Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.N1C=CC=CC=1>C1COCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1cnc(N)cc1OCc1cccs1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)Oc2ccccc2)cc1OCc1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenyl chloroformate (3.46 ml, 27.6 mmol) was added drop wise to a mixture of 6-amino-4-(thiophen-2-ylmethoxy)nicotinonitrile (intermediate 284, 2.90 g, 12.54 mmol) and pyridine (4.46 ml, 55.2 mmol) in THF (100 ml) at room temperature. The reaction mixture was stirred for 16 h at room temperature and then partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer washed with saturated brine, dried over MgSO4 and evaporated. The residue was purified by normal phase chromatography: 80 g RediSep® column, eluting with a gradient from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a beige solid. (UPLC-MS 3) tR 1.14; ESI-MS 352.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Br)nc1
Product: ClCc1ccc(Br)nc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
3.69 g (19.7 mmol) of the compound from Example 4A are initially introduced into the reaction vessel under argon and 25 ml thionyl chloride are added dropwise at −60° C. (bath temperature). The mixture is stirred at −60° C. for 1 h. It is concentrated at RT on a rotary evaporator, and 50 ml saturated sodium bicarbonate solution and 50 ml ethyl acetate are added to the residue. The aqueous phase is extracted with ethyl acetate (four times with 25 ml each time). The combined organic phases are dried over sodium sulfate and filtered, the solvent is removed on a rotary evaporator and the residue is dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:13][OH:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:1]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=1)=[N:13][OH:14]
Reactant: Nc1cccc(C(=NO)C(F)(F)F)c1
Reactant: BrCCOCCBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: ON=C(c1cccc(N2CCOCC2)c1)C(F)(F)F
Yield: 89.3 %

Procedure:
A mixture of 1-(3-aminophenyl)-2,2,2-trifluoroethanone oxime (1.7 g), bromoethyl ether (2.246 g), and i-Pr2NEt (2.57 g) in toluene (20 mL) was refluxed for 4 hours. After cooling, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (50% ethyl acetate in hexane) to give the title compound as an oil (2.04 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[Si:46]([O:63][CH2:64][C:65]1[C:66]([NH2:71])=[N:67][CH:68]=[CH:69][CH:70]=1)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[Si:46]([O:63][CH2:64][C:65]1[C:66]([NH:71][C:24]([C:23]2[CH:22]=[N:21][N:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH2:13][CH2:14][C@@H:10]4[C:4]4[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:16][C:17]=23)=[O:26])=[N:67][CH:68]=[CH:69][CH:70]=1)([C:59]([CH3:60])([CH3:61])[CH3:62])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)[Si](OCc1cccnc1N)(c1ccccc1)c1ccccc1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)Nc3ncccc3CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (303 mg, 0.848 mmol) in DMF (5 mL) was added triethylamine (103 mg, 1.02 mmol), followed by dropwise addition of 2,4,6-trichlorobenzoyl chloride (227 mg, 0.933 mmol). The reaction was stirred for two hours. 3-((tert-Butyldiphenylsilyloxy)methyl)pyridin-2-amine (369 mg, 1.02 mmol) was added and the reaction mixture was heated to 60° C. for 5 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 10% MeOH/DCM to give (R)-N-(3-((tert-butyldiphenylsilyloxy)methyl)pyridin-2-yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, to which was added THF (5 mL) and TBAF (848 μL, 0.848 mmol). The reaction mixture was stirred for one hour, then quenched with saturated NH4Cl (1 mL) and then concentrated under reduced pressure to give crude (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(3-(hydroxymethyl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, to which was added HCl (4M in dioxane, 5 mL). The reaction mixture was sealed and heated to 100° C. for four hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with DCM (20 mL) and the organic layer was washed with saturated NaHCO3 (5 mL), water (5 mL) and brine (5 mL). The organic layer was concentrated under reduced pressure to give crude (R)-N-(3-(chloromethyl)pyridin-2-yl)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, to which was added DMF (10 mL) and Cs2CO3 (276 mg, 0.848 mmol). The reaction mixture was heated to 60° C. for 4 hours, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 10% MeOH/DCM to afford the title compound (8.0 mg, 2.2% yield). MS (apci) m/z=432.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzyl bromide (25.0 g), and to the mixture was added pyrrolidine (24.1 ml) at 0° C. The reaction mixture was stirred at room temperature for 60 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 1-(4-nitrobenzyl)pyrrolidine (23.5 g) as orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:22]#N)[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1(C[Mg]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:22][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)CC2CCCCC2)CC1
Reactant: Br[Mg]CC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(CC2CCCCC2)CC2CCCCC2)CC1
Yield: 46 %

Procedure:
A solution of 4-(1-cyano-2-cyclohexyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.81, 5.65 mmol) in THF (20 mL) and cyclohexylmethylmagnesium bromide (1.51 g, 22.60 mmol, 0.4 M in Et2O) was stirred at 23° C. for 24 h. The reaction was quenched with EtOAc and washed with brine, dried (Na2SO4), and evaporated. Final purification by flash chromatography (hexane-EtOAc 15:1) afforded 1020 mg of the title compound. MS m/z 393.3 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])=[CH:11][N:10]([CH:25]([CH3:29])[C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[O:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])=[CH:11][N:10]([CH:25]([CH3:29])[C:26]([NH:37][CH:35]3[CH2:36][O:33][CH2:34]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)O)cc1NC(=O)c1n[nH]c2cncnc12
Reactant: NC1COC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)NC2COC2)cc1NC(=O)c1n[nH]c2cncnc12
Reaction time: 6 h
Yield: 52.3 %

Procedure:
A solution of 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)propanoic acid (66.0 mg, 0.150 mmol, 1 equiv), oxetan-3-amine hydrochloride (41.0 mg, 0.374 mmol, 2.50 equiv), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uranium hexafluorophosphate (114 mg, 0.299 mmol, 2.00 equiv), and N,N-diisopropylethylamine (522 μL, 2.99 mmol, 20.0 equiv) in N,N-dimethylformamide (1.0 mL) was heated at 50° C. After 6 h, the reaction mixture was concentrated, and the resulting residue was partitioned between saturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (10 mL). The aqueous was extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded product (39 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.70 (s, 1H), 9.33 (m, 1H), 9.02 (d, J=6.5 Hz, 1H), 8.77 (dd, J=4.2, 1.5 Hz, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 7.50 (dd, J=8.9, 2.7 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.27-7.31 (m, 2H), 5.06 (q, J=7.1 Hz, 1H), 4.80 (m, 1H), 4.73 (m, 2H), 4.44 (m, 2H), 3.84 (s, 3H), 1.66 (d, J=7.1 Hz, 3H). LCMS (ESI): M+H=496.1.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21](C(OC4C=CC=CC=4)=O)[C:22](=O)[O:23]C4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[N:40]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([N:49]4[CH2:50][CH2:51][CH:46]([N:40]5[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]5)[CH2:47][CH2:48]4)=[O:23])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCCC5)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 9 h
Yield: 28.3 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (15.5 g, 29.7 mmol) synthesized in Production example 5-2 was dissolved in dimethylformamide (180 ml); 4-piperidinopiperidine (20.0 g, 119 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 9 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and concentrated to about 100 ml. The residue was allowed to be kept cool at 5° C. overnight to precipitate crystals. The crystals were filtered off and washed with ethyl acetate to yield the title compound (4.0 g, 8.4 mmol, 28%) as white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.[Br:26]N1C(=O)CCC1=O>CN(C=O)C.[Cl-].[Na+].O>[Br:26][C:5]1[N:4]=[CH:3][C:2]([N:7]2[CH2:12][CH2:11][CH:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[N:1][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnccn3)CC2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnc(Br)cn3)CC2)CC1
Reaction time: 8 h

Procedure:
The tert-butyl 1′-pyrazin-2-yl-4,4′-bipiperidine-1-carboxylate (16 mg, 0.046 mmol, prepared as described for Example 8) and N-bromosuccinimide (8.2 mg, 0.046 mmol) were dissolved in DMF (0.2 ml) and the solution stirred overnight at 50 C. The slurry was diluted with 15% brine:water (40 ml) and extracted with ethyl acetate (3×25 ml). The combined organic fraction was washed with brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 20% acetone:hexanes to yield the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>[OH-].[K+].CCO>[O:20]1[CH:24]=[CH:23][C:22]([CH:25]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])=[CH:21]1
Reactant: O=Cc1ccoc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccoc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 69.8 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.20 g, 0.78 mmol) was reacted with 3-furaldehyde (0.083 g, 0.86 mmol) in 2 mL of 4% KOH in EtOH for 48 hours at room temperature to afford 0.182 g (70%) of the title compound, mp 116-117° C.: APCI-MS m/e 335.3 (M+ +1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl.[CH2:9]([O:11][C:12](=[O:16])[C:13](Cl)=[O:14])[CH3:10].[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:9]([O:11][C:12](=[O:16])[C:13]([C:20]1[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=1)=[O:14])[CH3:10]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(OC)cc1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
Aluminum chloride (84.30 g, 632 mmol) was added to chloroform (300 ml) and chloroglyoxylic ethyl ester (60 g, 439 mmol) was added dropwise to the resulting suspension over 20 minutes at 0° C. The reaction mixture was stirred for 40 minutes at 5° C. At the same temperature, anisole (68.79 g, 636 mmol) was slowly added dropwise to the reaction solution and then stirred for 12 hours at 10° C. When the reaction is completed, the reaction solution was cooled and, after adding cooling water (100 ml), extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and then concentrated to obtain the title compound as a yellow solid (TLC identification). The resulting compound was used in the next reaction without further purification.
Reaction SMILES: N[CH2:2][C:3]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16]([C:18]1([C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[CH2:20][CH2:19]1)=[O:17])=[CH:10][CH:9]=2)(C)[CH3:4].C(=O)([O-])[O-].[K+].[K+].IC.O.[CH3:39][N:40]([CH:42]=O)[CH3:41]>>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:18]3([C:16]([NH:15][C:11]4[CH:12]=[C:13]5[C:8](=[CH:9][CH:10]=4)[NH:7][C:6]([C:3]([CH3:4])([CH3:2])[CH2:42][N:40]([CH3:39])[CH3:41])=[CH:14]5)=[O:17])[CH2:20][CH2:19]3)=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: CN(C)C=O
Reactant: CC(C)(CN)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CN(C)CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of N-(2-(1-amino-2-methylpropan-2-yl)-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (20 mg, 0.051 mmol) in DMF (1 mL) was added potassium carbonate (35 mg, 0.26 mmol) and iodomethane (7.0 μL, 0.11 mmol). The mixture was stirred for 2 h. Water was added and the mixture was extracted with dichloromethane. Combined organic phases were dried over magnesium sulfate, evaporated, coevaporated with toluene (3×) and purified by silica gel chromatography (0-30% EtOAc in hexane) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(1-(dimethylamino)-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (7 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 7.15 (s, 1H), 7.01-6.95 (m, 3H), 6.85 (d, J=7.9 Hz, 1H), 6.10 (d, J=0.9 Hz, 1H), 6.02 (s, 2H), 2.43 (s, 2H), 2.24 (s, 6H), 1.68 (dd, J=3.7, 6.7 Hz, 2H), 1.33 (s, 6H), 1.08 (dd, J=3.7, 6.8 Hz, 2H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[CH:8]([NH2:10])[CH3:9].C(N(CC)CC)C.[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1>C(#N)C>[CH:18]1([CH2:21][NH:10][CH:8]([C:3]2[N:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH3:9])[CH2:20][CH2:19]1
Reactant: BrCC1CC1
Reactant: CC(N)c1ncccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NCC1CC1)c1ncccn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-pyrimidin-2-yl-ethylamine hydrochloride (50 mg, 0.313 mmol), triethylamine (95 mg, 1 mmol) and cyclopropylmethyl bromide (0.034 ml, 0.344 mmol) in acetonitrile was stirred at 80° C. overnight. After evaporation of the solvents, addition of aqueous sodium hydrogencarbonate, extraction (3 times with dichloromethane), drying of the combined organic layers over sodium sulfate and evaporation of the solvents, crude cyclopropylmethyl-(1-pyrimidin-2-yl-ethyl)-amine was obtained which was used immediately in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17]2)=[O:15])[C@@H:10]([NH2:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([C:41]1[CH:42]=[C:43]([N:47]=[C:48]=[O:49])[CH:44]=[CH:45][CH:46]=1)(=[O:40])[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17]2)=[O:15])[C@@H:10]([NH:30][C:48]([NH:47][C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:38](=[O:40])[CH3:39])[CH:42]=2)=[O:49])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@@H](N)C1
Reactant: CC(=O)c1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(NC(=O)N[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 16 h
Yield: 38.3 %

Procedure:
In a dry flask (3R,4S)-3-amino-4-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (77 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2.5 mL) and triethylamine (20 μL, 0.143 mmol) and 3-acetylphenylisocyanate (50 μL, 0.36 mmol) were added. The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo and purified by preparative reverse-phase HPLC (10-90% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (40 mg, 38%). 1H NMR (300 MHz, CDCl3), δ: 7.98 (d, J=8, 1H), 7.83 (m, 2H), 7.74 (m, 1H), 7.65 (m, 2H), 7.56 (m, 1H), 7.46 (m, 1H), 7.01 (m, 2H), 6.87 (m, 1H), 3.09 (m, 1H), 2.51-2.77 (m, 7H), 2.42 (m, 1H), 1.23-1.78 (m, 11H), 1.42 (s, 9H). HRMS (ESI), C32H42FN4O5 m+/z: calc.=581.3139, found=581.3142.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([Cl:18])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc2ccccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc2ccccc2c1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-naphthylacetic acid (0.960 g, 5.15 mmol) in methylene chloride (10 mL) was added oxalyl chloride (0.58 mL, 6.7 mmol) and DMF (1 drop). After 1.5 hours, the solvent was evaporated to give 2-naphthylacetyl chloride. A solution of the 2-naphthylacetyl chloride in THF (3 mL), cooled to -78° C., was slowly cannulated into a stirred solution of the lithium salt of 4 -(S)-(+)-4-isopropyl-2-oxazolidinone (prepared by treating, at -78° C., a solution of 4 -(S)-(+)-4 -isopropyl-2-oxazolidinone (0.60 g, 5.2 mmol) in THF (4 mL) with a solution of butyllithium (1.6 M in hexane) for 15 min). After 2 hours, 10% citric acid and ethyl acetate were added. The organic phase was washed with NaHCO3 and brine, dried (MgSO4), and concentrated. Flash column chromatography of the residue (15% ethyl acetate/hexanes) gave 4 -(S)-4 -isopropyl-3-(2-naphthylacetyl)-2-oxazolidinone as a slightly yellow oil (0.91 g, 60%).
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[C:7]([O-:10])([O-])=[O:8].[K+].[K+].[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH2:21][CH2:22]C=C(C)C)[N:15]=1>O.C(O)(C)(C)C>[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH2:21][CH2:22][C:7]([OH:10])=[O:8])[N:15]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=CCCc1cc(Cl)nc(Cl)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)CCc1cc(Cl)nc(Cl)n1
Reaction time: 16 h
Yield: 49.8 %

Procedure:
The above synthesis may be carried out as follows: To a solution of LDA (1.28 g, 12 mmol) in THF (30 mL) at −78° C. was added 2,4-dichloro-6-methylpyrimidine (1.96 g, 12 mmol) in THF (15 mL). After stirring for 15 minutes, 3,3-dimethylallyl bromide (1.79 g, 12 mmol) in THF (5 mL) was added dropwise. After the reaction warmed to ambient temperature, water and ethyl acetate was added. The organic layer was separated, the solvent was removed in vacuo, and the residue was chromatographed (ethyl acetate/hexane, 1/19) to give 2.06 g (74%) of 2,4-dichloro-6-(4-methyl-3-pentenyl)pyrimidine (1H NMR (CDCl3) δ 7.15 (s, 1), 5.10 (t, 1), 2.80 (t, 2), 2.45 (m, 21, 1.70 (s, 3), 1.55 (s, 3)). To a solution of NaIO4 (17 g, 81 mmol) and KMnO4 (251 mg, 1.59 mmol) in water was added K2CO3 (1.29 g, 9.38 mmol) and 2,4dichloro-6-(4-methyl-3-pentenyl)pyrimidine (2.06 g, 8.9 mmol) in t-butanol. After stirring for 16 hours, the reaction was acidified to pH 3 and extracted with ethyl acetate. The organic layer was extracted with aqueous NaHCO3. The aqueous layer was acidified to pH 3 and extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to give 980 mg of 3-(2,4-dichloropyrimidin-6-yl)propionic acid (the compound of formula (XIX)), 1H NMR (CDCl3) δ 7.30 (s, 1), 3.05 (t, 2), 2.90 (t, 2). The acid was coupled to piperonylamine under standard conditions with isobutyl chloroformate and N-methylmorpholine to give the compound of formula (XX). Imidazole was added under standard conditions (1-trimethylsilylimidazole and CsF in DMF at 60° C.) to give N-[(1,3-benzodioxol-5-yl)ethyl]-6-chloro-2-(1H-:imidazol-1-yl)pyrimidine-4-propionamide (the compound of formula (Ihh)); MS: 386 (M+H)+.