Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:7]2[N:6]=1
Reactant: COC(=O)Cc1nn2ccccc2c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1nn2c(c1C(=O)OC)CCCC2
Yield: 90.9 %

Procedure:
Methyl 2-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (42.0 mg, 0.17 mmol), as prepared according to the procedure described in Stefan Löber, S.; Hübner, H.; Gmeiner B.; Biorg. Med. Chem. Lett. 12(17), 2377 (2002), was dissolved in MeOH (5 mL) and was hydrogenated on an H-Cube® hydrogenation apparatus with 10% Pd/C at 40° C. for 1 hour. The methanol solution was removed in vacuo to afford methyl 2-(2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylate (39 mg, 91%), which was used directly in the next step without further purification.
Reaction SMILES: CC1(C)C2C(=C[C:8]([C:12](=[O:14])C)=CC=2)C(=O)CC1.[CH3:17][C:18]1([CH3:32])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28](=[O:30])[CH3:29])[CH:26]=2)[C:21](=[O:31])[CH2:20][CH2:19]1.C(O)CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:29][C:28]1([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:31])[CH2:20][CH2:19][C:18]3([CH3:32])[CH3:17])[O:14][CH2:12][CH2:8][O:30]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2=O
Reactant: CC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Solvent: O
Product: CC1(C)CCC(=O)c2ccc(C3(C)OCCO3)cc21
Temperature: 25 °C

Procedure:
A solution of 1.80 g (8.34 mmol) of a 1:5 mixture of 3,4-dihydro-4,4-dimethyl-7-acetyl-naphthalen-1(2H)-one (Compound D14a); and 3,4-dihydro-4,4-dimethyl-6-acetyl-naphthalen-1(2H)-one (Compound D14b) in 50 mL benzene was combined with 517.7 mg (8.34 mmol) of ethylene glycol and 20.0 mg (0.11 mmol) of p-toluenesulfonic acid monohydrate. The resulting solution was heated to reflux for 18 h, cooled to room temperature, and concentrated under reduced pressure. The title compound was isolated by column chromatography (10% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:11]=[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[N:4]=1.[C:14]([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:23][C:24](O)=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:14]([O:18][C:19]([NH:21][C@H:22]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:23][C:24]([N:8]1[CH2:9][CH2:10][N:5]2[N:4]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:11]=[C:6]2[CH2:7]1)=[O:25])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1nc2n(n1)CCNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2nc(C(F)(F)F)nc2C1)Cc1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (28.8 mg, 0.15 mmol, from Step D) and (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 50.0 mg, 0.15 mmol) in DMF (3 mL) was added hydroxybenzotriazole (HOBT, 26.1 mg, 0.19 mmol) at 0° C. The reaction was stirred at 0° C. for 5 min, then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 37.0 mg, 0.19 mmol) was added. After removal of the ice-bath, the reaction was allowed to stir at ambient temperature for 16 h. After removal of the DMF by evaporation, the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Concentration followed by preparative TLC (10% methanol/dichloromethane) gave the title compound as a foamy solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:12]([NH:15][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[CH2:13][CH3:14]
Reactant: O=C1CCc2ccccc2C1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3,4-dihydro-1-H-naphthalen-2-one (5 g, 34 mmol) in 1,2-dichloroethane (250 mL), propyl amine (2.8 mL, 34 mmol) was added, followed by addition of sodium triacetoxyborohydride (22 g, 102 mmol). The reaction was stirred at ambient temperature under nitrogen for 24 hours, at which time it was concentrated in vacuo. The remaining solid was partitioned between 1 M sodium hydroxide and ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was acidified with 1 M HCl in ether and 6.3 g of propyl-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine was collected as a pale pink precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:14](=[O:17])(=[O:16])[NH2:15])=[C:6]([CH2:8][CH2:9][NH:10]C(=O)C)[CH:7]=1.[OH-].[K+].Cl>>[NH2:10][CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[S:14]([NH2:15])(=[O:17])=[O:16]
Reactant: CC(=O)NCCc1cc(Cl)ccc1S(N)(=O)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: NCCc1cc(Cl)ccc1S(N)(=O)=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
A mixture of N-[2-(5-chloro-2-sulfamoyl-phenyl)-ethyl]-acetamide (209 mg, 0.76 mmol) and potassium hydroxide aqueous solution (2 mol/L, 3 mL, 6 mmol) was stirred at 100° C. for 4 h. After cooling to room temperature, the reaction was neutralized with 2N of aqueous hydrochloric acid solution. The mixture was concentrated to dryness and the residue was diluted with solvent (3% MeOH in DCM, 200 mL) and stirred for 1 h. The mixture was filtered and the filtrate was concentrated to afford the title compound as a gray solid (150 mg, 0.64 mmol, 85% yield). MS (ESI) m/z 235.1, 237.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Product: COc1cccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(3-methoxy-phenyl)-acrylic acid.
Reaction SMILES: Br[CH:2]1[CH2:4][CH2:3]1.[CH3:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[BH4-].[Na+]>>[CH:2]1([CH:8]([C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH3:5])[NH2:9])[CH2:4][CH2:3]1
Reactant: Cc1ccccc1C#N
Reactant: BrC1CC1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ccccc1C(N)C1CC1
Yield: 108.5 %

Procedure:
The title compound was synthesized according to method G, utilizing Mg powder (240 mg, 10 mmol), bromocyclopropane (1.21 g, 10 mmol), 2-methylbenzonitrile (468 mg, 4 mmol), and NaBH4 (380 mg, 10 mmol). The reaction mixture was concentrated and purified by Biotage SiO2 column (gradient: MeOH/DCM 0-20%) to give cyclopropyl(o-tolyl)methanamine as a yellow oil (0.70 g, 87%) which solidified upon standing. 1H NMR (400 MHz, CD3OD) δ ppm 8.49 (d, J=7.6 Hz, 1H), 7.27-7.22 (m, 1H), 7.20-7.17 (m, 2H), 3.75 (d, J=8.4 Hz, 1H), 2.35 (s, 3H), 1.37-1.27 (m, 1H), 0.71-0.63 (m, 1H), 0.53-0.46 (m, 1H), 0.38-0.31 (m, 1H), 0.29-0.33 (m, 1H); MS ESI 145.0 [M+H]+, calcd for [C11H15N—NH2+H]+ 145.1.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[CH2:4][N:5]([C:10]1[C:15]([CH2:16]C)=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:18])[C:6](=[O:9])[CH2:7][Cl:8].CN(C)C(=O)CN(C1C(C)=CC=CC=1C)C(=O)CCl.CN(C)C(=O)CN(C1C(CC)=CC=CC=1C)C(=O)CCl.C(NC(=O)CN(C1C(C)=CC=CC=1C)C(=O)CCl)C.C(N)(=O)C.CN(C)C(=O)CN(C1C(C)=CC=CC=1Cl)C(=O)CCl.CNC(=O)CN(C1C(C)=CC=CC=1Cl)C(=O)CCl.CNC(=O)CN(C1C(CC)=CC=CC=1CC)C(=O)CCl>>[CH3:1][NH:2][C:3](=[O:19])[CH2:4][N:5]([C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:18])[C:6](=[O:9])[CH2:7][Cl:8]
Reactant: CCc1cccc(C)c1N(CC(=O)NC)C(=O)CCl
Agent: CC(N)=O
Agent: CCNC(=O)CN(C(=O)CCl)c1c(C)cccc1C
Agent: CCc1cccc(C)c1N(CC(=O)N(C)C)C(=O)CCl
Product: CNC(=O)CN(C(=O)CCl)c1c(C)cccc1C

Procedure:
N-methyl-[N'-(2-methyl-6-ethylphenyl)-N'-chloroacetyl-amino]-acetamide; N,N-dimethyl-[N'-(2,6-dimethylphenyl)-N'-chloroacetylamino]-acetamide; N,N-dimethyl-[N'-(2-methyl-6-ethylphenyl)-N'-chloroacetylamino]-acetamide; N-ethyl-[N'-(2,6-dimethylphenyl)-N'-chloroacetylamino]-acetamide; N-ethyl-N'-(2-methyl-6-ethylphenyl)-N'-chloroacetylamino]-acetamide; N,N-dimethyl-[N'-(2-chloro-6-methylphenyl)-N'-chloroacetyl-amino]-acetamide; N-methyl-[N'-(2-chloro-6-methylphenyl)-N'-chloroacetylamino]-acetamide; N-methyl[N'-(2,6-diethylphenyl)-N'-chloroacetylamino]-acetamide.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:8](I)([CH3:10])[CH3:9]>C(O)C>[CH:8]([S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)([CH3:10])[CH3:9]
Reactant: Sc1ccncc1
Reactant: CC(C)I
Solvent: CCO
Product: CC(C)Sc1ccncc1

Procedure:
A mixture of 4-mercaptopyridine (555 mg, 5 mmoles) and isopropyl iodide (0.50 ml) in ethanol (5 ml) was heated under reflux for 4 hours and then evaporated under reduced pressure. The residue was dissolved in a small amount of water, made alkaline with aqueous sodium hydroxide and extracted with ethyl acetate. The extract was washed with a small amount of water, dried and evaporated under reduced pressure to give the product as an oil. Yield, 670 mg (88%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([OH:21])=[O:20])[C:14]2=[CH:13][C:12]=1[CH3:22])=[O:10].ClC1C=CC=C(C(OO)=[O:31])C=1.CCCCCC>C(Cl)(Cl)Cl.CS(C)=O>[CH3:1][N:2]1[C:6]([S:7]([CH3:8])=[O:31])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([OH:21])=[O:20])[C:14]2=[CH:13][C:12]=1[CH3:22])=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)O)n1C
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CCCCCC
Product: Cc1cc2n(c1C(=O)c1ccc(S(C)=O)n1C)CCC2C(=O)O
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A solution of 0.2 g of 5-(1-methyl-5-methylthio-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylic acid in 20 ml chloroform and a few drops of dimethylsulfoxide was treated with 0.1 g of m-chloroperbenzoic acid (MCPBA) and stirred overnight. Hexane was then added carefully, and the mixture was cooled and the resulting yellow crystals was collected by filtration to give 195 mg of 5-(1-methyl-5-methylsulfinyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid. m/e 334.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([NH:11][C@@H:12]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)=[O:14])=[O:10])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[N:30]([C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1)=[C:31]=[S:32].CCN(C(C)C)C(C)C>C(#N)C>[I:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[C@@H:2]([NH:1][C:31]([NH:30][C:33]2[CH:34]=[CH:35][C:36]([S:39](=[O:41])(=[O:40])[NH2:42])=[CH:37][CH:38]=2)=[S:32])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)CC[C@H](NC(=O)[C@@H](N)CCC(=O)OC)C(=O)NCc1ccc(I)cc1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CC[C@H](NC(=O)[C@H](CCC(=O)OC)NC(=S)Nc1ccc(S(N)(=O)=O)cc1)C(=O)NCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (S)-methyl 4-(tert-butoxycarbonylamino)-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate (0.448 g, 0.723 mmol) in DCM (10 mL) and TFA (4.0 mL) was stirred at room temperature overnight. After the solvent was evaporated, the reaction mixture was diluted with DCM, washed with sat. K2CO3 and concentrated in vacuo to afford (S)-methyl 4-amino-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate. A solution of the above product ((S)-methyl 4-amino-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate), 4-isothiocyanatobenzenesulfonamide (0.171 g, 0.80 mmol) in acetonitrile (10 mL) containing DIPEA (0.40 mL) was stirred at room temperature under nitrogen for 48 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography 5% MeOH in DCM as eluent to give (S)-methyl 5-(4-iodobenzylamino)-4-((S)-5-methoxy-5-oxo-2-(3-(4-sulfamoylphenyl)thioureido)pentanamido)-5-oxopentanoate (0.469 g) as a white solid. MS (ESI), 756 (M+Na)+, 377 (M/2+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][C:12]3[C:20]4[C:19]([C:21]([O:23]C)=[O:22])=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][N:13]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.O.[OH-].[Li+:27]>O1CCCC1.O>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][CH2:11][C:12]3[C:20]4[C:19]([C:21]([O-:23])=[O:22])=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][N:13]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Li+:27]
Reactant: COC(=O)c1cccc2[nH]nc(CNCC34CCN(CC3)CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cccc2[nH]nc(CNCC34CCN(CC3)CC4)c12
Yield: 136.8 %

Procedure:
A mixture of methyl 3-((quinuclidin-4-ylmethylamino)methyl)-1H-indazole-4-carboxylate (2.9 g, 8.9 mmol) from Step A above and lithium hydroxide monohydrate (1.1 g, 26.7 mmol) in tetrahydrofuran/water (1:1, 30 mL) was stirred at reflux until the reaction was complete by LC-MS. The solvent was removed under reduced pressure to give lithium 3-((quinuclidin-4-ylmethylamino)methyl)-1H-indazole-4-carboxylate as a brown solid (3.9 g, quantitative yield): 1H NMR (500 MHz, CD3OD) δ 7.49 (d, J=8.5 Hz, 1H), 7.43 (d, J=7.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 4.17 (s, 2H), 2.82 (t, J=8.0 Hz, 6H), 2.26 (s, 2H), 1.42 (t, J=8.0 Hz, 6H); MS (ESI+) m/z 315 (M+H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]([O:7][C:8]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH:12](Br)[CH2:11]1)=[O:9])[CH3:6]>C(O)C>[CH2:5]([O:7][C:8]([CH:10]1[CH2:15][CH2:14][C:13]2[N:1]=[C:2]([NH2:4])[S:3][C:12]=2[CH2:11]1)=[O:9])[CH3:6]
Reactant: NC(N)=S
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Solvent: CCO
Product: CCOC(=O)C1CCc2nc(N)sc2C1
Temperature: 25 °C
Yield: 80 %

Procedure:
Thiourea (0.672 g, 8.835 mmol) was taken in ethanol (30 mL). To this stirred solution was added 3-Bromo-4-oxo-cyclohexane carboxylic acid ethyl ester (2.2 g, 8.835 mmol). The reaction was refluxed for 2 hrs. The reaction mixture was allowed to cool to room temperature and ethanol was evaporated under reduced pressure, the residue was partitioned between water and ethyl acetate. The water layer was collected and basified using sat. sodium bicarbonate solution, extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to afford 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester (1.6 g)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:34]([N:9]1[CH2:8][CH2:7][C:6]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (0.24 g, 0.576 mmol), triethylamine (0.32 ml) and catalytic amount of 4-Dimethylaminopyridine in 6.0 mL of CH2Cl2 was added a solution of acetyl chloride (0.068 ml, 0.864 mmol) in 1.0 mL of CH2Cl2. The reaction stirred at room temperature for 4 h and washed with H2O, brine, dried over MgSO4, filtered through a pad of silica gel and concentrated to provide 0.242 g (100%) of the desired product as a colorless gum. Electrospray Mass Spec: 422.2 (M+H)+
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].[F:25][C:26]1[CH:27]=[C:28]([C:40]#[N:41])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=2)=[CH:30][CH:31]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:38][C:35]3[CH:36]=[CH:37][C:32]([C:29]4[C:28]([C:40]#[N:41])=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)=[CH:33][CH:34]=3)[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Reactant: N#Cc1cc(F)ccc1-c1ccc(CO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccc(F)cc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4-fluoro-4′-(hydroxymethyl)biphenyl-2-carbonitrile (1.4 g), 1,1′-(azodicarbonyl)dipiperidine (2.2 g), tributylphosphine (2.2 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (2 g, 86%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:25]([O:24][C:22](=[O:23])[CH:15]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:26]
Reactant: CCOC(=O)C(OC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(OC1CCN(C)CC1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(Ethoxycarbonyl-phenyl-methoxy)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g) in dichloromethane (25 mL) is added trifluoroacetic acid (18 mL). After 30 minutes at room temperature, the volatiles are removed under reduced pressure. Water (30 mL) is added and the solution is basified by adding a solution of saturated sodium carbonate to pH 10. The aqueous phase is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure to give (1-methylpiperidin-4-yloxy)phenylacetic acid ethyl ester used without further purification.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:6]([CH3:9])=[N:7][CH:8]=1)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[C:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[CH2:11][O:10][C:5]1[C:4]([CH3:20])=[C:3]([CH2:1][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:8]=[N:7][C:6]=1[CH3:9])#[N:16]
Reactant: Cc1ncc(C=O)c(C)c1OCc1cccc(C#N)c1
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Product: Cc1ncc(CNc2ccc(-c3ccc(C#N)cc3)cc2)c(C)c1OCc1cccc(C#N)c1
Yield: 29.9 %

Procedure:
The reductive amination of 3-(5-formyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (27) (10.0 g, 37.6 mmol) and 4-amino-4′-cyanobiphenyl (8.8 g, 45.1 mmol), as described in Example 21, gave 4′-{[5-(3-cyano-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-biphenyl-4-carbonitrile (28) (5.0 g, 30% yield) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([CH2:23][F:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:24][CH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1
Reactant: FCc1cc(Cl)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FCc1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 65 mg, 0.211 mmol), 4-chloro-6-(fluoromethyl)pyrimidine (Intermediate 26, 40 mg, 0.232 mmol) and DIPEA (0.074 mL, 0.423 mmol) were added together in N-methyl-2-pyrrolidone (2 mL) and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was heated at 100° C. for 3 hours, allowed to cool to room temperature and diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (6 mg);
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]([C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][NH:15]1)=[O:13].[N:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[C:21]=[O:22].O>ClCCl>[CH3:10][O:11][C:12]([C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]1[C:21](=[O:22])[NH:20][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:25][CH:24]=1)=[O:13]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
Diisopropylethylamine (0.782 g, 5.5 mmol) was dropped into a suspension of compound (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester (1.0 g, 5.5 mmol) in anhydrous dichloromethane (50 mL), the mixture was stirred at room temperature for 10 minutes. 1-isocyanato-4-(trifluoromethoxy)benzene (1.116 g, 5.5 mmol) was added to the suspension and the mixture was continued to be stirred for 2 hours at room temperature. The mixture was poured into water (50 mL), the resulting mixture was filtrated. The liquid was extracted with dichloromethane (3×50 mL). The organic layers was combined, washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The residue combined with the filter cake yielded 1.86 g (97%) of the target compound. 1H NMR (300 MHz, CDCl3): δ 7.41 (d, 2H, J=9.0 Hz), 7.14 (d, 2H, J=8.7 Hz), 6.59 (s, 1H), 4.64 (t, 2H, J=7.5 Hz), 3.78-3.73, (m, 4H), 3.59 (d, 1H, J=9.9 Hz), 2.36-2.21 (m, 2H); LC-MS: 349.1 [M+1]+.