Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:17][CH:18]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>C([O-])([O-])=O.[Na+].[Na+].CCO.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1cccc(CNCCNc2ccccc2Br)c1)N1CCCCC1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccccc1-c1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Yield: 31.6 %

Procedure:
To a solution of (3-{[2-(2-bromo-phenylamino)-ethylamino]-methyl}-phenyl)piperidin-1-yl-methanone (Example 17; 0.051 g, 0.12 mmol) and 2-methoxybenzeneboronic acid (0.037 g, 0.25 mmol) in 2 M Na2CO3/EtOH/toluene (1:1:4, 6 mL) was added Pd(PPh3)4 (0.014 g, 0.012 mmol), and the resulting solution was stirred at reflux for 16 h. The solution was partitioned with EtOAc (20 mL) and satd aqueous NaHCO3 (20 mL), and the aqueous layer was back-extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (10% CH3OH/CH2Cl2) to provide a tan oil (0.0168 g, 28%). MS (ESI): mass calculated for C28H33N3O2, 443.26; m/z found, 444.2 [M+H]+, 466.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.38-7.22 (m, 7H), 7.08-6.97 (m, 3H), 6.78-6.72 (br s, 2H), 4.15 (br s, 1H), 3.69-3.76 (br m, 4H), 3.68 (s, 3H), 3.29-3.24 (br m, 4H), 2.86-2.76 (m, 2H), 1.75-1.49 (br m, 8H). 13C NMR (100 MHz, CDCl3): 170.2, 156.8, 145.8, 140.4, 136.5, 131.9, 130.7, 129.0, 128.9, 128.6, 128.4, 128.0, 126.4, 125.3, 124.9, 121.1, 116.8, 111.2, 110.5, 55.6, 53.2, 48.7, 47.8, 43.5, 43.6, 26.5, 25.6, 24.5.
Reaction SMILES: [OH:1][CH:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5]=2[CH2:4][CH2:3]1.[ClH:24]>C(Cl)Cl.O1CCOCC1>[ClH:24].[ClH:24].[N:11]1([C:10]2[C:5]3[CH2:4][CH2:3][CH:2]([OH:1])[C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2CCC3O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: OC1CCc2c1ncnc2N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 4-(7-hydroxy-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazine-1-carboxylate (0.37 g, 1.2 mmol) in DCM (20 mL) was added HCl in dioxane (4M, 5 mL). The mixture was stirred at room temperature overnight. The solvent was removed to afford the 4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.25 g, 98%). MS (APCI+) [M+H]+221.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[N:20]2[CH2:23][CH:22]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21]2)=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[N:20]2[CH2:21][CH:22]([S:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:9])[CH2:23]2)=[CH:15][CH:14]=1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CC(Sc3ccccc3)C2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccccc1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
0.25 g of meta-chloroperbenzoic acid is added at room temperature to a solution of 0.40 g of 1-[bis(4-chlorophenyl)methyl]-3-(phenylsulfanyl)azetidine in 20 cm3 of dichloromethane. After stirring for 3 hours at room temperature, the reaction mixture is washed with 30 cm3 of a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (particle size 0.06-0.200 mm, height 25 cm, diameter 2 cm), eluting under an argon pressure of 0.8 bar with an ethyl acetate/cyclohexane 20/80 by volume mixture and collecting 60-cm3 fractions, fractions 9 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa), taken up in heptane in order to isolate 100 mg of 1-[bis(4-chlorophenyl)methyl]-3-[(RS)-phenylsulfinyl]azetidine in the form of a white solid [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 3.01 (broad t, J=7.5 Hz: 1H); 3.32 (broad t, J=7.5 Hz: 1H); 3.45 (broad t, J=7.5 Hz: 2H); 3.59 (mt: 1H); 4.45 (broad s,: 1H); from 7.15 to 7.65 (mts: 13H)].
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[CH3:32][N:33]([CH2:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([N:48]([CH3:50])[CH3:49])=[C:44]([NH2:47])[CH:45]=2)[CH2:40][CH2:39]1)=[O:37])[CH3:34].[CH3:51][NH2:52]>>[CH3:49][N:48]([CH3:50])[C:43]1[CH:42]=[C:41]2[C:46](=[CH:45][C:44]=1[NH:47][C:3]1[NH:4][C:5]3=[N:21][CH:20]=[CH:19][C:6]3=[C:7]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=3[C:15]([NH:52][CH3:51])=[O:17])[N:16]=1)[N:38]([C:36](=[O:37])[CH2:35][N:33]([CH3:32])[CH3:34])[CH2:39][CH2:40]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: CN
Reactant: CN(C)CC(=O)N1CCc2cc(N(C)C)c(N)cc21
Agent: Cl
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2N(C)C)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Yield: 44 %

Procedure:
In a manner analogous to a procedure outlined previously, 2-[(2-{[5-(dimethylamino)-1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide was prepared from 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrochloride, 1-[(dimethylamino)acetyl]-N5,N5-dimethyl-2,3-dihydro-1H-indole-5,6-diamine, and methyl amine to afford the title compound (0.20 g, 44% over 3 steps). ESIMS (M+H)+=546. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 6 H) 2.58 (s, 6H) 2.81 (d, J=3.61 Hz, 3 H) 3.02-3.14 (m, 2 H) 3.18 (s, 211) 4.16 (t, J=8.23 Hz, 2 H) 6.27 (br. s., 1 H) 6.87-6.99 (m, 2 H) 7.06 (s, 1 H) 7.32-7.45 (m, 1 H) 7.66 (s, 1 H) 8.38 (d, J=8.23 Hz, 1 H) 8.56 (br. s., 1 H) 8.77 (s, 1H) 10.17 (s, 1 H) 11.30 (br. s., 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][C:7]=1[CH3:12])=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:12][C:7]1[O:8][C:9]([CH3:11])=[CH:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(C)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
2,5-Dimethyl-3-furancarboxylic acid ethyl ester (14.6 g) (synthesized in accordance with the method described in J.A.C.S., 59, 2525 (1937)) was dissolved in ethanol (100 15 ml), and 1N aqueous sodium hydroxide (100 ml) was added. The mixture was stirred at room temperature for 1 hour, and then stirred under reflux for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. precipitated crystals were recrystallized from acetone-hexane to give 2,5-dimethyl-3-furancarboxylic acid (7.3 g) as crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[CH:8]=[O:9].OOS([O-])=O.[K+].Cl.[OH2:19].[CH3:20]O>CCOC(C)=O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[C:8]([O:19][CH3:20])=[O:9]
Reactant: O
Reactant: CO
Reactant: Cc1ccc(CO)cc1C=O
Agent: Cl
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CO)ccc1C
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
To a stirring solution of 800 mg of 5-(hydroxymethyl)-2-methylbenzaldehyde in 20 mL of MeOH was added 3.4 g (5.5 mmol) of Oxone. The mixture was stirred at r.t. for 3.75 h and 2 mL of MeOH was added. After 2.5 h, 15 mL of 1N HCl, 45 mL of H2O, and EtOAc were added, and the layers separated. The aqueous layer was extracted, the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (30% EtOAc/hexanes) provided 377 mg of methyl 5-(hydroxymethyl)-2-methylbenzoate as a yellow oil with some impurity.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:34][N:35]=[C:36]=[O:37]>C(Cl)Cl>[CH3:34][NH:35][C:36](=[O:37])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: CN=C=O
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(=NCc2ccccc2)CC1
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a stirred solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (2.0 g) in CH2Cl2 (40 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 g) followed by the dropwise addition of methyl isocyanate (0.39 g) in CH2Cl2 (10 ml). The reaction was monitored via TLC and after 3 hours the solution was concentrated and the precipitate was collected and recrystallized from acetonitrile to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate (1.85 grams).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].O(CC)[C:13]([S-])=[S:14].[K+].Cl>N1C=CC=CC=1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:13](=[S:14])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Combine 2-amino-4-nitrophenol (15.8 g, 102 mmol) and potassium ethyl xanthate (18.3 g, 114 mmol) in pyridine (200 mL). Heat the reaction at reflux for 1 h. Allow the reaction to cool to room temperature and pour into concentrated HCl (100 mL) and ice. Filter and wash the solids with 1N HCl to remove excess pyridine. Dry the solids under house vacuum at 50° C. for 2 days to obtain the title compound (15.85 g, 79%). 1H NMR (400 MHz, DMSO-d6): δ 8.18 (dd, 1H, J=8.8, 2.2 Hz), 7.93 (d, 1H, J=2.2 Hz), 7.73 (d, 1H, J=8.8 Hz).
Reaction SMILES: [NH3:1].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])=[CH2:4].[Cl-].[NH4+]>CCOCC>[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:1])(=[O:13])=[O:12])=[CH2:4]
Reactant: C=C(C)c1ccccc1S(=O)(=O)Cl
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C(C)c1ccccc1S(N)(=O)=O
Yield: 101.4 %

Procedure:
A solution of anhydrous ammonia (1 ml, 40 mmol) in ether (25 ml) was cooled to 0° and to this was added 2-(1-methylethenyl)benzenesulfonyl chloride of Example 13 (2.9 g, 13 mmol). After stirring for 2 hours at 0° to 5° the ammonium chloride was removed by filtration of the filtrate concentrated to an oil which crystallized on standing to give 2.6 g of the title compound, m.p. 76°-85°.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:35])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:69]1([O:73][C:74]([N:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)=[O:75])[CH2:72][CH2:71][CH2:70]1>CN(C=O)C.ClCCl>[CH:69]1([O:73][C:74]([N:76]2[CH2:81][CH2:80][N:79]([C:31](=[O:32])[C@H:30]([NH:29][C:27]([C:18]3[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6](=[O:7])[NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:35])[N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:19]=3)=[O:28])[CH3:34])[CH2:78][CH2:77]2)=[O:75])[CH2:72][CH2:71][CH2:70]1
Reactant: O=C(OC1CCC1)N1CCNCC1
Reactant: C[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reaction time: 1 h

Procedure:
To a solution of 100 mg (R)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionic acid in 2 ml DMF were added 0.14 ml DIPEA, 78 mg HATU and 0.38 mg 1-cyclobutoxycarbonyl-piperazine. After stirring for 1 h it was diluted with dichloromethane and extracted with aqueous LiCl (4 w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([N+:15]([O-])=O)[CH:4]=1.C(O)C>[Ni].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccccc2)c(N)c1
Reaction time: 3 h
Yield: 100.4 %

Procedure:
A Parr bottle charged with 4-methoxy-2-nitrobiphenyl (27.6 g, 120 mmol), Raney nickel (1.5 g), ethanol (100 mL), and H2O (100 mL) was rocked under hydrogen (60 psi) for 3 h. The suspension was filtered through Celite, the cake washed with ethanol (500 mL) and tetrahydrofuran (500 mL), and the filtrate concentrated in vacuo. The residual suspension was digested with CH2Cl2 (300 mL), washed with H2O (300 mL), and the organic portion extracted with 1 N HCl (4×200 mL). The combined extracts were made basic with 50% NaOH, extracted with CH2Cl2 (3×200 mL), and the organic extracts washed with brine (300 mL), dried (K2CO3), filtered, and concentrated in vacuo to give 24 g (100%) of the title compound which was used without further purification: 1H NMR (300 MHz, CDCl3) δ 3.78 (s, 3H), 3.90 (br s, 2H), 6.34 (d, J=2 Hz, 1H), 6.41 (dd, J=8, 2 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 7.15-7.33 (m, 2H), 7.36-7.41 (m, 3H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]([C:19]1[N:20]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][N:23]=1)=O.O>O1CCCC1>[C:24]([N:20]1[CH:21]=[CH:22][N:23]=[C:19]1/[CH:17]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.811 g, 20.3 mmol) in tetrahydrofuran (60 ml) was added dropwise ethyl (diethoxyphosphoryl)acetate (4.33 ml, 21.8 mmol) and the mixture was stirred for 30 min. A solution of 2-formyl-1-tritylimidazole (5.28 g, 15.6 mmol) in tetrahydrofuran (30 ml) was added dropwise and the mixture was stirred for 8 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgSO4). After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (9:1-1:1, v/v). The title compound (3.28 g, 52%) was obtained as a colorless powder from the object fraction.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16](Cl)[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([NH2:33])[CH3:32])=[CH:27][CH:26]=1.CS(C)=O.CCN(C(C)C)C(C)C>[Cl-].[Na+].O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:33][C@H:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=2)[CH3:32])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1ccc(OC(F)(F)F)cc1
Temperature: 85 °C

Procedure:
To a microwave vial with a stir bar was added (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (75.0 mg, 0.224 mmol) and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (59.7 mg, 0.247 mmol), followed by DMSO (0.9 mL) and DIEA (118 ul, 0.673 mmol). The vial was capped and the reaction mixture heated in a preheated oil bath at 85° C. for 2 hr. The mixture was diluted with brine and extracted with EtOAc two times. The combined organic phases were dried over sodium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a brown solid film, (yield assumed quantitative). LCMS m/z 503.2 (M+H)+, Rt 1.24 min.
Reaction SMILES: [C:1]([Cl:4])(=O)C.Cl.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]>CO>[ClH:4].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:1])=[O:12]
Reactant: CC(=O)Cl
Reactant: NCCCCC(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)CCCCN

Procedure:
Acetyl chloride (5 mL) was added into methanol (150 mL) to prepare hydrogen chloride in methanol solution, and 5-aminopentanoic acid (1 g) was added. The mixture was kept at the room temperature overnight, and evaporated to isolate methyl 5-aminopentanoate hydrochloride. A mixture of the methyl 5-aminopentanoate hydrochloride (251 mg), cinnamoic acid (74 mg), HBTU (168 mg), diisopropylethylamine (0.87 mL), and dimehylformamide (2 mL) was kept at the room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water twice (10 mL each) followed by brine (10 mL), dried (Na2SO4), and evaporated to isolate (4-methoxycarbonyl)butyl cinnamamide (1, 100 mg). A mixture of (4-methoxycarbonyl)butyl cinnamamide (1, 100 mg), benzaldehyde phenylhydrazone (2, 113 mg), chloramine-T trihydrate (160 mg), and methanol (2 mL) were heated under refluxing for 22 hours. The reaction mixture was diluted with 50% ethyl acetate in n-hexanes (40 mL), filtered, and evaporated. The residue was purified by column chromatography (silica gel 20 g, eluent: 0 to 10% ethyl acetate gradient in hexanes) to isolate methyl 5-(1,3,5-triphenyl-4,5-dihydro-pyrazole-4-carbonyl) aminopentanoate (3, 13 mg) and methyl 5-(1,3,4-triphenyl-4,5-dihydro-pyrazole-5-carbonyl)aminopentanoate (4, 103 mg). Regiochemistry of each isomer was identified by 1H- and 13-C NMR chemical shifts of the CH adjacent to the amide carbonyl. 5-(1,3,5-Triphenyl-4,5-dihydro-pyrazole-4-carbonyl)aminopentanoic acid (5, FN1-9U) were obtained from 3 by a standard ester hydrolysis condition as shown in the preparation of FN1-2. MS: 464.9 (M+Na), 442.9 (M+H), 325.8, 297.9. 5-(1,3,4-Triphenyl-4,5-dihydro-pyrazole-5-carbonyl)aminopentanoic acid (6, FN1-9S) were obtained from 4 by a similar manner to the preparation of FN1-2. MS: 464.9 (M+Na), 442.9 (M+H), 325.8, 297.9.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][NH:11][N:10]=2)[CH:8]=1)#[N:2].Cl[CH2:29][C:30]1[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:29][C:30]3[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=3)[N:10]=2)[CH:8]=1)#[N:2]
Reactant: COc1ccc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Reactant: Cn1ccnc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1-c1nn(Cc2nccn2C)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
To a solution of N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.56 mmol) in 3 mL of DMF was added 2-(chloromethyl)-1-methyl-1H-imidazole (109 mg, 0.84 mmol) and cesium carbonate (547 mg, 1.68 mmol). The reaction mixture was stirred at room temperature for 3 hours, then diluted with ethyl acetate and filtered. The filtrate was washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 82.2 mg (32%) of N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=454.1; 1H NMR (400 MHz, CDCl3) δ: 9.53 (s, 1H), 8.73 (dd, 1H), 8.64 (s, 1H), 8.48 (dd, 1H), 8.26 (s, 1H), 7.80 (d, 1H), 7.68 (dd, 1H), 7.06 (d, 1H), 6.97 (m, 2H), 6.83 (s, 1H), 5.42 (s, 2H), 3.85 (s, 3H), 3.63 (s, 3H).
Reaction SMILES: Cl.Cl.Cl[C:4]1[N:9]=[C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:23]4[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=4[N:21]=3)[CH2:15][CH2:14]2)[CH:7]=[CH:6][N:5]=1.[O-2:37].[Ca+2].[H][H]>[Pd].CO>[OH2:37].[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:24]2[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]=[C:20]2[NH:19][CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][NH:10][C:8]3[CH:7]=[CH:6][N:5]=[CH:4][N:9]=3)[CH2:14][CH2:15]2)=[CH:31][CH:30]=1.[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:24]2[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]=[C:20]2[NH:19][CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][NH:10][C:8]3[CH:7]=[CH:6][N:5]=[CH:4][N:9]=3)[CH2:14][CH2:15]2)=[CH:31][CH:30]=1
Reactant: [H][H]
Reactant: [O-2]
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4ccnc(Cl)n4)CC3)nc3ccccc32)cc1
Agent: [Pd]
Agent: Cl
Agent: [Ca+2]
Solvent: CO
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4ccncn4)CC3)nc3ccccc32)cc1
Product: O

Procedure:
A mixture of 3.2 parts of N-[1-[2-[(2-chloro-4-pyrimidinyl)-amino]ethyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine dihydrochloride, 3 parts of calcium oxide and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 20%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.1 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-pyrimidinylamino)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine hemihydrate; mp. 133.9° C. (compound 94)