cl)nc1N
Product: CCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1

Procedure:
The titled compound was prepared analogously to Intermediate D by replacing 5-chloropyridine-2,3-diamine with 6-chloropyridine-2,3-diamine;
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>C(Cl)(Cl)Cl.CS(C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH:33]([O:36][C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=2[F:16])[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(N)c2c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
To a mixture of 277 mg of ethyl 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 318 mg of 1-t-butoxycarbonyl-3-hydroxypyrrolidine, 194 mg of DBU and 3 ml of DMSO was added 74 mg of 55% sodium hydride while the former was stirred at room temperature. After the resultant mixture was stirred for 1 hour at room temperature, the reaction mixture was diluted with chloroform and then successively washed with 10% citric acid and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness. The residue was recrystallized from ethanol, whereby 120 mg of 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([O:16][CH3:17])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].ClC(OC)=O>C(Cl)Cl.CCOC(C)=O>[CH3:17][O:16][C:13]([CH3:15])([CH3:14])[C@H:9]([NH:8][C:6]([O:5][CH3:1])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: COC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)O)C(C)(C)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of Example 203B (163 mg, 0.66 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL) and the solution was stirred at room temperature for 1 h. Solvent was removed in vacuo and the residue was suspended in saturated NaHCO3, extracted with EtOAc, the organic extracts combined, washed with brine, dried (Na2SO4), filtered and solvent removed in vacuo. The residue was dissolved in dioxane (1 mL) and 1 M NaOH (1.1 mL, 2.175 mmol) was added followed by the dropwise addition of methyl chloroformate (0.102 mL, 1.3 mmol). The solution was stirred at room temperature for 16 h, diluted with EtOAc, washed with 1 N HCl, brine, dried (Na2SO4), filtered and solvent removed in vacuo to give the title compound (96 mg, 0.468 mmol, 71%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1.O.[OH-].[Na+]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 101.5 %

Procedure:
Methyl 4-(1H-benzimidazol-2-yl)benzoate (Step A) (2.63 g) is stirred in THF (50 mL) and water (10 mL) with sodium hydroxide (2.08 g) at reflux for 4 hours. The solvent is evaporated and the residue treated with 2N hydrochloric acid (100 mL). The resulting suspension is collected, washed with methanol/ethyl acetate and dried to give 2.52 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH:18]=3)[N:10]=[N:9]2)=[CH:4][CH:3]=1>Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccc(F)cc3)nn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2cc(C3=CCNCC3)nn2)cc1

Procedure:
tert-Butyl 4-[1-(4-fluorophenyl)-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (50 mg) prepared in Example 13 was dissolved in 4.0 ml of 4N-hydrochloric acid/ethyl acetate, the mixture was stirred for one night and, after evaporation of the solvent in vacuo, a saturate sodium hydrogen carbonate and chloroform were added. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound as a mixture.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Br:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:14]([C:12]1[S:13][C:9]([Br:8])=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: OCCNCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)s1)N(CCO)CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
To a stirred solution of diethanolamine (1.45 g, 13.8 mmol) in THF (20 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) and triethylamine (0.71 ml, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (0.98 g, 77%) as a white solid. MS (ISP) 330.0 [(M+H)+], mp 70° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:3]=[N:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(=O)c1ncc(F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ncc(Oc2ccc(F)cc2)cn1
Temperature: 50 °C
Yield: 25.4 %

Procedure:
A solution of 1-(5-fluoropyrimidin-2-yl)ethanone (700 mg, 5.0 mmol) and 4-fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was treated with potassium carbonate (829 mg 6.0 mmol) and heated to 50° C. for 3.5 h. The reaction mixture was poured into 20 mL water, and extracted with EtOAc (2×20 mL). Organics were washed with 20 mL each water, brine, and dried over Na2SO4. Mixture was filtered and concentrated on silica gel. Column chromatography (10-100% EtOAc/hept) gave 295 mg (25%) 1-(5-(4-fluorophenoxy)pyrimidin-2-yl)ethanone as a white solid used directly in the following step. MS m/z 233.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 2H), 7.23-7.07 (m, 4H), 2.78 (s, 3H).
Reaction SMILES: [ClH:1].C1C=C[C:5]2N(O)N=[N:8][C:6]=2C=1.CCN(C(C)C)C(C)C.[N:21]1[CH:26]=C[C:24]([N:27]2[CH2:32]CC3(CCNCC3)C[CH2:28]2)=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:5][CH2:6][N:8]=[C:26]=[N:21][CH2:22][CH2:23][CH2:24][N:27]([CH3:28])[CH3:32].[ClH:1]
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN=C=NCCCN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HCl (503 mg, 2.62 mmol), HOBT (177 mg, 1.311 mmol) and DIPEA (0.6 ml) were added to a solution of the product just obtained in step 5 (400 mg, 1.3114 mmol) in methylene chloride (10 ml). The reaction mixture was stirred at 25° C. for 30 min and then cooled to 0° C. and 3-pyridin-4-yl-3,9-diaza-spiro[5.5]undecane (364 mg, 1.57 mmol) was added. The reaction mixture was stirred at 25° C. for 12 h, subsequently diluted with methylene chloride and washed with sat. NH4Cl solution and with NaHCO3 solution. The organic phase was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:7]=[N:8][S:9][C:10]=1[C:11]([OH:13])=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:11]([C:10]1[S:9][N:8]=[N:7][C:6]=1[CH3:5])(=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccccc1
Reactant: Cc1nnsc1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: Cc1nnsc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To 2.0 g (15 mimol) of thionyl chloride was added 0.50 g (3.5 mmol) of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid. After heating the mixture with stirring for 2 hours, the thionyl chloride was distilled off under reduced pressure, and the residue was added to a solution of 1.8 g (15 mmol) of aluminum chloride in 20 ml benzene and made to react with heating for 3 hours. After the reaction was completed, the reaction mixture was poured into ice water, the objective product was extracted with ethyl acetate, the organic layer was ashed with a saturated aqueous solution of sodium chloride and dried, the solvent was distilled off under educed pressure, and the residue was purified by silica gel column chromatography using 4:1 mixture of n-hexane and ethyl acetate. Thus, 0.69 g of the objective compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][NH:20][C:21]([C@@H:23]3[CH2:26][CH2:25][N:24]3C(OC(C)(C)C)=O)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>ClCCl>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][NH:20][C:21]([C@@H:23]3[CH2:26][CH2:25][NH:24]3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2cc(CNC(=O)[C@@H]3CCN3)ccc12
Yield: 121.7 %

Procedure:
10 mL Trifluoroacetic acid was added to a solution of 2,4 g of N-(1-amino-isoquinolin-6-ylmethyl)-1-tert.butoxycarbonyl-azetidin-2(S)-carboxamide in 5.0 mL dichloromethane. The solvent was removed i.vac to give 2.1 g of the title compound as trifluoroacetate salt. MS: 371.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:21]2)[C:9](=[O:34])[CH:8]=1)(=O)=O.[CH3:37][N:38](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:37]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:24][CH2:25]2)[C:9](=[O:34])[CH:8]=1)#[N:38]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cc(OS(=O)(=O)C(F)(F)F)c3ccc(F)cc32)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cc(C#N)c3ccc(F)cc32)CC1
Temperature: 90 °C
Yield: 46 %

Procedure:
To a solution of 1-{2-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]ethyl}-7-fluoro-2-oxo-1,2-dihydro-4-quinolinyl trifluoromethanesulfonate (0.17 g, 0.32 mmol) in DMF (10 ml) was added zinc cyanide (0.036 g, 0.3 mmol), tris(dibenzylideneacetone)dipalladium (0.022 g, 0.024 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (0.056 g, 0.1 mmol) and degassed with argon. The mixture was heated at 90° C. for 18 h. The solution was allowed to cool then separated between ethyl acetate and brine. The organics were dried and concentrated then the residues combined with the crude from a similar experiment conducted on half the scale. Chromatography of the combined material over silica (10 g SPE gradient elution with ethyl acetate/methanol 0-3%) provided a brown oil which solidified as the title compound (0.113 g, 46%).