Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:26]2[C@@H:22]([CH2:23][C@@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:25]2)[C:21](=[O:37])[NH:20][C@@:19]2([C:38]([O:40]CC)=[O:39])[C@@H:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[OH-].[Li+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:26]2[C@@H:22]([CH2:23][C@@H:24]([O:29][Si:30]([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:32])[CH3:31])[CH2:25]2)[C:21](=[O:37])[NH:20][C@@:19]2([C:38]([OH:40])=[O:39])[C@@H:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCNC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Agent: CC(C)(C)OC(=O)N[C@H]1CNCCC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C1=O
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCNC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CNCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,4R,6S,14S,18R)-7-cis-14-tert-Butoxycarbonylamino-18-(tert-butyldimethylsilyloxy)-2,15-dioxo-3,12,16-triazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid, ethyl ester (0.84 g, 1.30 mmol.) in THF (30 mL), methanol (15 mL), and water (4 mL), was added powdered lithium hydroxide hydrate (0.31 g, 12.90 mmol.). The resultant light yellow slurry was stirred at rt under N2 overnight. The mixture was then concentrated in vacuo, and partitioned between hexane/ether (1:1) and water. The organic phase was discarded, and the aqueous phase was treated with 1 N HCl until pH 5. This acidic solution was extracted with EtOAc (3×). The combined EtOAc extracts were dried (MgSO4) and concentrated in vacuo to give 0.495 g (61%) of (1S,4R,6S,14S,18R)-7-cis-14-tert-Butoxycarbonylamino-18-(tert-butyldimethylsilyloxy)-2,15-dioxo-3,12,16-triazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid as an off-white solid: LC-MS (Phenomenex 10 μm C18 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A 100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nM. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.36 min), MS m/z 621 (M++1).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:17]1([CH:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O>[C:17]1([CH:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3([CH3:16])[CH2:7][C:6]4[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=4[O:4]3)[CH2:28][CH2:27]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(COC(c3ccccc3)c3ccccc3)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 93.8 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.5 g), 4-[(diphenylmethoxy)methyl]piperidine (3.0 g), and triethylamine (7.4 mL) was stirred under argon gas at 180° C. for 15 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:1) to provide 2.4 g of 2-[[4-[(diphenylmethoxy)methyl]-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine. Yield 95%. This product was treated with 0.45 g of oxalic acid and, then, recrystallized from ethanol to provide 1.8 g of the title compound. Yield 58%.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:24].[Na+].OO>C1COCC1>[C:9]1([CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH2:3][OH:24])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: C=CCOCCCCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCOCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A solution of Intermediate 11 (0.40 g, 2.10 mmol) in THF (5 mL) was cooled to 0° C. A 0.5 M solution of BBN (5 mL, 2.52 mmol) in THF was added, and the resulting mixture was stirred 1 hour at 0° C. and 2 hours at room temperature. A solution of 2M NaOH (1 mL) and hydrogen peroxide (1 mL, 35%) was successively added and the mixture stirred 1 hour at room temperature. The solution was then concentrated and the residue dissolved in ether (25 mL), washed with water (2×15 mL) and brine (5 mL), dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel (hexane/AcOEt, 6:1) afforded the title compound (0.24 g, 55%) as oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O.C(OCC)(=O)C.O1CCCC1>[CH3:24][S:25]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1)(=[O:27])=[O:26]
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reaction time: 2 h
Yield: 70.6 %

Procedure:
1.4 g of potassium carbonate dissolved in 20 ml of water was added to 1.15 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane dissolved in 40 ml of ethyl acetate and 20 ml of tetrahydrofuran. Then, 0.57 g of methanesulfonyl chloride was added thereto and the mixture was stirred for 2 hours. After the organic layer was collected by separation and dried, the solvent was removed. The resulting crystals were recrystallized from tetrahydrofuran-isopropyl ether to obtain 1.08 g of 2-methylsulfonylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[C:27]1([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CS(C)=O>[C:27]1([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:12]2([CH3:11])[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCCCCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC1(NCCCCc2ccccc2)COc2ccc3c(c2O1)CC(=O)N3
Temperature: 85 °C
Yield: 26.3 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.05 g, 2.80 mmole) and phenylbutylamine (1.99 ml, 12.5 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, 200 ml of water was added and the mixture was extracted twice with 300 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 1% methanol/CH2Cl2 as eluant. The free base of the title compound (0.26 g, 30%) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.25 g of the (S) enantiomer of the title compound as an tan solid fumarate, one-half hydrate, m.p. 185°-186° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1n[nH]c2ccccc2c1=O
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1n[nH]c2c(c1=O)CCCC2
Yield: 61.1 %

Procedure:
To 4-oxo-1,4-dihydrocinnoline-3-carboxylic acid ethyl ester (4.5 g) dissolved in trifluoroacetic acid (20 ml) was added platinum oxide (0.2 g). The reaction mixture was hydrogenated at 50 psi until no further uptake of hydrogen was observed. The catalyst was collected by filtration, the filtrate was poured onto ice, the pH was raised to pH6 with base, the resulting precipitate was collected by filtration, washed with water and dried to give a solid (2.8 g, 61%). δH (250 MHz; DMSO-d6) 1.26 (3H, t, J=7 Hz, CH3), 1.68 (4H, m, CH2), 2.33 (2H, t, J=5.5 Hz, CH2), 2.62 (2H, t, J=5.5 Hz, CH2), 4.25 (2H, t, J=7 Hz, CH2), 13.19 (1H, br s, NH), m/z (ESP+) 223 (MH+).
Reaction SMILES: [CH2:1]([O:3]C(C1C=CC=CC=1)C=O)C.[CH2:13]([O:20][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:22]=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:1][OH:3])[CH2:22][OH:23])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(C=O)c1ccccc1
Reactant: O=CC(OCc1ccccc1)c1ccccc1
Product: OCC(CO)(OCc1ccccc1)c1ccccc1

Procedure:
The procedure in Example 6 was repeated except that 2-ethoxy-2-phenylethanal was replaced with 2-benzyloxy-2-phenylethanal, to obtain 2-benzyloxy-2-phenyl-1,3-propanediol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6]C(S(O)(=O)=O)=[CH:4][CH:3]=1.[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[C:18]([OH:24])[CH:17]=1)(=[O:14])[CH3:13].C(OC1C=CC(N)=C(O)C=1)(=O)C.CC(C(=O)C)C(=O)C>>[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:7]([CH3:6])=[C:2]([CH3:1])[C:3]([CH3:4])=[N:23]2)=[C:18]([OH:24])[CH:17]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1ccc(NN)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)C(C)C(C)=O
Agent: CC(=O)Oc1ccc(N)c(O)c1
Product: CC(=O)Oc1ccc(-n2nc(C)c(C)c2C)c(O)c1
Yield: 52.2 %

Procedure:
230 mg of the title compound was prepared in a manner similar to Example 54b) by using 4-hydrazinyl-3-hydroxyphenyl acetate 4-methylbenzenesulfonate (0.6 g), which was prepared from 4-amino-3-hydroxyphenyl acetate (1.0 g) in a manner similar to Example 54a), and 3-methylpentane-2,4-dione (1.0 g).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27](=[CH:33]N(C)C)[C:28](OCC)=[O:29])=[C:23]([F:37])[CH:22]=1)#[N:20].C(O)(=O)C.CCN(C(C)C)C(C)C>CC(O)C.CS(C)=O>[CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:28]([OH:29])=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][C:23]=3[F:37])[CH:33]=[N:17]2)=[N:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCc4ccccc4)cn3)c2O)c(F)c1
Temperature: 23 °C
Reaction time: 18.5 h
Yield: 10 %

Procedure:
Combined N-benzyl-6-hydrazinylnicotinamide (53.3 mg, 0.220 mmol) and ethyl 2-(4-cyano-2-fluorophenyl)-3-(dimethylamino)acrylate (75 mg, 0.286 mmol) in 2-propanol (1 mL) and added acetic acid (0.038 mL, 0.660 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 18.5 hours, Hunig's base (0.230 mL, 1.320 mmol) was added, and the reaction mixture was stirred at 60° C. for 6 hours. The reaction mixture was cooled to 23° C. and concentrated via rotary evaporation to furnish a brown oil which was dissolved in DMSO (1 mL), filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with DMSO (2×0.5 mL), and purified via preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using a gradient of 50-80% ACN (with 0.035% TFA) in water (with 0.05% TFA). Product containing fractions were combined and concentrated via rotary evaporation to furnish an off-white solid which was collected by filtration, rinsed with water (5×2 mL), and dried in vacuo to give the title compound (9.1 mg, 10.01% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.53 (d, J=5.81 Hz, 2 H) 7.21-7.40 (m, 5 H) 7.72 (dd, J=8.34, 1.52 Hz, 1 H) 7.87 (dd, J=11.75, 1.39 Hz, 1 H) 8.29 (br. s., 1 H) 8.42-8.54 (m, 2 H) 8.60 (br. s., 1 H) 8.95-9.03 (m, 1 H) 9.29 (t, J=5.94 Hz, 1 H) 13.78 (br. s., 1 H). MS m/z [M+H]+ 414.3.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH2:31][NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:28]([O-])=[O:29])=[CH:23][CH:22]=1.[K+].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.CCOCC>[ClH:20].[ClH:1].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([CH2:31][NH:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:28]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:29])=[CH:25][CH:26]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: O=C([O-])C(CNCC(F)(F)F)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C(CNCC(F)(F)F)c4ccc(Cl)cc4)CC3)c21
Reaction time: 18 h
Yield: 110.8 %

Procedure:
A solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 98 umol) and potassium 2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (31.2 mg, 98 umol) in DMF (1.0 mL) was treated with DIEA (36 uL, 205 umol) and HBTU (41 mg, 107 umol), respectively, at room temperature. The mixture was allowed to stir for 18 hours to completion, and the solution was partitioned between ethyl acetate and water. The aqueous portion was extracted twice, and the organics were combined. The organic portion was washed with water (3×), then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9:1 ethyl acetate:MeOH) to afford the pure free-base as a colorless oil. This material was dissolved in ether (1.0 mL), then treated with excess 2.0M HCl in ether. The suspension was concentrated in vacuo to afford the pure 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(2,2,2-trifluoroethylamino)propan-1-one dihydrochloride (31 mg, 99%) as a white solid. LCMS (APCI+) m/z 498.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:25][CH2:26]1)(=[O:33])[CH3:32]
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccncc3)cc(Cl)n2n1
Reactant: CC(=O)NC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CS(C)=O
Product: CC(=O)NC1CCN(c2cc(NC(=O)C3CC3c3ccncc3)nc3cc(C)nn23)CC1
Yield: 9.1 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(pyridin-4-yl)cyclopropanecarboxamide (13D, 100 mg, 0.305 mmol) and N-(piperidin-4-yl)acetamide (87 mg, 0.610 mmol) in NMP (1 mL) was stirred at room temperature overnight. The mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (10-40% MeCN)/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (12 mg, 9%). 1H NMR (DMSO-d6) δ: 10.98 (s, 1H), 8.45 (d, J=5.8 Hz, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J=6.1 Hz, 2H), 6.08 (s, 1H), 4.28 (br. s., 2H), 3.88 (br. s., 2H), 3.15 (d, J=3.0 Hz, 2H), 2.40-2.47 (m, 2H), 2.30-2.37 (m, 3H), 1.85-1.96 (m, 2H), 1.81 (s, 3H), 1.46-1.62 (m, 3H). ESI-MS: m/z 434.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:17]([CH:19]([CH3:25])[C:20](OCC)=O)=[O:18]>>[CH2:1]([N:13]1[C:17](=[O:18])[CH:19]([CH3:25])[CH:20]=[N:16][CH2:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNCCN
Reactant: CCOC(=O)C(C)C=O
Product: CCCCCCCCCCCCN1CCN=CC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 228.1 g (1 mole) of N-dodecylethylenediamine and 130.1 g (1 mole) of ethyl 2-formylpropionate. At 140° to 145° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-dodecyl-6-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C@H:12]([CH3:16])[C:13]([NH2:15])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.CO.ClCCl>C1COCC1>[N:7]1([C@H:12]([CH3:16])[CH2:13][NH2:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C[C@H](C(N)=O)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](CN)N1CCCC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Under a nitrogen atmosphere 31.65 ml 1 M Lithiumaluminiumhydrid solution (THF) are taken and combined with 1 g (7.032 mmol) (R)-2-pyrrolidin-1-yl-propionamide, dissolved in 2 ml THF, at 0° C. The reaction mixture is stirred for 48 h at 50° C. The reaction mixture is combined with 100 ml of methanol and then with the same amount of dichloromethane while cooling with ice. Approx. 25 g silica gel are added to this mixture and the solvent is eliminated in vacuo. This silica gel applied to a suction filter which has previously been charged with approx. 75 g silica gel. The suction filter is washed batchwise with a total of 500 ml of a mixture of dichloromethane, methanol and aqueous conc. ammonia (90:9:1). The majority of the solvent is eliminated at a vacuum of 200 mbar and a sump temperature of approx. 50° C. The product is distilled at 69-71° C. and 10 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][C:4]3[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3-Fluoro-phenoxy)-1H-indole-2-carboxylic acid 141 (preparation see below) and amine 5.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[OH:14][C:15]([C@:18]1([N+]#[C-])[C@@H:21]([CH2:22][CH:23]=[CH2:24])[N:20]([C:25](=[C:30]([CH3:32])[CH3:31])[C:26]([O:28][CH3:29])=[O:27])[C:19]1=[O:33])([CH3:17])[CH3:16].N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[OH:14][C:15]([C@@H:18]1[C@@H:21]([CH2:22][CH:23]=[CH2:24])[N:20]([C:25](=[C:30]([CH3:32])[CH3:31])[C:26]([O:28][CH3:29])=[O:27])[C:19]1=[O:33])([CH3:17])[CH3:16]
Reactant: [C-]#[N+][C@]1(C(C)(C)O)C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: C=CC[C@@H]1[C@@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Yield: 96.6 %

Procedure:
Tributyltin hydride (0.707 ml) was added to a mixture of methyl 2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (630 mg) and azobisisobutyronitrile (34 mg) in benzene (6 ml) at room temperature, and the mixture was refluxed for 15 minutes. The reaction mixture was cooled and chromatographed on silica gel (20 g) eluting with a mixture of hexane and ethyl acetate (3:1-1:1) to give a 3:1 mixture (559 mg) of methyl 2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate and its (3R,4R)-isomer.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]23[CH2:18][C:15]([C:19]([O:21]C)=[O:20])([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[O:9])[CH:5]=[N:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]23[CH2:18][C:15]([C:19]([OH:21])=[O:20])([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: COC(=O)C12CCCC(NC(=O)c3cncc(C)n3)(CC1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cncc(C(=O)NC23CCCC(C(=O)O)(CC2)C3)n1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of methyl 5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylate (1.28 g, 4.21 mmol) and LiOH (0.15 g, 6.25 mmol) in methanol (30 mL) and H2O (3 mL) was refluxed for two hours. After cooled to room temperature, methanol was removed under reduced pressure. The residue was partitioned between water (50 mL) and diethyl ether (50 mL) to remove organic impurities. The aqueous phase was adjusted to pH 1˜2 with 2N aq. HCl and then extracted with dichloromethane (3×50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 1.11 g (91%) of 5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic acid as a white solid. ESI-MS m/z: 290 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[Cl:29][C:30]1[N:31]=[CH:32][S:33][C:34]=1[CH:35]=O.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][CH2:35][C:34]2[S:33][CH:32]=[N:31][C:30]=2[Cl:29])[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=Cc1scnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2scnc2Cl)CC1
Yield: 74 %

Procedure:
Add sodium triacetoxyborohydride (30.50 g, 144 mmol) to a stirred solution of 4-amino-1-N-Boc-piperidine (18.00 g, 89.9 mmol), 4-chloro-thiazole-5-carbaldehyde (13.09 g, 88.7 mmol), acetic acid (5.5 mL, 96.1 mmol), and 1,2-dichloroethane (350 mL). Stir the reaction for 18 hours at room temperature under nitrogen. Pour the reaction into 2N NaOH (400 mL) and extract with ethyl acetate (3×150 mL). Wash the ethyl acetate with brine (2×150 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 75% ethyl acetate/hexanes then with 100% ethyl acetate to yield 21.78 g (74%) of 4-{[(4-chloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=332.1 (M+1); 1H NMR (CDCl3): δ=8.67 (s, 1H), 4.10-4.02 (m, 4H), 2.88-2.82 (m, 2H), 2.74-2.67 (m, 1H), 1.92-1.89 (m, 2H), 1.49 (s, 9H), 1.37-1.28 (m, 3H).