Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1([C:18]([F:21])([F:20])[F:19])[O:7][C:6]([CH2:9][CH2:10][C:11]#[N:12])([F:8])[C:5]([CH2:14][CH2:15][C:16]#[N:17])([F:13])[O:4]1.N.[H][H]>[Co].[Cr].[Co].O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1([C:18]([F:19])([F:20])[F:21])[O:4][C:5]([CH2:14][CH2:15][CH2:16][NH2:17])([F:13])[C:6]([CH2:9][CH2:10][CH2:11][NH2:12])([F:8])[O:7]1
Reactant: [H][H]
Reactant: N#CCCC1(F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)CCC#N
Agent: [Co]
Agent: [Cr]
Agent: N
Solvent: C1CCOC1
Product: NCCCC1(F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)CCCN
Temperature: 110 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
In a 1400 ml Hastelloy-C Shaker tube was charged the 2,2-bis(trifluoromethyl)-4,5-di(2-cyanoethyl)-4,5-difluoro-1,3-dioxolane of Example 43 (56.3 g, 0.16 mole), tetrahydrofuran (320 ml) and Raney-Cobalt catalyst (14.4 g). The tube was sealed and cool-evacuated. Ammonia (64 g, 3.765 mole) was transferred into the tube and the tube was pressurized with hydrogen gas to 500 psi. The tube was then heated to 110° C. and the hydrogen pressure was adjusted to 1500 psi. The heating was continued for 18 hrs at this temperature. After the tube was cooled, the product mixture was filtered to remove the catalyst, and solvent was removed in vacuo. The residue was d.:stilled to give the desired product 46 g (80% yield) as a clear, colorless, viscous liquid, Bp. 80° C./0.06 mmHg. H-1 NMR (CDCl3): 3.02 (m, 4H), 2.30 (m, 4H), 1.97 (m, 4H), 1.50 (s, br, --NH2); F-19 NMR (CDCl3): -80.5 (m, 6F), [-108.8 (m, br, trans), -110.6 (m, br cis) (2F total)].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:20]3[CH:19]=2)=[CH:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>[Pd].CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:20]3[CH:19]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: COc1cnc2[nH]c(C(=CC3CCCO3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc2[nH]c(C(CC3CCCO3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 19 %

Procedure:
A mixture of 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (315 mg, 0.79 mmol) and 10% palladium on activated carbon (100 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-ethyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (60 mg, 18.9%) as a light yellow solid: LC/MS m/e calcd for C21H24N2O4S [M+H]+ 401.5, observed 401.3.
Reaction SMILES: O.NN.[C:4]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][O:29][N:30]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:23][CH2:22]1)(=[O:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)C>[NH2:30][O:29][CH2:28][CH2:27][CH:24]1[CH2:25][CH2:26][N:21]([C:4](=[O:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1
Reactant: CCCCCCCCCCCCCCCC(=O)N1CCC(CCON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)N1CCC(CCON)CC1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
Hydrazine hydrate (0.14 ml, 2.96 mmol) was added to a solution of 2-[2-(1-(hexadecanoyl)piperidin-4-yl)ethoxy]isoindole-1,3-dione (1.52 g, 2.96 mmol) in ethanol (30 ml). The reaction mixture was heated to reflux for 75 min and cooled to room temperature. The formed precipitation was removed by filtration. The solvent of the filtrate was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g), using a mixture of dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 800 mg of 1-[4-(2-(aminooxy)ethyl)piperidin-1-yl]hexadecan-1-one.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:26].[Li]CCCC.[O:32]=[C:33]1[CH2:36][CH:35]([C:37]2[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:34]1.CC(=O)OCC>C1COCC1>[Cl:26][C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)[CH:24]=[CH:25][C:2]=1[C:33]1([OH:32])[CH2:34][CH:35]([C:37]2[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:36]1
Reactant: Clc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Reactant: COC(=O)c1cccc(C2CC(=O)C2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C2CC(O)(c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3Cl)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a stirring solution of compound 1a (1.67 g, 3.5 mmol) in dry THF (30 mL) was added n-BuLi (2.5 M in hexane, 1.2 eq, 1.69 mL) dropwise over 10 min at −78° C. under a nitrogen atmosphere. This was stirred for 1 h at this temperature before adding a solution of compound 1c (0.72 g, 1 eq) in dry THF (10 mL) dropwise and stirred for 1 h at this temperature. The reaction mixture was allowed to warm to rt slowly and left stirring overnight. The reaction was quenched with a solution of saturated ammonium chloride solution (50 mL) and EA (250 mL). The organic layer was separated and the aq. layer was washed with EA (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the crude product as a brown oil. The product was isolated following CC with PE/EA (19:1 to 3:1). The reaction and purification was repeated twice on the same scale and the combined product (3.13 g) was repurified under the same conditions to afford the final product 1 (1.7 g, 19%). 1H NMR (CDCl3): 7.93 (m, 1H), 7.90-7.85 (m, 1H), 7.50-7.30 (m, 5H), 6.88 (s, 1H), 6.75-6.72 (m, 1H), 4.80 (s, 2H), 3.88 (s, 3H), 3.20-3.10 (m, 1H), 3.00-2.91 (m, 2H), 2.60-2.49 (m, 2H), 2.15-2.08 (m, 1H), 1.30-1.25 (m, 2H), 1.15-1.10 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][Si](C(C)C)(C(C)C)C(C)C)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1coc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1coc2cc(O)ccc12
Reaction time: 0.5 h

Procedure:
17.9 g (51.4 mMol) 6-Triisopropylsilanyloxy-benzofuran-3-carboxylic acid methyl ester are dissolved in 200 ml DMF. Then 34 g (108 mMol) tetrabutylammoniumfluorid trihydrate are added. After 30 min, the mixture is poured into 400 ml EtOAc and 600 ml water, the aq. phase is separated off and extracted 3 times with EtOAc. The organic layers are washed 4 times with water, brine and dried (Na2SO4). Then char coal is added and the mixture filtered. Partial concentration of the filtrate gives the crystalline title compound, which is filtered off and washed with ether and hexane: m.p.: 200-201° C. More product can be isolated from the filtrate by addition of 280 g SiO2, concentration, application to a chromatography column (SiO2; hexane/EtOAc 3: 1) and eluation with hexane/EtOAc 3:1.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([O:21][C:20]([F:19])([F:29])[F:30])[CH:23]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OC(F)(F)F)c1
Yield: 60.3 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 270 mg of 3-(trifluoromethoxy)aniline in place of the 2,4-difluoroaniline. 230 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[3-(trifluoromethoxy)phenyl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:28](=[O:29])[N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: Cc1cccc(N(C(=O)Cl)c2ccccc2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N(C(=O)N2CCN(C(=O)OCc3ccccc3)C[C@H]2C(=O)O)c2ccccc2)c1
Yield: 116.2 %

Procedure:
A mixture of 264 mg (1 mmole) of (S)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid, 265 mg (1.1 mmole) of N-(3-methylphenyl)-N phenylcarbamoyl chloride. 390 mm (3 mmole) of DIEA in 5 mL of DMF was stirred for 16 hr at room temperature. The solution was concentrated in vacuo and the residure was taken up in 50 mL of CH2CL2 and washed with 2×25 mL of 1N HCl. Concentration in vacuo gave 0.55 g of an oil, which was carried on in Step C.
Reaction SMILES: C(O)C.C([O:11][C:12]1[CH:37]=[CH:36][C:15]([CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[O:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]1[O:29][C:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:21][CH2:22][CH:17]([CH2:16][C:15]3[CH:36]=[CH:37][C:12]([OH:11])=[CH:13][CH:14]=3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1
Reactant: C(=C1CCN(c2ccc(OC3CCCCO3)cc2)CC1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc(CC2CCN(c3ccc(OC4CCCCO4)cc3)CC2)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Ethanol (20 ml) and ethyl acetate (10 ml) were added to 4-[4-(benzyloxy)benzylidene]-1-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]piperidine prepared in Reference Example 366. A palladium on carbon (0.378 g) was added to the mixture, and stirred at 50° C. for 4 hours under a hydrogen atmosphere. The insoluble matter was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1→4:1) to afford the title compound as a colorless amorphous compound (1.10 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH: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)[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[OH:3][CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(O)c1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
1,1-Dimethylethyl 4-[(2-acetyl-4-pyridinyl)oxy]-1-piperidinecarboxylate (1.62 g, 5.06 mmol) was dissolved in 50.0 mL of anhydrous DCM and the solution cooled to −78° C. Diisobutylaluminumhydride (15.2 ml, 15.2 mmol, 1.0M solution in hexanes) was added dropwise over 15 min and the reaction continued to be stirred at −78° C. for 1.5 h. The reaction was quenched with 50 mL of saturated sodium potassium tartrate solution, warmed to rt and stirred overnight. The organics were separated, washed with brine and dried over MgSO4. The crude was purified via silica gel chromatography to give 0.962 g (59% yield) of the title compound, 1H NMR (300 MHz, Chloroform-d) δ 8.40 (d, J=5.8 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.77 (dd, J=5.8, 2.4 Hz, 1H), 4.82-4.97 (m, J=6.5, 6.5 Hz, 1H), 4.51-4.74 (m, 1H), 3.62-3.83 (m, 2H), 3.29-3.53 (m, 2H), 1.90-2.08 (m, 2H), 1.66-1.90 (m, 2H), 1.55 (d, J=6.5 Hz, 3H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][NH2:12])=[C:4]([F:10])[S:5][C:6]=1[CH2:7][C:8]#[CH:9].CC[O:15][C:16]([CH:18]1[C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]1)=O.C(O)(=O)C>O>[Cl:1][C:2]1[C:3]([N:11]2[C:16](=[O:15])[CH:18]3[C:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)=[N:12]2)=[C:4]([F:10])[S:5][C:6]=1[CH2:7][C:8]#[CH:9]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: C#CCc1sc(F)c(NN)c1Cl
Solvent: CC(=O)O
Solvent: O
Product: C#CCc1sc(F)c(N2N=C3CCCCC3C2=O)c1Cl
Yield: 56.1 %

Procedure:
A mixture of 4-chloro-2-fluoro-5-propargylthiophenylhydrazine (1.2 g), ethyl 2-cyclohexanonecarboxylate (0.85 g) and acetic acid (10 ml) was heated under reflux for 2 hours, followed by cooling. Water was added thereto, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and a saturated sodium hydrogen carbonate solution, dried and concentrated. The residue was crystallized from a mixture of n-hexane and ether to give 0.87 g of 2-(4-chloro-2-fluoro-5-propargylthiophenyl)-3,3a,4,5,6,7-hexahydro-2H-indazol-3-one. M.P., 170°-171° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.B([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:35]([OH:37])=[O:36])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:14][C:10]3[CH:9]=[CH:8][C:7]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=4[O:41][CH3:42])[C:35]([OH:37])=[O:36])=[CH:26][C:11]=3[C:12]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:16][CH:17]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3OC)cc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a 150 mL sealed tube was added 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (1.252 g, 3 mmol), 3-borono-4-methoxybenzoic acid (0.882 g, 4.50 mmol), cesium carbonate (1.466 g, 4.50 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.069 g, 0.060 mmol), dioxane (18 mL) and water (3.60 mL). The vial was sealed and heated in an oil bath over night at 85° C. The reaction mixture was then filtered through celite and concentrated in vacuo. Cold 0.5N HCl was then added and the heterogeneous mixture was stirred for 30 minutes. The resulting product, a white solid was filtered, washed with water and dried overnight to give a quantitative yield of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxy benzoic acid which was carried on without further purification. LCMS m/z 420.88 (M+H), Rt 2.002 min., 88% purity.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](F)=[CH:5][N:4]=1)#[N:2].[CH3:10][O-:11].[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:11][CH3:10])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ccc(F)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C#N)nc1
Yield: 42.8 %

Procedure:
A solution of 2-cyano-5-fluoropyridine (0.65 g, 5.3 mmol) in sodium methoxide (1.83 mL of 25% wt. solution in methanol, 7.95 mmol) was stirred at 0° C. for 1.5 hours and 2 hours at ambient temperature. The reaction was then diluted with ethyl acetate and washed with water and brine. Removal of the solvent in vacuo afforded 304 mg (43%) of 2-cyano-5-methoxypyridine.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:4]2[C:9]([C:10]=1[CH2:11]O)=[CH:8][CH:7]=[CH:6][CH:5]=2.S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl>[Cl:25][CH2:11][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=2)(=[O:14])=[O:15])[C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)n2c(C)c(CO)c3ccccc32)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2c(C)c(CCl)c3ccccc32)cc1
Reaction time: 0.17 h
Yield: 103.6 %

Procedure:
To a stirred solution of (2-methyl-1-tosyl-1H-indol-3-yl)methanol (500 mg, 1.59 mmol) in chloroform (20 mL), thionyl chloride (0.23 mL, 3.18 mmol) was added dropwise at 0° C. and stirred for 10 min. Then the mixture was heated under reflux for 3.5 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in diethyl ether and evaporated to dryness under reduced pressure to yield the title compound (550 mg, quant.). The compound was directly used for the next step without further purification. [TLC Rf=0.58 (ethyl acetate/hexane 20:80)].
Reaction SMILES: [CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19]
Reactant: Cn1nc(-c2ccc(N)cc2)c2ccccc2c1=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nc(-c2ccc(NS(C)(=O)=O)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.3 %

Procedure:
To a mixture of 2-methyl-4-(4-aminophenyl)-1-(2H)-phthalazinone (8.77 g, 34.9 mmol), CH2Cl2 (300 mL) and pyridine (3.11 mL, 38.4 mmol) at 0° C. was added dropwise methanesulfonyl chloride (2.97 mL, 38.4 mmol) in CH2Cl2 (20 mL) over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 12 hours. Additional pyridine (0.5 mL) and methanesulfonyl chloride (0.5 mL) was added and the mixture was stirred as such for 2 hours. The reaction mixture was poured into 2N HCl, the organic layer was separated and then washed with water and dried over Na2SO4. The solvent was removed in vacuo and the residue was azeotroped with toluene and CH2Cl2 to afford 9.0 g (78%) of 2-methyl-4-(4-methylsulfonylaminophenyl)-1-(2H)-phthalazinone as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([NH2:15])[NH:5][N:4]=1)[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH2:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]2[NH:15][C:25](=[O:26])[CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c(N)c1-c1ccc(C)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CCc1nn2c(-c3ccc(F)cc3)cc(=O)[nH]c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
3-Ethyl-4-(4-methylphenyl)-1H-pyrazol-5-amine (200 mg) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (250 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 280 mg of the target compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([CH:14]3[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1.CCN(C(C)C)C(C)C>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([CH:14]2[CH2:15][CH2:16][C:17]([CH3:20])([CH3:21])[CH2:18][CH2:19]2)[N:13]=1
Reactant: CC1(C)CCC(n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CCC(n2nc(-c3cc(CNC(=O)C(C)(C)C)ccc3Cl)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
To a solution of 5-(5-(aminomethyl)-2-chlorophenyl)-2-(4,4-dimethylcyclohexyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-73, 0.070 g, 0.202 mmol) in dry THF (5.0 mL), DIPEA (2.0 mL) and pivaloyl chloride (0.30 g, 0.242 mmol) were added and the reaction mass was stirred at RT for 16 h. After completion of the reaction, the reaction mass was quenched with water and extracted with 10%.MeOH:DCM. The organic layer was washed with dilute HCl and concentrated. The obtained crude was purified with column chromatography on basic alumina by eluting with 2.0% MeOH:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.44 (s, 6H), 1.47 (s, 9H), 1.81-1.94 (m, 8H), 3.86-3.90 (m, 1H), 4.40 (s, 2H), 7.33 (d, J=1.5 Hz, 1H), 7.45 (s, 7.50 (d, J=2.1 Hz, 1H), 8.16 (t, 1H), 11.93 (s, 1H); MS (m/z): 419.21 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]#[N:21])[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl>C(O)C.[Pt]=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:15][CH2:16]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: N#CCCCN1CCC(c2c[nH]c3cc(F)ccc23)CC1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: NCCCCN1CCC(c2c[nH]c3cc(F)ccc23)CC1
Yield: 101.5 %

Procedure:
To a solution of 6-fluoro-3-(1-(3-cyanopropyl)-4-piperidyl)indole (453 mg, 1.6 mmol) in ethanol (30 mL) was added platinum oxide (110 mg) and a concentrated hydrochloric acid (0.8 mL), and the resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. After filtrating the reaction mixture through Celite, the filtrate was concentrated, and a saturated aqueous sodium hydrogencarbonate was added to pH of 10, and the resulting mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated to afford 6-fluoro-3-(1-(4-aminobutyl)-4-piperidyl)indole (470 mg, yield: 100%) as a pale yellow solid. To a solution of this amine (68 mg, 0.23 mmol) in DMF (0.22 mL) was added lH-pyrazole-1-carboxamidine hydrochloride (35 mg, 0.23 mmol) and diisobutylethylamine (31 mg, 0.23 mmol), and the mixture was stirred at room temperature overnight. After washing with diethyl ether, the reaction mixture was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=4:1) to afford a free form (61 mg, yield: 77%) of the title compound as a yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form (61 mg) in methanol was concentrated and was then freeze-dried to afford the title compound (53 mg) as a white amorphous solid.