Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]=[N:4][S:5]([C:8]1[N:9]([CH3:18])[N:10]=[C:11]2[C:16]=1[C:15]([OH:17])=[CH:14][CH:13]=[CH:12]2)(=[O:7])=[O:6].[H-].[Na+].Br[CH2:23][CH2:24][F:25]>CN(C=O)C>[CH3:1][N:2]([CH3:19])[CH:3]=[N:4][S:5]([C:8]1[N:9]([CH3:18])[N:10]=[C:11]2[C:16]=1[C:15]([O:17][CH2:23][CH2:24][F:25])=[CH:14][CH:13]=[CH:12]2)(=[O:6])=[O:7]
Reactant: FCCBr
Reactant: CN(C)C=NS(=O)(=O)c1c2c(O)cccc2nn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C=NS(=O)(=O)c1c2c(OCCF)cccc2nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
4.2 g (15 mmol) of N1,N1 -dimethyl-N2 -[(4-hydroxy-2-methyl-2H-indazol-3-yl)sulfonyl]formamidine was added to a suspension containing 0.6 g (15 mmol) of 60% sodium hydride in 50 ml of DMF, and the mixture was stirred at room temperature for one hour. Further, 2 g (16 mmol) of 1-bromo-2-fluoroethane was added thereto, and the mixture was stirred at room temperature for 12 hours. The mixture was poured into ice water, and the formed crystals were collected by filtration and washed with water and IPE to obtain the desired product. This product was used for the subsequent reaction without purification. Obtained amount: 3.4 g (yield: 69.5%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][C:27]([F:32])([CH2:30][NH2:31])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH2:28][C:27]([F:32])([F:26])[CH2:30][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCC(F)(F)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(F)(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 447, 1H NMR (400 MHz, CD3OD) δ ppm 8.09-8.07 (d, 1 H), 7.95 (s, 1 H), 7.86-7.84 (d, 1 H), 7.77-7.69 (m, 2 H), 7.64-7.58 (m, 2 H), 6.26 (s, 1 H), 5.34 (s, 2 H), 4.53 (s, 2 H), 4.23 (t, 2 H), 3.74-3.66 (m, 4 H), 2.48 (s, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCOCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCc1cn(S(=O)(=O)c2cccc([N+](=O)[O-])c2)c2ccccc12
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cccc(S(=O)(=O)n2cc(CCCC(=O)O)c3ccccc32)c1
Reaction time: 8 h
Yield: 14.1 %

Procedure:
To a solution of 4-[1-(3-nitrobenzenesulfonyl)indol-3-yl]butyric acid (1.0 g) in 1,4-dioxane (15 ml) and methanol (15 ml) was added 10% palladium on carbon (0.93 g). The mixture was hydrogenolized for 8 hours at room temperature. The catalyst was filtered off and the solvent was removed in vacuo. The residue was purified by a column of silica gel to give a yellow solid of 4-[1-(3-aminobenzenesulfonyl)indol-3-yl]butyric acid (0.13 g).
Reaction SMILES: [O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[C:16]([C:17](O)=[O:18])[C:9]=12)[CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C@H:3]([N:6]1[C:17](=[O:18])[C:16]2=[CH:15][NH:14][C:10]3[C:9]2=[C:8]([CH:13]=[CH:12][N:11]=3)[CH2:7]1)[CH2:4][CH3:5]
Reactant: CC[C@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@H](C(=O)N1CCCC1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 19.7 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (S)-4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (8.7 mg, 0.026 mmol). N,N-dimethylformamide (2 mL), HATU (12.02 mg, 0.032 mmol) and 4-methylmorpholine (3.20 mg, 0.022 mmol) were added and the solution was allowed to stir at room temperature for 1 h. The solvent was removed and the resulting residue was further purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow solid (1.6 mg, 19.5%). 1H NMR (500 MHz, CD3OD) δ 0.88-1.04 (m, 3 H) 1.75-1.98 (m, 4 H) 1.98-2.05 (m, 2 H) 3.43-3.50 (m, 3 H) 3.50-3.57 (m, 1 H) 5.07 (s, 2H) 5.62 (dd, J=8.79, 6.83 Hz, 1 H) 7.13 (d, J=4.88 Hz, 1 H) 7.81 (s, 1 H) 8.28 (d, J=5.37 Hz, 1 H). [M+H] calc'd for C17H20N4O2, 313; found, 313.6.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]3[CH:12]=[C:11]([C:13]([OH:15])=O)[O:10][C:8]3=[CH:9][C:4]=2[NH:3][C:2]1=[O:16].C(N(CC)CC)C.[CH2:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:13]([C:11]2[O:10][C:8]3[C:7](=[CH:6][C:5]4[O:1][C:2](=[O:16])[NH:3][C:4]=4[CH:9]=3)[CH:12]=2)=[O:15])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1cc2cc3oc(=O)[nH]c3cc2o1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc2cc3oc(=O)[nH]c3cc2o1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.5 %

Procedure:
A mixture of 0.42 g (1.9 mmol) of 3H-furo[2,3-f]benzoxazole-2-one-6-carboxylic acid, 0.3 ml (2.1 mmol) of triethylamine, 0.35 ml (2.0 mmol) of 4-benzylpiperidine, 0.76 g (2.0 mmol) of HBTU (Advanced Chem. Tech.) and 10 ml of dimethylformamide is stirred at room temperature for 6 h. The reaction mixture is concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:aceton=2:1 as eluent, then the product is crystallized with diethylether to yield 0.39 g (54%) of the title compound. Mp.: 205-210° C. (diethyl ether).
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+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([Cl:28])[C:26]=1[F:27])[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:24]=[C:25]([Cl:28])[C:26]=1[F:27]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cc(Cl)c(F)c(Cl)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(Cl)c(F)c(Cl)c1
Yield: 64.9 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 360 mg of 3,5-dichloro-4-fluoroaniline in place of the 2,4-difluoroaniline. 259 mg of N-(3,5-dichloro-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH3:17])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:6]=1[F:13].[H][H]>C(OCC)(=O)C.[C].[Pd]>[OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:6]=1[F:13]
Reactant: CCCCC(O)C#Cc1ccc(F)c(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC(O)CCc1ccc(F)c(F)c1F
Yield: 91.4 %

Procedure:
In 730 mL of ethyl acetate, 183 g of 1-(3-hydroxy-1-heptynyl)-2,3,4-trifluorobenzene was dissolved, and 9 g of 5% palladium carbon (50% in water) was added. Then, the mixutre was stirred for 6 hours at a hydrogen pressure of 0.4 MPa. After the catalyst was removed by filtration (using cellulose), the solvent was evaporated under a reduced pressure to obtain 170 g of 1-(3-hydroxyheptyl)-2,3,4-trifluorobenzene as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[CH:27](N(CC)C(C)C)(C)[CH3:28].C(OS(C(F)(F)F)(=O)=O)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:13])=[O:14])[CH2:27][CH3:28])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1NS(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CCOS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CCN(c1nccnc1C(=O)OC)S(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester (Example 2.1) (1.5 g) in acetonitrile (20 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.71 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before dropwise addition of a solution of ethyltrifluoromethanesulfonate (0.71 ml) in acetonitrile (5 ml) at ambient to temperature. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (eluent: dichloromethane) to give 3-[(2-chloro-5-trifluoromethyl-phenyl-methanesulfonyl)-ethyl-amino]-pyrazine-2-carboxylic acid methyl ester as a beige solid (0.968 g). 1H-NMR (400 MHz, CDCl3): 8.57 (d, 1H), 8.52 (d, 1H), 7.77 (m, 1H), 7.50-7.56 (m, 2H), 4.64 (m, 2H), 4.01 (q, 2H), 4.00 (s, 3H), 1.23 (t, 3H) ppm.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:20]=1[NH2:21].C([O-])(O)=O.[Na+].O>CS(C)=O.C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:21][C:20]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:19]=3[CH3:18])[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Nc2ccnc(Cl)n2)no1
Reactant: COc1cc(C)c(N)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(Nc2nccc(Nc3cc(C(C)(C)C)on3)n2)cc1OC
Temperature: 110 °C

Procedure:
To a slurry of (5-L-butyl-isoxazol-3-yl)-(2-chloro-pyrimidin-4-yl)-amine (0.110 g, 0.435 mmol, Step A) in DMSO (0.110 mL) was added 2-methyl-4,5-dimethoxyaniline (0.073 g, 0.435 mmol). The mixture was heated in a sealed tube at 110° C. for 90 min until TLC indicated the disappearance of starting materials. The mixture was taken up in CH2Cl2 (5 mL) followed by the addition of NaHCO3 (aq., sat. 1 mL) and H2O (5 mL). Extraction with CH2Cl2 (5×5 mL), followed by drying with MgSO4 and filtration yielded a crude mixture that was concentrated under reduced pressure. Purification by chromatography (97:3 CH2Cl2:MeOH) on silica gel afforded the title compound as a purple solid. MS m/z=384.2. Calc'd for C20H25N5O3: 383.45.
Reaction SMILES: [NH2:1]/[C:2](=[N:24]\C(=O)OC(C)(C)C)/[C:3]1[S:4][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:19]=[C:18]([CH:20]4[CH2:22][CH2:21]4)[NH:17][N:16]=3)[C:11]([Cl:23])=[CH:10][N:9]=2)=[CH:6][CH:7]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[Cl:23][C:11]1[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22]3)[NH:17][N:16]=2)=[N:13][C:8]([C:5]2[S:4][C:3]([C:2](=[NH:1])[NH2:24])=[CH:7][CH:6]=2)=[N:9][CH:10]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]
Reactant: CC(C)(C)OC(=O)/N=C(\N)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (Z)-tert-butyl amino(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)methylenecarbamate (Compound 328) (60 mg, 0.13 mmol) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 1 h. The solvent was distilled and recrystallized with ether (2 mL) to afford get 5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-carboximidamide (Compound 205) as TFA salt (55 mg, 72%). LC-MS (m/z)=360 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.77-0.81 (m, 2H), 0.97-1.01 (m, 2H), 1.97-2.01 (m, 1H), 6.43 (s, 1H), 7.90 (d, J=4.0 Hz, 1H), 8.01 (d, J=4.0 Hz, 1H), 8.50 (s, 1H), 9.34 (s, 2H), 9.44 (s, 2H), 9.56 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[CH2:10]([O:12][CH2:13][CH2:14][CH2:15]O)[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH2:14][CH2:13][O:12][CH2:10][CH3:11])=[CH:4][C:3]=1[Cl:9]
Reactant: CCOCCCO
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCCCOc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a solution of 4-bromo-3-chlorophenol (10.0 g), 3-ethoxypropanol (6.0 g) and triphenylphosphine (15.2 g) in tetrahydrofuran (50 ml) was added dropwise under nitrogen atmosphere at 0° C. diethylazodicarbonate (40% toluene solution, 25.2 g) for 15 minutes, and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue was added diethylether, and insoluble materials were filtered off. The filtrate was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane 1:5) and distilled under reduced pressure (1.5 mmHg, 190° C.) to give colorless oil of 4-bromo-3-chloro-(3-ethoxypropoxy)benzene (11.2 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[CH:12]([C@@H:13]1[CH2:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:11]
Reactant: CC1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of oxalyl chloride (319.4 mL of 2 M, 638.8 mmol) in CH2Cl2 (460 mL) is added DMSO (90.69 mL, 1.28 mol) over 30 minutes, keeping the internal temperature around-60° C. tert-Butyl (2S)-2-(hydroxymethyl)-4-methyl-pyrrolidine-1-carboxylate (55 g, 255.5 mmol) in CH2Cl2 (460 mL) is then added over 50 minutes at −78° C. The reaction mixture is stirred for 20 minutes before dropwise addition of DIPEA (445 mL, 2.55 mol). The reaction mixture is stirred at −78° C. for 2 hours and is allowed to warm to rt over 2 hours. To this mixture is added slowly 1N HCl (800 mL). After stirring, the organic phase is separated, dried over Na2SO4, filtered and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (0 to 20% EtOAc in Hexanes) to give tert-butyl (2S)-2-formyl-4-methyl-pyrrolidine-1-carboxylate (48.5 g, 227.4 mmol, 85%) as a brown oil (mixture cis/trans 77/23).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][N:20]1[CH2:23][CH:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21]1)[CH:13]=[CH:12]2)(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>CO>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][N:20]1[CH2:23][CH:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21]1)[CH:13]=[CH:12]2
Reactant: COC(=O)C1CN(Cc2ccc3cc(O[Si](C)(C)C(C)(C)C)ccc3c2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CN(Cc2ccc3cc(O)ccc3c2)C1
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of methyl 1-((6-(tert-butyldimethylsilyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate (4.5 g, 11.7 mmol) in methanol (50 mL) at 0° C. was added con. HCl (5 mL) dropwise. The reaction mixture was stirred at r.t for 1 h. The mixture was neutralized by sat. NaHCO3 and evaporated off most of solvent, extracted with DCM and washed with brine, dried over Na2SO4 and concentrated to obtain crude product. The crude product was purified by silica gel chromatography (DCM:MeOH=40:1), extracted with DCM and washed with brine, dried over Na2SO4 and concentrated to obtain crude product. The crude product was purified by silica gel chromatography (DCM:MeOH=40:1) to give the title compound (1.5 g, 47%) as a gray solid. ESI-MS (M+1)+: 272.0. 1H NMR (400 MHz, CDCl3) δ: 8.14 (s, 1H), 7.59-7.52 (m, 2H), 7.39-7.28 (m, 2H), 7.09-7.04 (m, 2H), 3.92 (s, 2H), 3.86-3.82 (m, 2H), 3.70 (s, 3H), 3.63-3.59 (m, 2H), 3.52-3.46 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:11]2)[CH:3]=1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][C:33]=1[F:41])#[N:31].C([O-])(O)=O.[Na+].N#N>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([NH:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:21])[CH2:11]3)[CH:3]=2)=[CH:34][C:33]=1[F:41])#[N:31]
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C(F)(F)F)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Yield: 55 %

Procedure:
To a mixture of cis-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-N-(phenylmethyl)-6-(trifluoromethyl)-3-piperidinecarboxamide (100 mg, 0.234 mmol) and (4-cyano-3-fluorophenyl)boronic acid (57.8 mg, 0.351 mmol) in 1,4-dioxane (2 mL) was added saturated aqueous NaHCO3, and N2 gas was bubbled through the mixture for 10 minutes into a 5 mL microwave vial. Pd(Ph3P)4 (40.5 mg, 0.035 mmol) was added, and N2 gas was bubbled through the mixture for an additional 5 minutes. The vial was capped, and the reaction mixture was heated overnight over a hot plate at 100° C. The reaction was diluted with water (5 mL), and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting yellow oil was purified on Biotage SNAP 10 g column with gradient of 0 to 40% EtOAc in Hexane over 30 minutes to afford the title compound (66 mg) as a yellow oil. LC-MS (ES) m/z=513 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](O)=[O:27]>>[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][N:11]=1)=[O:27]
Reactant: Cn1cccc1C(=O)O
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cn1cccc1C(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 76 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 1-methyl-2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 76% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH:15]([C:24]2[C:31]([F:32])=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[F:33])[C:16](=[O:23])[C:17]#[C:18][Si](C)(C)C)[CH:12]=[CH:11][CH:10]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH:15]([C:24]2[C:31]([F:32])=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[F:33])[C:16](=[O:23])[C:17]#[CH:18])[CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C#CC(=O)C(c1cccc(-c2ccc(F)cc2F)n1)c1c(F)cc(C#N)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CC(=O)C(c1cccc(-c2ccc(F)cc2F)n1)c1c(F)cc(C#N)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
To a solution of 4-[1-[6-(2,4-difluorophenyl)pyridin-2-yl]-2-oxo-4-(trimethylsilyl)but-3-yn-1-yl]-3,5-difluorobenzonitrile (from Step F above, 7.00 g, 15.02 mmol) in THF (200 mL) was added tetrabutylammonium fluoride hydrate (22.5 mL, 1.0 M in THF) at 0° C. After stirring at 0° C. for 10 min, the reaction was diluted with EtOAc (3×), washed with aqueous NH4Cl, H2O, brine, dried over MgSO4 and concentrated. The crude residue was purified using silica gel chromatography (hexanes/methylene chloride) to yield the title compound (5.31 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][CH:40]=[C:32]([O:31][CH3:30])[CH:33]=2)[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)N[C@H]2C[C@@H](C(=O)N3CCN(c4ccccc4C#N)CC3)N(Cc3ccccc3)C2)c1
Yield: 8.2 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 3-methoxy-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (5.5 mg, 8.2%) as light yellow oil. MS m/e=524.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:15](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]([CH3:38])[S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[NH2:16].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:16]/[N:15]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]([CH3:38])[S:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CN(c1ccccc1C=NN)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1ccc(CC(=O)N/N=C/c2ccccc2N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A flask is charged with (3,4-dimethoxyphenyl)acetic acid (0.34 mmol), 4-dimethylaminopyridine (0.66 mmol), a solution of N-{2-[hydrazonomethyl]phenyl}-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.33 mmol) in N,N-dimethylacetamide (1 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 mmol). The reaction is stirred at room temperature for 18 hours. The reaction is worked up by evaporating the reaction mixture. The product is purified on silica gel with ethyl acetate-methylene chloride mixtures or methanol-methylene chloride mixtures. A 58% yield of N-[2-((E)-{[(3,4dimethoxyphenyl)acetyl]hydrazono}methyl)phenyl]-N-methyl-4-(trifluoromethyl)benzenesulfonamide is obtained. 1H NMR (400 MHz, CDCl3) (mixture of geometric isomers) d 3.25 (s); 3.90 (2s); 4.10 (m); 6.58 (m); 6.87 (m); 6.96 (m); 7.45 (m); 7.82 (m); 8.20 (m); 8.29 (m); 8.90&8.96 (2bs). ESI− for C25H24F3N3O5S: m/z=534 (M−H)−.