Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][Br:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(CBr)cc1
Yield: 99.9 %

Procedure:
p-tert-butyltoluene (14.8 g; 0.10 mol) was dissolved in carbon tetrachloride, and N-bromosuccinimide (17.8 g; 0.10 mol) and benzoyl peroxide (200 mg) were added thereto. The mixture was refluxed for 2 hours, and then cooled. Insoluble matter was filtered off, followed by washing with carbon tetrachloride. The filtrate was concentrated under reduced pressure, and the residue was dissolved in n-hexane, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 22.7 g of p-tert-butylbenzyl bromide (yield: 100%). The thus-obtained product was analyzed by 1H-NMR, and was found to be a mixture of the target compound, starting compounds, and a dibromo compound (10:1:1). Sodium carbonate (10.6 g; 0.10 mol) was added to 40% solution of methylamine in methanol (200 ml). While the mixture was cooled in an ice bath, p-tert-butyl benzyl bromide (22.7 g; 0.10 mol) in methanol (20 ml) was added dropwise thereto. The mixture was removed from the ice bath, and stirred for 41 hours at room temperature. Methanol was removed under reduced pressure, and the residue was taken up in water, followed by extraction with ether (400 ml). The ether layer was extracted with 1N hydrochloric acid twice (200 ml and 100 ml), and the aqueous layer was extracted with ethyl acetate. The aqueous layer was alkalinized with aqueous 2N sodium hydroxide solution, and extracted with ether (400 ml), followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=200:1→100:1→20:1), to thereby yield 9.51 g of the target compound (yield: 53.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)C(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 72.9 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropanoate (346 mg, 0.77 mmol) was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2× EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 245 mg (73% yield) of acid 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropanoic acid. MS found: (M+H)+=389.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:20])[NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:21]([O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=1)[CH3:22].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]([NH:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[O:20])=[CH:27][CH:26]=1)[CH3:22]
Reactant: CCOC(=O)c1ccc(CO)cc1
Reactant: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(COC(=O)CCCNC(=O)NC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 12 h
Yield: 76.2 %

Procedure:
To a solution of 4-(3-adamantan-1-yl-ureido)butyric acid 822 (1.23 g, 0.83 mmol), DMAP (0.05 g, 0.42 mmol), and the above alcohol (0.15 g, 0.83 mmol) in methylene chloride (30 mL) was added EDCI (0.16 g, 0.83 mmol) at room temperature. After stirring for 12 h, the reaction mixture was washed with 1 N NaOH aqueous solution (15 mL) and water (30 mL), and the organic layer was dried over Na2SO4 and concentrated. Then the residue was purified by column chromatography on silica gel eluting hexane and ethyl acetate (5:1) to provide 849 (0.28 g, 75%) as a white solid: 1H NMR (CDCl3) 1.40 (3H, t, J=6.9 Hz), 1.66-1.68 (6H, m), 1.84 (2H, quint, J=6.9 Hz), 1.94-1.96 (6H, m), 2.05-2.07 (3H, m), 2.44 (2H, t, J=6.9 Hz), 3.17 (2H, q, J=6.9 Hz), 4.02 (1H, s), 4.17 (1H, s), 4.38 (2H, q, J=6.9 Hz), 5.17 (2H, s), 7.40 (2H, d, J=7.8 Hz), 8.00 (2H, d, J=7.8 Hz); LC-MS (ESI) m/z calcd for C25H34N2O5 [M+H]+ 443.25. found [M+H]+ 443.25; mp 96-99 C. Anal. (C25H34N2O5) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>COCCOCCOC>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:25])[NH:15][C:13]1[CH:14]=[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:10]=[CH:11][N:12]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1cc(Nc2cccc(Cl)c2)ncn1
Solvent: COCCOCCOC
Product: O=C(Nc1cc(Nc2cccc(Cl)c2)ncn1)Nc1ccccc1Cl
Yield: 52.4 %

Procedure:
A solution of N-(3-chloro-phenyl)-pyrimidine-4,6-diamine (110 mg, 0.5 mmol) and 2-chlorophenyl isocyanate (60 μL, 0.5 mmol) in diglyme (1.5 mL) is stirred at 80° C. for 18 h. The precipitate which formed over time is filtered and washed with hexane/ethyl acetate to afford the pure title compound (98 mg, 52%).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:27])[F:26])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[NH2:28][C:29]1[N:33]([CH3:34])[CH:32]=[N:31][C:30]=1[C:35]#[N:36]>C(OCC)C>[C:35]([C:30]1[N:31]=[CH:32][N:33]([CH3:34])[C:29]=1[NH:28][C:11]([C:13]1[C:21]2[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=2[C:16]([O:24][CH:25]([F:26])[F:27])=[CH:15][CH:14]=1)=[O:12])#[N:36]
Reactant: Cn1cnc(C#N)c1N
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Solvent: CCOCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(C#N)ncn3C)c2o1
Yield: 34.6 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (100 mg) and 5-amino-1-methyl-1H-imidazole-4-carbonitrile (65 mg). Purification by column chromatography on silica eluting with 0-5% methanol in ethyl acetate afforded, after trituration with diethyl ether, the title compound as a white solid (33 mg)
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13](O)[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:65]=[N+:66]=[N-:67])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:65]([CH:13]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[CH:11][N:10]=1)[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[N+:66]=[N-:67]
Reactant: CCC(CC)C(O)c1nccn1Cc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)C(N=[N+]=[N-])c1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To 1-(1-benzyl-1H-imidazol-2-yl)-2-ethylbutan-1-ol (1.78 g, 6.88 mmol) in THF (50 mL) at 0° C. was added triphenylphosphine (2.71 g, 10.3 mmol), diethyl azodicarboxylate (1.62 mL, 10.3 mmol) and diphenylphosphorylazide (2.22 mL, 10.3 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with EtOAc and extracted 2 times with 1N HCl. The aqueous layer was washed EtOAc, then basicified with saturated aqueous NaHCO3 and extracted twice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, 100% CHCl3, then MeOH/CHCl3/Et3N, 1:98.5:0.5) to yield a pure oil in 30% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10](N)=[N:9][N:8]=2)[CH:2]=1.C(O)(=O)C.[ClH:17].N([O-])=O.[Na+]>O.[Cu]>[Cl:17][C:10]1[S:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][N:9]=1
Reactant: Nc1nnc(-c2cccnc2)s1
Reactant: Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1nnc(-c2cccnc2)s1
Temperature: 23 °C
Yield: 72 %

Procedure:
To a mixture of 5-pyridin-3-yl-[1,3,4]thiadiazol-2-ylamine (5.5 g, 30.9 mmol) and copper powder (0.335 g, 5.27 mmol), in a mixture of glacial acetic acid (93 mL) and concentrated hydrochloric acid (19 mL) at 0° C., was added dropwise a solution of sodium nitrite (10.67 g, 154.6 mmol) dissolved in water (13 mL). The reaction mixture was then allowed to warm to 23° C. overnight. The reaction mixture was diluted with 300 g of ice, resulting in an emulsion, and extracted with dichloromethane (3×200 mL). The emulsion was then passed through a medium porosity scintered glass funnel containing celite. The cake was stirred and washed well with chloroform. The filtrate was combined with the organic extracts. The organic phase was dried over MgSO4 and concentrated to dryness to give the title compound as a yellow solid (4.42 g, 72%): 1H NMR (300 MHz, CDCl3) δ 9.08 (br s, 1H), 8.78 (br s, 1H), 8.29 (dt, J=8, 2 Hz, 1H), 7.49 (dd, J=8, 5 Hz, 1H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH:23]1([CH2:22][CH:15]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1cccnc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
LDA (50.1 mL of a 1.5 mmol mL-1 solution in c-C6H12, 7.6 mmol) was added to a stirred solution of ethyl 3-pyridylacetate (1.15 g, 6.9 mmol) in anhydrous THF-HMPA (3:1, 260 mL) at −78° C. After 30 min, iodomethylcyclopentane (1.46 g, 6.9 mmol) was added, then stirring was continued at −78° C. for 4.5 h. The mixture was allowed to warm to 20° C., before being stirred for 16 h. The reaction mixture was carefully quenched with saturated aqueous NH4Cl (20 mL), then H2O (100 mL) was added. The mixture was extracted with EtOAc (3×50 mL), then the extracts were dried (Na2SO4). Filtration, solvent evaporation, and column chromatography (n-C6H4-EtOAc) furnished ethyl 3-cyclopentyl-2-pyridin-3-ylpropionate: m/z (ES+)=248.3 [M+H]+. Step 2: A stirred solution of this compound (0.73 g, 3.0 mmol) in THF (3 mL) was treated with 2M NaOH (3 mL, 6.0 mmol). After 16 h at 20° C., the organic solvent was removed under reduced pressure, then the pH of the remaining solution was adjusted to 6.5, before being extracted with EtOAc. The EtOAc extracts were dried (Na2SO4), filtered, and concentrated to give the title compound: m/z (ES+)=220.2 [M+H]+. Preparation 3: (E)-3-Cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)acrylic Acid
Reaction SMILES: [N:1]([CH:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[C:15]1([C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH:4]([NH2:1])[CH3:5])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(N=[N+]=[N-])c1sc2ccccc2c1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
2-(1-Azidoethyl)-3-phenylbenzo[b]thiophene (211 mg, 0.76 mmol) was dissolved in a mixture THF (4 mL) and water (0.27 mL) and triphenylphosphine (237 mg, 0.91 mmol) added. The mixture was stirred at RT for 1 h then additional triphenylphosphine (237 mg) was added. The reaction mixture was stirred at RT for 1 h then the reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% MeOH in DCM) affording the title compound as a white solid (160 mg, 83%). 1H NMR (CDCl3, 400 MHz): δ 7.84 (1H, dd, J=7.63, 1.55 Hz), 7.52-7.27 (8H, m), 4.56-4.44 (1H, br), 1.76 (2H, s), 1.47 (3H, d, J=6.21 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22].[C:29]([Cu])#[N:30].CN(C=O)C.CCCCCC>CCOC(C)=O>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:6]3[S:5][C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]=3[C:29]#[N:30])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Br)c(C)nc12
Reactant: N#C[Cu]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3C#N)c(C)nc12
Temperature: 150 °C
Yield: 27.2 %

Procedure:
50 mg of 3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.11 mmol), and 30 mg of CuCN (0.33 mmol) are put into 4 ml vial with 2 ml of DMF and the vial is capped with a Teflon cap. The vial is heated at 150° C. overnight. The reaction mixture is applied onto a silica-gel chromatography column (Hexane:AcOEt=5:1) to give 12.3 mg of the title compound. Yield 28%. Mass spectrum (m/e): 411 (M+1). 6.77 (s, 1H), 3.89 (t, J=4.8 Hz, 4H), 3.61 (t, J=5.0 Hz, 4H), 3.32 (m, 1H), 2.62 (s, 3H), 2.59 (s, 3H), 1.86 (m, 4H), 0.90 (t, J=7.4 Hz, 6H).
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[S:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=1.C(O)C.ICC>ClCCl>[CH2:2]([S:17][C:13](=[N:12][C:9]1[CH:8]=[CH:7][C:6]([Br:5])=[CH:11][CH:10]=1)[CH:14]([CH3:15])[CH3:16])[CH3:3]
Reactant: CC(C)C(=S)Nc1ccc(Br)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCI
Solvent: ClCCl
Solvent: CCO
Product: CCSC(=Nc1ccc(Br)cc1)C(C)C
Temperature: 60 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
In a 300 mL three-neck flask were put 3.4 g (50 mmol) of sodium ethoxide, 13 g (50 mmol) of N-(4-bromophenyl)isobutyrthioamide synthesized in Step 2, and 80 mL of ethanol, and the mixture was stirred at room temperature for 2 hours. After the stirring, 4.0 mL of iodoethane was added to this mixture, and the mixture was stirred at 60° C. for 6 hours. After the stirring, ethanol was distilled off to give a brown oily substance. This oily substance was dissolved in dichloromethane, and washed with water and a saturated aqueous solution of sodium hydrogen carbonate. After the washing, anhydrous magnesium sulfate was added to the organic layer for drying. This mixture was subjected to gravity filtration, and the resulting filtrate was concentrated to give 13 g of N-[1-(ethylsulfanyl)isobutylidene]-4-bromoaniline as a brown oily substance in a yield of 88%. The reaction scheme of Step 3 is shown in (b-3) below.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[H-].[Na+].[CH2:34]([O:36][C:37](=[O:40])[CH2:38]Br)[CH3:35]>>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([N:13]([C:6]3[C:7]([O:11][CH3:12])=[N:8][C:9]([CH3:10])=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=3)[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:40])=[O:15])[CH2:17][CH2:18]2)[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=1
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)=O)c(C)nc3OC)CC2)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc(C(C)=O)c(C)nc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
1-[(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxylphenyl)piperazine(200 mg, 0.5 mmol) was dissolved in dimethylfornamide(15 ml) and thereto sodium hydride(18.5 mg, 0.5 mmol) was added, then followed by stirring at room temperature for 15 min, and ethylbromoacetate(83.5 mg, 0.5 mmol) was added. The resulting mixture was stirred at room temperature for 3 hrs, concentrated under the reduced pressure to remove the used solvent, and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[F:41][C:42]1([F:53])[CH2:46][CH2:45][N:44]([CH2:47][C@@H:48]([NH2:52])[CH:49]([CH3:51])[CH3:50])[CH2:43]1>CN(C=O)C>[F:53][C:42]1([F:41])[CH2:46][CH2:45][N:44]([CH2:47][C@@H:48]([NH:52][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=2)[CH:49]([CH3:50])[CH3:51])[CH2:43]1
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CC(C)[C@H](N)CN1CCC(F)(F)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N[C@H](CN2CCC(F)(F)C2)C(C)C)cc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
3,4-Dimethylbenzoic acid (130 mg, 0.87 mmol) and TBTU (279 mg, 0.87 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to 0° C. and NMM (0.287 mL, 2.61 mmol) was dropwise added. After 10 min at 0° C. was (S)-1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-2-amine (Compound O) (167 mg, 0.87 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with HCl (1M aq. solution, 5 mL), NaHCO3 (saturated, 2×5 mL) and brine (5 mL), and filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (143 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 0.65-1.03, 1.61-1.92, 2.00-2.21, 2.23, 2.53-3.03, 3.66-4.22, 7.19, 7.55, 7.61, 7.87. Total no of protons: 26.
Reaction SMILES: [CH2:1]([PH:8](=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11](N(CC)CC)[CH3:12].C(OC(Cl)=O)C>ClCCl>[CH2:11]([O:10][PH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])[CH3:12]
Reactant: CCN(CC)CC
Reactant: O=[PH](O)Cc1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCO[PH](=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13.34 g of benzylphosphinic acid are dissolved in 150 ml of dichloromethane, the solution is cooled to 5°, and 8.64 g of triethylamine are added dropwise. An exothermic reaction takes place. The mixture is cooled to 5° again, and 9.3 g of chloroformic acid ethyl ester are added dropwise within a period of 30 minutes. A precipitate forms in an exothermic reaction with the evolution of gas. The mixture is allowed to warm to room temperature and is then stirred at room temperature for 3 hours, taken up in dichloromethane and washed with water, and the organic solvent is removed. The crude product is distilled under a high vacuum, yielding benzylphosphinic acid ethyl ester having a boiling point of 96°-100° (5×10-6 bar).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10]
Reactant: Cc1ccccc1B(O)O
Reactant: Clc1cccc(Cl)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1c(Cl)cccc1Cl
Yield: 92.8 %

Procedure:
1-Bromo-2,6-dichlorobenzene (90 mg,-0.40 mmol) reacted with 2-methylphenylboronic acid (82 mg, 0.60 mmol) using 2/4 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and K3PO4 (254 mg, 1.20 mmol) in toluene at 100° C. to give the title compound (88 mg, 76%): 1H-NMR (400 MHz, CDCl3): δ 8.07 (d, 2H, J=8.07 Hz), 7.28-7.18 (m, 3H), 7.15 (t, 1H, J=8.13 Hz), 7.00 (d, 1H, J=7.25 Hz), 1.99 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 139.23, 136.91, 136.16, 135.09, 129.90, 129.04, 129.01, 128.39, 127.88, 125.81, 19.30. GC/MS(EI): (M+).
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11]2)(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH:18]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])=O.CCCCCC.C(OCC)(=O)C>C(O)C.N1CCCCC1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=1[CH:18]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([S:5](=[O:7])(=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH:9]=2)[NH:13][C:12]1=[O:17]
Reactant: COC(=O)c1ccccc1C=O
Reactant: CC(C)NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COC(=O)c1ccccc1C=C1C(=O)Nc2ccc(S(=O)(=O)NC(C)C)cc21
Temperature: 25 °C

Procedure:
A solution of rpm281 (0.149 g, 0.586 mmol) and methyl 2-formylbenzoate (0.105 g, 0.645 mmol, 1.1 eq) in ethanol (10 ml) was stirred in presence of piperidine (1 drop) at 80° C., under Ar for 1 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (15 ml) and washed with HCl 1M (10 ml). The organic extracts were collected, dried over Na2SO4 and the solvent removed under reduced pressure to afford a orange solid. The pure compound rpm347 was obtained after trituration with hexane/ethyl acetate mixture (6:4) (10 ml) as a off-white solid (0.135 g, 0.337 mmol, 60%), mp 271-273° C. MS (API-ES): m/z 401 (M+H)+; HRMS (API-ES) m/z Found: 401.1173 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([C:11]([OH:13])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1cc2c(cn1)C(C(=O)O)CC2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CCc2cc(N)ncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid from Step F in methanol (10 mL) was treated dropwise with a solution of trimethylsilyl diazomethane in diethyl ether (2.0 M, 1.96 mL) at 0° C. After complete addition, the reaction warmed to room temperature and stirred 30 min, then was concentrated. The resulting residue was dried under high vacuum to afford the title compound LC/MS (M+1)+=193.0;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.Cl[C:20]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: Nc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Temperature: 100 °C

Procedure:
To a resealable tube was added 4-aminophenol (1.3 g, 12 mmol), cesium carbonate (7.8 g, 24 mmol), and DMSO (16 ml, 0.75 M). The mixture was heated to 100° C. for 5 minutes, and then 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (2.5 g, 12 mmol) was added, and the reaction mixture was heated to 130° C. overnight. Upon completion, as judged by LCMS, the reaction mixture was allowed to cool to RT and diluted with water. The resulting precipitate was filtered, and the solid washed with water and diethyl ether. The solid was then taken up in 9:1 CH2Cl2:MeOH and passed through a pad of silica gel with 9:1 CH2Cl2:MeOH as eluent. The solvent was concentrated in vacuo to provide the desired product, 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine. MS m/z=280 [M+1]+. Calc'd for C15H13N5O: 279.30.