Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([NH:31][C:32]([C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)=[O:33])[CH:25]=[CH:24]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[C:7]([C:6]1[CH:10]=[C:2]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([NH:31][C:32]([C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)=[O:33])[CH:25]=[CH:24]3)[CH:3]=[CH:4][C:5]=1[O:11][CH3:12])(=[O:8])[NH2:9]
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: COc1ccc(I)cc1C(N)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)cc1C(N)=O
Temperature: 25 °C
Yield: 15.2 %

Procedure:
5-iodo-2-methoxybenzamide (47.9 mg, 0.173 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (140.4 mg, 0.370 mmol), Fibercat palladium catalyst (Johnson-Matthey, 70.1 mg), and K2CO3 (2 M in water, 0.65 ml, 1.3 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.8 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 85 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (4×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13%->100% EtOAc/hexanes). This crude material was then purified via HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (10.6 mg, 15%). MS (ESI pos. ion) m/z: 403 (M+H). Calc'd Exact Mass for C23H18N2O3S: 402.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]([N:16]1[CH2:20][C:19]([CH2:22]Br)([CH3:21])[CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C:17]1=[O:31])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH3:8].C[O-].[Na+]>CO>[CH3:6][C:7]([N:16]1[CH2:20][C:19]2([CH3:22])[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])([CH2:21]2)[C:17]1=[O:31])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH3:8]
Reactant: CC1(CBr)CN(C(C)(C)c2cccc(Cl)c2)C(=O)C1c1ccccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(c1cccc(Cl)c1)N1CC2(C)CC2(c2ccccc2F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To 20 ml of tetrahydrofuran were added 0.7 g of 1-[1-methyl-1-(3-chlorophenyl)ethyl]-4-bromomethyl-4-methyl-3-(2-fluorophenyl)pyrrolidine-2-one and 0.35 g of a 28% methanol solution of sodium methoxide, and the solution was then stirred at room temperature for 1 hour. After the solvent was distilled off, ice water was added to the solution, and extraction was then made with ethyl acetate. Next, the resultant extract was dried over anhydrous sodium sulfate, and after concentration, column chromatography was done to obtain 0.5 g of the desired 3-[1-methyl-1-(3-chlorophenyl)ethyl]-5-methyl-1-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-one.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][CH:43]=1)[O:27][C@H:28]([CH2:39][CH3:40])[C:29]([O:31]CC1C=CC=CC=1)=[O:30])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[OH-].[Na+]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][CH:43]=1)[O:27][C@H:28]([CH2:39][CH3:40])[C:29]([OH:31])=[O:30])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1
Reactant: CC[C@@H](Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@H](Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
Benzyl (R)-2-[3-[N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenoxy]butyrate (72 mg) was dissolved in ethanol (3 mL), and a 4 N aqueous sodium hydroxide solution (0.5 mL) was added at 0° C. Then, the resulting mixture was stirred at room temperature for 1 hour. The reaction liquor was concentrated under reduced pressure, and then was dissolved in chloroform (30 mL). The solution was washed with a saturated aqueous solution of ammonium chloride and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (chloroform/methanol=10/1) to obtain a colorless solid (61 mg, 100%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)[NH2:4].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][N:16]=1.N>>[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[N:9]([CH:11]=[CH:12][N:13]=4)[CH:10]=3)[N:4]=2)=[CH:22][CH:23]=1
Reactant: NC(=NO)c1ccc2nccn2c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: N
Product: Clc1ccc(-c2nc(-c3ccc4nccn4c3)no2)cn1

Procedure:
The title compound was prepared according to Method D using N′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and 6-chloronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=1.2 Hz, 1H), 7.74-7.84 (m, 2H), 7.87 (d, J=8.3 Hz, 1H), 8.20 (s, 1H), 8.59 (dd, J=8.5, 2.6 Hz, 1H), 9.20 (dd, J=2.4, 0.8 Hz, 1H), 9.47 (t, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 298 (M+H)+, 300 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:36])[C@H:10]([CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[CH3:35])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[OH-].[Na+]>>[CH3:17][C:15]([CH3:18])([O:14][C:12]([NH:11][CH:10]([C:9]([OH:36])=[O:8])[CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:22][C:21]=1[CH3:35])=[O:13])[CH3:16]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCc2ccccc2)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O

Procedure:
O-benzyl-Boc-2,6-dimethyltyrosine benzyl ester, prepared as in Example 12 (5 g, 10.21 mmol), was treated with NaOH(3.27 g, 81.70 mmol), as described in Example 1, giving the title compound. NMR: benzyl methylene at ∫4.99s (2 protons). EXAMPLE 27
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[N:13]O>N.[Ni]>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[NH2:13]
Reactant: Cc1cc(C)c2c(c1)C(=NO)CCC2
Agent: [Ni]
Agent: N
Product: Cc1cc(C)c2c(c1)C(N)CCC2
Reaction time: 20 h
Yield: 92.5 %

Procedure:
5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine: A catalytic amount of Raney nickel (slurry in water) was washed with dry MeOH under argon in a round bottom flask. To a solution of the washed Raney Ni in methanolic ammonia (25 mL, 7N), was added 5,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one oxime (example 166b) (420 mg, 2.22 mmol), and the mixture was stirred under a balloon of H2 for 20 hr. Upon completion, the reaction was filtered through celite, the filtrate was concentrated in vacuo, diluted with EtOAC, washed with water and brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure to afford 360 mg of 5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine (93%). 1H NMR (500 MHz, CDCl3): δ 1.66-1.83 (m, 4H), 1.96 (m, 2H), 2.19 (s, 3H), 2.28 (s, 3H), 2.55 (m, 1H), 2.66 (m, 1H), 3.97 (m, 1H), 6.88 (s, 1H), 7.09 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([C:17]([F:18])([F:20])[F:19])[CH2:15][O:16][C:29]3=[O:31])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCC(Nc1nc(-c2ccc(Br)cc2)cs1)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCC(C(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
2-{[4-(4-Bromophenyl)-1,3-thiazol-2-yl]amino}-3,3,3-trifluoropropan-1-ol (0.61 g, 1.6 mmol), prepared in the previous step, was dissolved in 48 mL methylene chloride. Triethylamine (2.2 mL, 16 mmol) was added and the solution was cooled to 0° C. Triphosgene (1.20 g, 4.15 mmol) was added in two portions and the mixture was stirred at 0° C. for 45 min and then at 25° C. for 2 h. The mixture was poured into 250 mL of saturated aqueous sodium bicarbonate and the layers were separated. The organics were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 2% acetone/hexane to 10% acetone/hexane) afforded the title compound (0.47 g, 75%) as a white solid, mp 154-156° C. HRMS: calcd for C13H8BrF3N2O2S+H, 392.95202; found (ESI, [M+H]+), 392.9518. Analytical HPLC: retention time 10.6 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min 1.2 mL/min 5 μL injection.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH2:17]([N:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][NH2:23])[CH3:18]>CCOCC>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:23][CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH3:25])[CH2:17][CH3:18]
Reactant: COC(=O)/C=C\C(=O)O
Reactant: CCN(CC)CCCN
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCN(CC)CCCN[C@@H](CC(=O)OC)C(=O)O
Yield: 53.3 %

Procedure:
71.5 g (0.5 mol+10% excess) of maleic acid-monomethyl ester are reacted, in the manner described in Example 1, with 100 ml of triethylamine and 65.1 g (0.5 mol) of 3-diethylaminopropylamine. The reaction product is mixed with 500 ml of ether, the mixture is filtered and the residue is washed with ether. After drying at 60° C. in vacuo, the crude product is recrystallised in acetone to yield 69.44 g (53.4% of theory) of a white crystalline aspartic acid derivative, the melting point of which is 154.5°-156.5° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:10]([N+:25]([O-:27])=[O:26])[CH:9]=1)(C)(C)C>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:10]([N+:25]([O-:27])=[O:26])[CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)Cc2ccc(F)cc2)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: Nc1ccc(NC(=O)Cc2ccc(F)cc2)c([N+](=O)[O-])c1
Yield: 95.4 %

Procedure:
To a stirred suspension of {4-[2-(4-fluorophenyl)-acetylamino]-3-nitro-phenyl}-carbamic acid tert-butyl ester (2.40 g, 6.16 mmol) in methylene chloride (5 mL) trifluoroacetic acid (5 mL) was added. After 15 minutes methylene chloride was distilled off and the residual solution was transferred into saturated aqueous NaHCO3 solution (200 mL) with sonication. The precipitate was filtered, washed with water and dried in vacuo to furnish 1.70 g of the title compound as a red-brown solid. Yield 96.3%. LC/MS; tR=2.25 (UV, ELSD) 89%, 100%. 1H NMR (DMSO-d6): 3.59 (s, 2H); 5.65 (b, 2H, NH2); 6.83 (dd, 1H); 7.08 (d, 1H); 7.15 (t, 2H), 7.21 (d, 1H); 7.32 (dd, 2H); 9.91 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH3:20][N:21]([CH3:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:25]3[CH2:26][CH2:27][CH:22]([N:21]([CH3:28])[CH3:20])[CH2:23][CH2:24]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CN(C)C1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 24.4 %

Procedure:
The title compound of Example 2 (1.0 g, 3.40 mmol) was reacted with N,N-dimethyl-4-piperidinamine (0.48 g, 3.74 mmol) by the method of Example 4. Following chromatographic separation, 0.32 g of the title product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)[CH2:6][C:5]2([CH3:22])[CH3:21]>C(O)C.Cl.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[CH2:6][C:5]2([CH3:22])[CH3:21]
Reactant: CC1(C)CC(c2ccccc2[N+](=O)[O-])Nc2ccc(Cl)cc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 35.9 %

Procedure:
To a stirred solution of 6-chloro-4,4-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (7.7 g, 24.3 mmol) in ethanol and 10% hydrochloric acid was added iron powder (7.0 g, 125.4 mmol). The resulting mixture was stirred at 90° C. for 3 h. Then the insoluble solid was filtered off and the filtrate was concentrated in vacuum. The residue was extracted with ethyl acetate, washed with saturated sodium carbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (2.5 g, yield 35.7%) LC/MS m/e obsd. (ESI+) [(M+H)+] 287.2.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:4]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])=[C:1]=[S:3]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: S=C=S
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1cccc(N=C=S)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 3-aminobenzoic acid (0.20 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 24 hours. To the obtained reaction mixture, a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) was dropwise added over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further two hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the residue, ethyl acetate (4 mL) and water (2 mL) were added, and the organic layer was concentrated under reduced pressure to dryness to obtain 3-isothiocyanatobenzoic acid as a cream-colored solid (0.25 g, yield: 96%, HPLC purity: 95%, HPLC retention time: 3.6 min). LC-MS ES-178 (retention time: 4.0 min, condition 1).
Reaction SMILES: O.[C:2]([O:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]([OH:16])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].CCN=C=NCCCN(C)C.Cl.[CH3:29][N:30]([CH3:32])[NH2:31].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:29][N:30]([CH3:32])[NH:31][C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:8])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CN(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 79 %

Procedure:
H2O (0.0953 g, 0.71 mmol, 1.1 eq) was added to a stirred solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.1615 g, 0.64 mmol, 1 eq) in 5 ml anhydrous CH2Cl2 at 0° C. under Ar. After 30 min EDCI.HCl (0.135 g, 0.71 mmol, 1.1 eq) was added. After 1 h 1,1-Dimethylhydrazine (0.058 ml, 0.046 g, 0.77 mmol, 1.2 eq) and DIPEA (0.33 ml, 0.25 g, 1.92 mmol, 3 eq) were added sequentially. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo and the residue partitioned between EtOAc/water. The layers were separated. The aqueous layer was saturated with NaCl and extracted with EtOAc (×2). The combined EtOAc fractions were dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo. Purification via flash chromatography yielded 0.1489 g, 0.51 mmol, 79% yield) of (R)-tert-butyl 2-(2,2-dimethylhydrazinecarbonyl)pyrrolidine-1-carboxylate with some impurity. TFA (0.5 ml, 0.74 g, 6.49 mmol) was added to a stirred solution of (R)-tert-butyl 2-(2,2-dimethylhydrazinecarbonyl)pyrrolidine-1-carboxylate (0.045 g, 0.155 mmol, 1 eq) in anhydrous CH2Cl2 under Ar. After 1 h the solvent was removed in vacuo to generate (R)—N′,N′-dimethylpyrrolidine-2-carbohydrazide.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:11]1([CH2:17][CH2:18][CH2:19][OH:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:20][CH2:19][CH2:18][CH2:17][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: OCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(OCCCN2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Chloro-4-fluorobenzonitrile (5.0 g) and 3-(1-piperidinyl)-1-propanol (3.4 g) were stirred in DMSO (70 ml) at rt under argon. Sodium hydride (60% wt in mineral oil, 1.976 g) was then added and the reaction stirred at rt for 5 h. The reaction mixture was diluted with ethyl acetate (200 ml), washed with saturated sodium hydrogen carbonate (100 ml), water (3×100 ml), brine (100 ml), dried (MgSO4) and evaporated. The crude product was then purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)] and fractions containing pure product were combined and evaporated to give the title compound (D26) as a white solid (6.29 g). MS electrospray (+ion) 279/281 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH:24](/B(O)O)=[CH:25]\[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(/C=C/c3ccccc3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), (E)-styrylboronic acid (45 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 50-80% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (5.8 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 3.85 (s, 3 H) 6.59 (d, J=2.27 Hz, 1 H) 7.22 (dd, J=8.08, 1.77 Hz, 1 H) 7.55 (t, J=7.83 Hz, 1 H) 7.59-7.70 (m, 4 H) 7.98-8.09 (m, 3 H) 8.20 (d, J=2.02 Hz, 1 H) 11.27 (s, 1 H). ESI-MS: m/z 399.3 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.C(N(CC)CC)C.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOCC>[S:36]([O:1][CH:2]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37]
Reactant: OC(CCCCOC1CCCCO1)CCCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC(CCCCOC2CCCCO2)CCCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.405 g (1.3 mmol) 5-hydroxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)-octane in 8 mL methylene chloride is added a few crystals of 4-dimethylaminopyridine followed by 0.5 mL (3.6 mmol) triethylamine and 0.5 g (2.6 mmol) p-toluenesulfonyl chloride. The reaction is stirred at room temperature for 18 hours and then diluted with ether. The ether layer is washed with saturated aqueous sodium bicarbonate, dried, filtered and evaporated to give an amber oil which is purified by chromatography over silica gel using ether/ethyl acetate (4:1) as eluent to yield 5-tosyloxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)-octane; NMR (CDCl3): delta 7.9 (d,2H), 7.4 (d,2H), 2.45 (s,3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[C:4]([Br:12])[N:3]=1.BrBr>C1COCC1>[Br:1][C:2]1[C:7]2[S:10][C:9]([NH2:11])=[N:8][C:6]=2[CH:5]=[C:4]([Br:12])[N:3]=1
Reactant: NC(=S)Nc1cc(Br)nc(Br)c1
Agent: BrBr
Solvent: C1CCOC1
Product: Nc1nc2cc(Br)nc(Br)c2s1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 20.1 %

Procedure:
To a cooled (−60-65° C.) solution of 2,6-dibromo-pyridin-4-yl-thiourea (0.50 g, 1.61 mmol) in THF (100 mL) was added bromine solution (0.20 mL in 45 mL THF, 3.69 mmol) drop wise over a period of 30 min maintaining the temperature to −60-65° C. The reaction mixture was stirred for 15 min at the same temperature and then slowly allowed to come to room temperature. The resulting mixture was heated up to 40° C. for 5 h. After completion of reaction (TLC monitoring), THF was distilled off, basified with aq. NH3 (25% solution, pH 10-12) and then extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (100-200 M, 10% ethyl acetate:hexane) to get the desired product as a white solid (0.10 g, 20%).
Reaction SMILES: C(OC([NH:11][CH:12]([C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=2[N:15]=1)[CH3:13])=O)C1C=CC=CC=1.[H][H]>CO.C(Cl)Cl.[Pd]>[Cl:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([CH:12]([NH2:11])[CH3:13])[NH:15][C:16]=2[CH:22]=1
Reactant: [H][H]
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(N)c1nc2ccc(Cl)cc2[nH]1

Procedure:
5.00 g (contaminated) of rac.-N-benzyloxycarbonyl-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine is dissolved in a mixture of 100 mL of methanol and 40 mL methylene chloride, combined with 1.0 g palladium on charcoal, and hydrogenated for 1 hour at 3.4 bar hydrogen pressure. The solvents are distilled off and the crude product is purified by chromatography with silica gel (eluent: methylene chloride/ethanol=95:5+0.2% ammonia). Yield: 1.08 g (25% over 3 steps); Rf value: 0.37 (silica gel; dichloromethane/ethanol=4:1+2% ammonia); C9H10ClN3 (195.65); mass spectrum: (M+H)+=196/198 (chlorine isotope).