Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10](Cl)[N:9]=2)[CH2:5][O:4][CH2:3]1.[S:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C.O>CN(C)C=O>[NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([N:22]3[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:19][CH2:20][CH2:21]3)[N:9]=2)[CH2:5][O:4][CH2:3]1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: NC1(CNc2nc(Cl)nc3ccccc23)COC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: NC1(CNc2nc(N3CCSc4ccccc4C3)nc3ccccc23)COC1
Temperature: 130 °C
Yield: 14.1 %

Procedure:
To a solution of N-[(3-aminooxetan-3-yl)methyl]-2-chloroquinazolin-4-amine (200 mg, 0.756 mmol) in N,N-dimethylformamide (4 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (125 mg, 0.756 mmol) and triethylamine (230 mg, 2.268 mmol). After being heated at 130° C. for 4 hours under microwave irradiation, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 42 mg of the desired product as a white solid (yield was 14%). MS obsd. (ESI+) [(M+H)+] 394, 1H NMR (400 MHz, CD3OD) δ ppm 7.75-7.73 (t, J=6.4, 1.2 Hz, 1 H), 7.56-7.53 (m, 1 H), 7.52-7.47 (m, 2 H), 7.43-7.41 (d, J=8.0 Hz, 1 H), 7.24-7.20 (m, 1 H), 7.15-7.08 (m, 2 H), 5.06 (s, 2 H), 4.69-4.67 (d, J=6.8 Hz, 2 H), 4.55-4.53 (d, J=6.4 Hz, 2 H), 4.42 (s, 2 H), 4.09 (s, 2 H), 2.97-2.95 (t, J=4.8, 4.4 Hz, 2 H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH:25]=4)=[N:22][N:23]=3)[CH:20]=2)[CH2:10][CH2:9]1)(C)(C)C.C(Cl)Cl.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[N:33]1([CH2:32][CH2:31][O:30][C:26]2[CH:25]=[C:24]([C:21]3[N:19]4[CH:20]=[C:15]([O:14][C@H:11]5[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]5)[CH:16]=[CH:17][C:18]4=[N:23][N:22]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccc3nnc(-c4cccc(OCCN5CCOCC5)c4)n3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Oc2ccc3nnc(-c4cccc(OCCN5CCOCC5)c4)n3c2)CC1

Procedure:
A solution of Example 14 step a (196 mg, 0.178 mmol) in TFA (2 mL) and DCM (10 mL) was stirred at RT for 0.5 H, then concentrated in vacuo to give the title compound (quantitative yield). LCMS (Method 2): Rt 0.38 min, m/z 438 [M-CF3CO2+].
Reaction SMILES: C([O:5][C:6](=[O:59])[C@@H:7]([NH:11][C:12]([C@@H:14]1[CH2:18][C@@H:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:21]=2)[CH2:16][C@H:15]1[C:38](=[O:58])[NH:39][C@H:40]([C:44](=[O:57])[NH:45][C@@H:46]([CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)[C:47]([O:49][CH3:50])=[O:48])[CH:41]([CH3:43])[CH3:42])=[O:13])[CH2:8][CH2:9][CH3:10])(C)(C)C.C([SiH](CC)CC)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:51]1([C@H:46]([NH:45][C:44]([C@@H:40]([NH:39][C:38]([C@@H:15]2[CH2:16][C@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:18][C@H:14]2[C:12]([NH:11][C@@H:7]([CH2:8][CH2:9][CH3:10])[C:6]([OH:59])=[O:5])=[O:13])=[O:58])[CH:41]([CH3:42])[CH3:43])=[O:57])[C:47]([O:49][CH3:50])=[O:48])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C1CCCCC1)C(C)C)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C1CCCCC1)C(C)C)C(=O)O
Reaction time: 2 h
Yield: 100.8 %

Procedure:
Tert.butyl ester 56 (28 mg, 0.034 mmol) and triethylsilane (14 μL, 0.088 mmol) was dissolved in DCM (2 mL) after which trifluoroacetic acid (2 mL) was added and the mixture was stirred for 2 h. Co-evaporation with toluene gave 57 (26 mg, 100%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Cl.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1.[O:20]1CCOCC1>>[CH3:1][C:2]1[C:10]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1cc2ccccn2n1
Reactant: ClCc1cccnc1
Reactant: C1COCCO1
Agent: Cl
Product: Cc1nn2ccccc2c1C(=O)c1cccnc1

Procedure:
To a solution of 110 g of 2-methylpyrazolo[1,5-a]pyridine in 600 ml of 1,4-dioxane was added 150 g of nicotinyl chloride hydrochloride with stirring. The resulting solution was heated to reflux for 2 hours, and after removal of solvent in vacuo, the residue was dissolved in 500 ml of water and neutralized with potassium carbonate. The aqueous layer was extracted with 500 ml of benzene, the extract was dried over anhydrous Na2SO4, and after removal of solvent, the residue was recrystallized from ethyl acetate-hexane to afford 110 g of the title compound. Concentrating the mother liquors gave a second crop of crystals, which weighed 10 g; total yield 120 g (61%), mp 89°-90° C.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]3[CH2:28][CH2:27]O[CH2:25][CH2:24]3)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1.FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH:30]1([S:33]([N:8]2[CH2:12][C@H:11]3[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]4[CH2:24][CH2:25][CH2:27][CH2:28]4)[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:14][CH2:15][C@H:10]3[CH2:9]2)(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)C3CC3)C[C@H]21)N1CCCC1

Procedure:
The title compound was prepared by substituting (2S)-N-[(3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-4-methyl-2-pyrrolidin-1-ylpentanamide from Example 250 for (S)-N-((3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-methyl-2-morpholinopentanamide and cyclopropanesulfonyl chloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in the procedures described in Example 319: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.14 (d, J=7.3 Hz, 1H), 4.33-4.40 (m, 1H), 3.82 (dd, J=9.9, 2.6 Hz, 1H), 3.57 (dd, J=9.9, 7.0 Hz, 1H), 3.41 (dd, J=9.6, 7.0 Hz, 1H), 3.22 (dd, J=9.6, 3.2 Hz, 1H), 3.16 (dd, J=9.2, 5.1 Hz, 1H), 2.60-2.70 (m, 7H), 2.04 (dq, J=11.9, 5.9 Hz, 1H), 1.79-1.97 (m, 3H), 1.56-1.67 (m, 6H), 1.33-1.40 (m, 1H), 1.16-1.23 (m, 2H), 0.99 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H), 0.86-0.92 (m, 2H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:26][CH:27]1CC1.[C-]#N.[K+]>>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:27][CH2:26]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OCC1CC1
Agent: [C-]#N
Agent: [K+]
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 10.37 g (0.03 mol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 35 ml of hydroxymethyl-cyclopropane and 0.5 g of potassium cyanide is stirred at 125° for 12 hours, during this time three 2-3 ml portions of the solvent being distilled off by the application of a slight vacuum. The mixture is subsequently evaporated in vacuo, the residue is partitioned between chloroform and water, the chloroform solution is washed successively with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue obtained is recrystallized from ethyl acetate, there being obtained cyclopropylmethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 195°-196 °.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]2[N:6]([CH:13]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH:15]=2)[N:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].CI.CCOC(C)=O>CN1C(=O)CCC1>[CH2:1]([S:3][C:4]1[C:5]2[N:6]([CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH3:21])[N:20]=3)[CH:15]=2)[N:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3nnn[nH]3)cc12
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCSc1c(C(N)=O)cnn2cc(-c3nnn(C)n3)cc12
Temperature: 23 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of 4-(ethylthio)-6-(1H-tetrazol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (164 mg, 0.567 mmol) in NMP (2.0 mL) were added K2CO3 (196 mg, 1.417 mmol) and MeI (0.043 mL, 0.680 mmol). The solution was stirred at 23° C. for 1 hr. To the reaction mixture was added 30 mL of EtOAc which was washed with 10% LiCl solution (2×10 mL), 10 mL of brine and dried over Na2SO4. Filtration and concentration yielded a crude product which was purified on silica gel column with EtOAc to afford the desired product (64 mg, 35% yield). MS (ES+) m/z: 304.08 (M+H); HPLC retention time: 2.180 min (analytical HPLC Method F).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][CH2:32][C@H:33]([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][CH2:32][C@H:33]([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: C[C@@H](O)CN
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC(C)n1cnc2c(NCc3cccnc3)nc(NC[C@@H](C)O)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 10.6 %

Procedure:
To a stirred solution of 2-fluoro-9-isopropyl-6-[(pyridin-3-ylmethyl)-amino]purine (300 mg, 1.05 mmol) in n-BuOH/DMSO (5 ml, 4:1) at room temperature under an argon atmosphere was added DIEA (2 ml, 10 eq, 10.5 mmol) followed by (R)-1-aminopropan-2-ol (395 mg, 5.25 mmol). The flask was fitted with a condenser and the reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL), the aqueous phase was extracted with more ethyl acetate (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient flash column chromatography on silica gel eluted with CHCl3:MeOH (100:0→95:5), to afford the pure product as a colorless oil (38 mg, 10.6%). δH (250 MHz, CDCl3) 1.15 (3 H, d, J 7.5, CHCH3OH), 1.45 (6 H, d, J 7.5, CH[CH3]2), 3.3-3.2 (1 H, m, NHCHHCHMeOH)), 3.45-3.36 (1 H, m, NHCHHCHMeOH), 3.96-3.9 (1 H, m, CHMe2), 4.58-4.47 (1 H, m, CHMeOH), 4.69 (2 H, d, J 5, NHCH2Ar), 5.23 (1 H, t, J 5, NHCH2CHMeOH), 6.32 (1 H, s, br, NHCH2Ar), 7.16-7.11 (1 H, m, ArH), 7.4 (1 H, s, ArH), 7.6 (1 H, d, J 7.5, ArH), 8.4 (1 H.d, J 2.5, ArH), 8.55 (1 H, s, ArH); δC (250 MHz, CDCl3) 160.07 (C), 154.95 (C), 154.7 (C), 151.1 (C), 149.27 (CH), 148.54 (CH), 135.3 (CH), 134.73 (CH), 123.39 (CH), 114.61 (C), 68.83 (CH), 50.09 (CH2), 46.49 (CH), 41.95 (CH2), 22.49 (2×CH3), 20.85 (CH3); m/z 342.2 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([CH:16]([C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:14][CH3:15]>CCCCCC.C(OCC)(=O)C>[CH2:12]([C:16](=[C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCCCC(C(=O)OCC)C(=O)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCC(C(=O)OCC)=C(Nc1ccc(C(=O)OC)cc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 30 h
Yield: 100.8 %

Procedure:
27.8 g of methyl 4-aminobenzoate and 47 g of diethyl 2-butyl-3-oxo-butanedioate were mixed and 2 g of activated siliporite were added. The mixture was stirred for about 30 hours at 60° C. and after chromatography (eluant: hexane-ethyl acetate 95-5), 70 g of the expected product were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH:4]([C:6]1([OH:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:5].[CH2:21]([Cl:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:28].[CH2:21]([O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]2([CH:4]([CH3:5])[CH2:3][N:2]([CH3:1])[CH3:20])[OH:19])=[CH:17][CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(CN(C)C)C1(O)CCCCC1c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CN(C)C)C1(O)CCCCC1c1ccc(OCc2ccccc2)cc1
Product: Cl
Reaction time: 3 h
Yield: 69.9 %

Procedure:
1-(2-Dimethylamino-1-methylethyl)-2-(p-hydroxyphenyl)-cyclohexanol (Example XXX) (5.6 g) in 50 ml dimethylformamide is treated with 3.8 g benzyl chloride and 6 g potassium carbonate and stirred 3 hours at 90°. The mixture is cooled, 200 ml water added and extracted with 7×50 ml ethyl acetate. The extract is washed with water, dried and concentrated. The residue is dissolved in 65 ml ethyl acetate and acidified with HCl gas to give 5.7 g product, m. 253°-4°.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10]>C1(C)C=CC=CC=1>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: C=O
Solvent: Cc1ccccc1
Product: O=Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.05 g of dried particles of size 3.5 μm with quaternary base groups from Example 3 was dispersed in 50 g toluene in presence of a steric stabilizer (H-190-332 from ICI). Then 0.4 g resorcinol and 0.6 g of 37% formaldehyde solution were added. After stirring for 5 hours, at 25° C., particles of size 6.4 μm were formed.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[N:10][C:11]([C:13]2[CH:17]=[C:16]([CH3:18])[O:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[O:12])[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH2:40]([O:42][C:43](Cl)=[O:44])[CH3:41]>ClCCl>[F:30][C:26]1[CH:25]=[C:24]([NH:23][C:9](=[N:10][C:11]([C:13]2[CH:17]=[C:16]([CH3:18])[O:15][C:14]=2[C:19]([F:20])([F:21])[F:22])=[O:12])[NH:8][CH:4]2[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:43](=[O:44])[O:42][CH2:40][CH3:41])[CH2:3]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(C(=O)N=C(Nc2cccc(F)c2)NC2CCCC(N)C2)c(C(F)(F)F)o1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC1CCCC(NC(=NC(=O)c2cc(C)oc2C(F)(F)F)Nc2cccc(F)c2)C1
Reaction time: 1 h
Yield: 102.8 %

Procedure:
N-(((3-Aminocyclohexyl)amino)((3-fluorophenyl)amino)methylene)-5-methyl-2-(trifluoromethyl)furan-3-carboxamide (0.150 g, 0.240 mmol) and diisopropylethyl amine (DIEA) (0.037 g, 0.288 mmol) were dissolved in dichloromethane (DCM) (5 mL). Ethylchloroformate (0.032 g, 0.288 mmol) was added and the reaction mixture was stirred for one hour. Then, the solvents were evaporated under a stream of nitrogen and the resulting residue purified by column chromatography (0-40%, hexanes:EtOAc) to yield 123 mg of the title compound (70% yield). LCMS (ESI): calc.=498; obs. M+H=499.5.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:23]=2[CH3:24])=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:38](OCCBr)(=[O:40])[CH3:39].CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:23]=2[CH3:24])=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:39][CH2:38][OH:40])[CH2:11][CH2:10]1)#[N:2]
Reactant: Cc1c(C(=O)Nc2ccc(N3CCCNCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(N3CCCN(CCO)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
N-[3-Cyano-4-(homopiperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (1.5 g), potassium carbonate (0.6 g) and 2-bromoethyl acetate (0.7 g) were added to dimethylformamide (20 ml) and the mixture was stirred at 60° C. for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. To the residue were added 2N aqueous sodium hydroxide solution (10 ml) and ethanol (20 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure and dilute hydrochloric acid was added. The obtained crystals were recrystallized from hydrous ethanol to give the title compound (1.1 g), melting point: 124° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:18]2[C:19]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[CH3:38])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[SH:43][CH2:44][CH2:45]O.B(F)(F)F.CCOCC>ClCCl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([C:18]2[CH:23]=[N:22][C:21]([N:24]3[CH2:29][CH2:28][C:27]4([O:30][CH2:45][CH2:44][S:43]4)[CH2:26][CH2:25]3)=[CH:20][C:19]=2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: OCCS
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(F)ccc1-c1cc(N2CCC3(CC2)OCCS3)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of 0.20 g (0.34 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 5 ml dichloromethane were added 0.03 g (0.4 mmol) 2-mercaptoethanol and 0.11 g (0.34 mmol) boron trifluoride etherate at 0° C. After 1 h the reaction mixture was allowed to warm to room temperature and stirred over night. Dilution with a 2 N aqueous sodium hydroxide solution was followed by extraction with 3 portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.22 g (98%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[CH:21]1([NH:26][C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([F:13])([F:12])[F:1])=[CH:6][CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccc(NC2CCCC2)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a mixture of 3.94 g of 2,2,2,4′-tetrafluoroacetophenone (20.5 mmol) and 3.35 ml triethylamine (24.0 mmol) in 40 ml of acetonitrile at 0° C. were added 5.9 ml of cyclopentylamine (59.8 mmol). The reaction was allowed to warm to room temperature and then heated to reflux for 14 h. After this time the reaction mixture was cooled to room temperature, concentrated and partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica (hexanes:EtOAc, 4:1) to give the title compound. 1H-NMR (CDCl3) δ 1.53–1.57 (m, 2H), 1.69–1.78 (m, 4H), 2.08–2.13 (m, 2H), 3.88–3.95 (m, 1H), 4.63 (brs, 1H), 6.60 (d, J=8.9 Hz, 2H), 7.92 (d, J=8.9 Hz, 2H). Mass Spectrum (CI+) m/e=258.1 (M+1).
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3]P(=O)(OC)OC.CC(C)([O-])C.[K+].[CH3:17][C:18]([CH3:25])([CH:23]=O)[C:19]([O:21][CH3:22])=[O:20]>O1CCCC1>[CH3:17][C:18]([CH3:25])(/[CH:23]=[CH:3]/[C:2](=[O:1])[CH3:10])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COP(=O)(CC(C)=O)OC
Reactant: COC(=O)C(C)(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)/C=C/C(C)=O
Reaction time: 0.25 h

Procedure:
To a solution of dimethyl (2-oxopropyl)phosphonate (4.09 mL, 30.0 mmol) in tetrahydrofuran (200 mL) at 0° C. was added potassium tert-butoxide (3.22 g, 28.7 mmol). After 15 minutes the reaction mixture was moved to room temperature, and after an additional 15 minutes methyl 2,2-dimethyl-3-oxopropanoate (3.39 g, 26.0 mmol) was added. The opaque reaction mixture was stirred for 21 hours and then partitioned between diethyl ether (100 ml) and water (100 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (100 mL, 50 mL). The combined organic layers were washed with aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-4% methanol/dichloromethane) to yield methyl (3E)-2,2-dimethyl-5-oxohex-3-enoate. 1H NMR (500 MHz, CDCl3) δ 6.95 (d, J=16.4 Hz, 1H), 6.09 (d, J=16.4 Hz, 1H), 3.71 (s, 3H), 2.29 (s, 3H), 1.37 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]2[CH2:16][CH2:17][C@@H:12]1[CH:13]([C:21](O)=[O:22])[CH:14]2[C:18](O)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OC)=O.[BH4-].[Na+]>C1COCC1.O>[OH:22][CH2:21][CH:13]1[CH:14]([CH2:18][OH:19])[C@H:15]2[N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C@@H:12]1[CH2:17][CH2:16]2
Reactant: O=C(O)C1C(C(=O)O)[C@@H]2CC[C@H]1N2C(=O)OCc1ccccc1
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)N1[C@@H]2CC[C@H]1C(CO)C2CO
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of (1R,4S)-7-(benzyloxycarbonyl)-7-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid (L) (2.33 g, 7.30 mmol) in THF (50 mL) was added N-methylmorpholine (2.00 mL, 18.25 mmol). The mixture was cooled to −25° C. before adding methyl chloroformate (1.41 mL, 18.25 mmol) dropwise. The mixture was stirred at −25° C. for 20 minutes and the solid was removed by filtration. The solution was carefully added to a solution of NaBH4 (1.65 g, 43.80 mmol) in water (100 mL) at 0° C. The mixture was stirred for 1 hour at room temperature. The acetone was removed under vacuum and the aqueous phase was extracted with EtOAc (×3). The combined organic phases were washed with 1 M NaOH, dried over MgSO4 and concentrated under vacuum to give (1R,4S)-benzyl 2,3-bis(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (LI) as a colorless oil (1.85 g, 6.35 mmol, 87% yield). 1H NMR (CDCl3) δ ppm 1.40 (brs, 1H), 1.54 (brs, 1H), 1.63 (brs, 2H), 1.81 (brs, 1H), 1.98 (brs, 1H), 3.50-3.56 (m, 1H), 3.58-3.67 (m, 2H), 3.69-3.78 (m, 1H), 4.10 (brs, 2H), 5.09 (brs, 2H), 7.34 (brs, 5H); ESIMS found for C16H21NO4 m/z 292 (M+H).