Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([O:8][CH2:9][O:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:22]([OH:25])[C:23]#[CH:24]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:25][CH2:22][C:23]#[C:24][C:2]1[CH:21]=[CH:20][C:5]([C:6]([O:8][CH2:9][O:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([C:4]#[C:5][CH2:6][OH:7])=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(OCOC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCOC(=O)c1ccc(C#CCO)cc1)c1ccc(C#CCO)cc1
Reaction time: 240 h
Yield: 167.9 %

Procedure:
Bis (triphenylphosphine)palladium dichloride (17.0 mg, 0.02 mmol) and cuprous iodide (2.0 mg, 0.01 mmol) are added to a suspension of methylene bis (p-bromobenzoate) (0.500 g, 1.21 mmol) prepared as described in Example 14 and propargyl alcohol (0.16 ml, 2.66 mmol) in triethylamine (10 ml) with good stirring, at 20° C., under a dry N2 atmosphere. After 10 days at 20° C., the triethylamine is removed under reduced pressure, water (20 ml) is added and the mixture is extracted with dichloromethane (3×15 ml). The dichloromethane phases are washed with hydrochloric acid (0.5M, 10 ml), dried (MgSO4) and the dichloromethane removed under reduced pressure to give 0.37 g (85%) of the crude product. 1H NMR (60 MHz, CDCl3): δ 3.67 (2H, s, OH), 4.47 (4H, s, CH2 --O), 6.18 (2H, s, O--CH2 --O), 7.2-7.5 (4H, Ar), 7.8-8.0 (4H, Ar).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[CH3:18])[CH2:6]1)=[O:4].[NH:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:13]1[C:12]([CH3:18])=[C:11]([N:7]2[C:8](=[O:10])[CH2:9][N:5]([C:3](=[O:4])[CH2:2][N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[CH:21]=[N:20]3)[CH2:6]2)[CH:16]=[CH:15][CH:14]=1
Reactant: c1cnc2[nH]ncc2c1
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1N1CN(C(=O)Cn2ncc3cccnc32)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-Chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (230 mg, 0.8 mmol, 1 eq), 1H-Pyrazolo[3,4-b]pyridine (96 mg, 0.8 mmol, 1 eq), Cesium carbonate (653 mg, 2.0 mmol, 2.5 eq) in DMF (6 ml) was stirred at room temperature overnight. It was diluted with ethyl acetate, washed with water and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 370.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[C:35]([F:37])[C:34](O)=[C:33]([Cl:39])[CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[C:35]([F:37])[C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:33]([Cl:39])[CH:32]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1cc(F)c(O)c(Cl)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(Cl)c1
Yield: 74 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), and 3-chloro-5-fluoro-4-hydroxy-benzoic acid methyl ester (CAS RN 369-15-3) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the desired compound as a colorless foam (74%). MS (Turbo Spray): 577.1 [M+H].
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:45]=[C:44]2[C:40]([CH:41]=[N:42][N:43]2[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:45]=[C:44]3[C:40]([CH:41]=[N:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCn1ncc2ccc(CCl)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCn1ncc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.390 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.199 g of 6-chloromethyl-1-(3-methoxypropyl)-1H-indazole are reacted. The title compound is obtained as a colourless oil. Rf=0.31 (2:1 EtOAc-heptane); Rt=6.12.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[NH2:5].[C:18]([N:21]1[CH2:28][S:27][CH2:26][C@@H:22]1[C:23]([OH:25])=[O:24])(=[O:20])[CH3:19]>>[C:18]([N:21]1[CH2:28][S:27][CH2:26][C@@H:22]1[C:23]([OH:25])=[O:24])(=[O:20])[CH3:19].[F:14][C:13]([F:15])([F:16])[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:4]([C:3]([OH:17])=[O:2])[NH2:5])=[CH:8][CH:9]=1
Reactant: COC(=O)C(N)Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)N1CSC[C@@H]1C(=O)O
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
from 4-(trifluoromethyl)-DL-phenylalanine methyl ester and N-acetyl-D-thioproline δH (DMSO-d6) 8.56-8.12 (1 H, m,NH), 7.68-7.55 (2 H, m, ArH), 7.51-7.37 (2 H, m, ArH),4.85-4.15 (4 H, m, NCH2S and 2×α-CH), 3.40-2.65 (4 H, m,SCH2CH and CH2Ar),2.06 (s) and 2.04 (s) and 1.80(s) and 1.71 (s); together (3 H, COCH3); m/z (ESI, 60 V), 391 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[N:11]=2)=O)=[N:4][O:5][N:6]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:7]([Cl:18])=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[N:11]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=O)Nc1cccc(Cl)n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Nc1nonc1C(Cl)=Nc1cccc(Cl)n1

Procedure:
A solution of 4-amino-N-(6-chloropyridin-2-yl)-1,2,5-oxadiazole-3-carboxamide (62 mg, 0.26 mmol) in benzene (5 mL) was treated with phosphorus pentachloride (0.12 g, 0.57 mmol) and stirred at reflux for 3 h. The reaction mixture was concentrated and rediluted with benzene and concentrated (3×) to give the desired product which was used immediately in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]([CH3:26])([CH3:25])[C:14]([NH:16][NH:17]C(OC(C)(C)C)=O)=[O:15])=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]([CH3:26])([CH3:25])[C:14]([NH:16][NH2:17])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)C(C)(C)Oc1ccc(Cl)c2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(Oc1ccc(Cl)c2ccccc12)C(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 166.4 %

Procedure:
Tert-butyl 2-{2-[(4-chloro-1-naphthyl)oxy]-2-methylpropanoyl}hydrazinecarboxylate (6.11 g) was dissolved in ethyl acetate (40 ml), 4M hydrogen chloride-ethyl acetate (20 ml) was added thereto, followed by stirring at room temperature for 8 hours. The solvent was evaporated under reduced pressure and the residue was washed with diisopropylether to obtain, as a white solid, 2-[(4-chloro-1-naphthyl)oxy]-2-methylpropanohydrazide monohydrochloride (4.23 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[O:14]1[CH2:19][CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH2:16][CH2:15]1.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-]>C(COC)OC.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.O>[O:14]1[CH2:15][CH:16]=[C:17]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:18][CH2:19]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
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: [Cl-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(C2=CCOCC2)c(C(F)(F)F)c1
Yield: 59 %

Procedure:
In a screw cap pressure tube, 4-fluoro-3-(trifluoromethyl)-benzonitrile (425 mg, 1.70 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (357.1 mg, 1.70 mmol) were dissolved in dimethoxyethane. Na2CO3 (2 M aq. sln, 2.5 ml) and LiCl (216.4 mg, 5.1 mmol) were added. N2 was bubbled through the mixture for 5 minutes. Pd(PPh3)4 (39.3 mg, 0.03 mmol) was added. The tube was sealed and the mixture heated to reflux for 20 h. The mixture was allowed to cool. H2O was added and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography; Pet. Ether, EtOAc (4:1) affording 254 mg (59%) the title compound.
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].CN(C)[CH:9]=[CH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH:2]([N:5]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)NN
Reactant: CCOC(=O)C(=O)C=CN(C)C
Agent: Cl
Product: CCOC(=O)c1ccnn1C(C)C

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using isopropylhydrazine hydrochloride and ethyl 4-(dimethylamino)-2-oxobut-3-enoate at 120° C. for hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-40%). tR: 4.74 min (HPLC 1); tR: 1.00 min (LC-MS 2); ESI-MS: 183 [M+H]+ (LC-MS 2); Rf=0.95 (hexane/EtOAc 1:1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:18][OH:19])=[C:6]([C:10](=[N:15][O:16][CH3:17])[C:11]([NH:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Cl:20][C:21]1[C:22](Cl)=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27].O>C1COCC1>[CH3:17][O:16][N:15]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[C:5]=1[CH2:18][O:19][C:22]1[C:21]([Cl:20])=[CH:29][C:25]([C:26]([O:28][C:5]([CH3:18])([CH3:6])[CH3:4])=[O:27])=[CH:24][N:23]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)C(=NOC)c1cccc(F)c1CO
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1cccc(F)c1COc1ncc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60%, 0.15 g, 3.7 mmol) was added to a solution of 3-fluoro-2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (0.54 g, 2.25 mmol) in dry THF (10 mL) and stirred for 10 minutes at 25° C. under N2 atmosphere. 5,6-Dichloronicotinic acid; t-butyl ester (0.59 g, 2.5 mmol) in 2-3 mL THF was added to this reaction mixture and stirred at 25° C. for about 2 hours. Water (40 mL) was added and the resulting mixture was extracted with ether (2×), dried (anhydrous Na2SO4), filtered and concentrated in vacuo to yield 1.2 g crude oil. Oil was chromatographed with dry pack silica gel (230-400 mesh) with descending solvent gradient from 100% petroleum ether to 80/20 pet ether/ethyl acetate as mobile phase. Elution and concentrated gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(t-butoxycarbonyl)-2-pyridinyl]oxy]methyl]-3-fluoro-benzeneacetamide (520 mg) as an oil. (98% E isomer; 2% Z isomer).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C([O:17][C:18](=[O:43])[CH2:19][CH2:20][NH:21][CH2:22][C:23]1[CH:42]=[CH:41][C:26]2[S:27][C:28]([C:30]3[CH:35]=[CH:34][C:33](Cl)=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[CH:29][C:25]=2[CH:24]=1)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:1]1([C:33]2[CH:34]=[CH:35][C:30]([C:28]3[S:27][C:26]4[CH:41]=[CH:42][C:23]([CH2:22][NH:21][CH2:20][CH2:19][C:18]([OH:43])=[O:17])=[CH:24][C:25]=4[CH:29]=3)=[CH:31][C:32]=2[C:37]([F:38])([F:40])[F:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)CCNCc1ccc2sc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(O)CCNCc1ccc2sc(-c3ccc(N4CCCCC4)c(C(F)(F)F)c3)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
Piperidine (30 μL, 2.0 mmol), Pd2 dba3 (2.7 mg, 0.003 mmol), potassium t-butoxide (59 mg, 0.53 mmol) and 1,3-bis-(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene HCl salt (2.6 mg, 0.006 mmol) are added sequentially to a solution of 3-{[2-(4-chloro-3-trifluoromethyl-phenyl)-benzo[b]thiophen-5-ylmethyl]-amino}-propionic acid tert-butyl ester (72 mg, 0.15 mmol) in 1,4-dioxane (0.8 mL). The mixture is irradiated in a microwave at 100° C. for 1 hour. The reaction is quenched with water and the mixture is concentrated in vacuo. The residue is dissolved in THF and aqueous 2N NaOH (4 mL, 1:1 v/v), and stirred at 60° C. for 3 hours. It is concentrated and purified with preparative LCMS to afford 20 mg of 3-{[2-(4-piperidin-1-yl-3-trifluoromethyl-phenyl)-benzo[b]thiophen-5-ylmethyl]-amino}-propionic acid, which is converted to HCl salt: 1H NMR (400 MHz, CD3OD) δ 8.15-8.00 (m, 4H), 7.87 (s, 1H), 7.63 (d, 1H), 7.57 (d, 1H), 4.48 (s, 2H), 3.44 (t, 2H), 3.03 (t, 4H), 2.89 (t, 2H), 1.90-1.80 (m, 4H), 1.75-1.65 (m, 2H); MS (ES) 463.4 (M+H+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[CH3:40][N:41](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)[CH3:42].C(N(C(C)C)C(C)C)C.CNC>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([N:41]([CH3:42])[CH3:40])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.007 g (0.15 mmole) dimethylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.041 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N,N-dimethyl-benzamide (I-125) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:20][CH:21]1[CH:23]([C:24](O)=[O:25])[C:22]1([CH3:28])[CH3:27])[CH2:16][CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[CH2:15]([O:20][CH:21]1[CH:23]([C:24]([O:14][CH2:13][C:9]2[NH:10][CH:11]=[CH:12][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:25])[C:22]1([CH3:27])[CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CCCCCOC1C(C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCOC1C(C(=O)OCc2[nH]ccc2Cc2ccccc2)C1(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-benzylpyrrolylmethyl alcohol (1.8 mmol), 3-(n-pentyloxy)-2,2-dimethylcyclopropanecarboxylic acid (2.0 mmol) and 4-dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of DMF is added N,N'-dicyclohexylcarbodiimide (2 mmol). The reaction mixture is stirred, under nitrogen, for about two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a rotary chromatograph eluting with ether/hexane to yield 3-benzylpyrrolylmethyl 3-(n-pentyloxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccccc2)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccccc2)c1

Procedure:
131 mg of compound 26 was obtained in a similar manner to those described in the Examples 1 and 2 using 223 mg of ethyl 4-(2-aminophenoxy)butyrate and 291 mg of 3-(1-benzylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]([F:30])([F:29])[CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:17][C:16]([F:30])([F:29])[F:15])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 520 mg, 13.0 mmol) was added to a stirred, cooled (0° C.) solution of methyl 3-bromo-4-hydroxybenzoate (Description 64, 3.0 g, 13.0 mmol) in N,N'-dimethylformamide (100 ml) and the mixture was stirred at 0° C. for 15 min. 2,2,2-Trifluoroethyltosylate (6.61 g, 26.0 mmol) in N,N'-dimethylformamide (50 ml) was added and the mixture was stirred at 100° C. for 16 h. The mixture was concentrated under reduced pressure to half volume and poured into aqueous sodium hydroxide solution (1 M, 300 ml). The mixture was extracted with ethyl acetate (2×350 ml) and the combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc to give the title compound as a colorless oil (1.37 g, 34%). 1H NMR (250 MHz, CDCl3) δ8.27 (1 H, d, J 2.1 Hz), 7.99 (1 H, dd, J 2.1, 8.6 Hz), 6.92 (1 H, d, J 8.6 Hz), 4.42-4.52 (2 H, quartet, J 7.9 Hz), and 3.91 (3 H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6](=[NH:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](C(CCCCCC)C([O-])=O)=[CH:11][CH:10]=1)=[NH:4].CN(C)C(NC(=N)NCC1C=CC(CC[N:43](CC)[C:44](=[O:46])[O-:45])=CC=1)=N>>[C:9]([O:45][C:44](=[O:46])[NH:43][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][NH:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:1])[CH3:26])=[NH:25])=[CH:14][CH:13]=1)([CH3:14])([CH3:10])[CH3:8]
Reactant: CCN(CCc1ccc(CNC(=N)NC(=N)N(C)C)cc1)C(=O)[O-]
Reactant: CCCCCCC(C(=O)[O-])c1ccc(CNC(=N)NC(=N)N(C)C)cc1
Product: CN(C)C(=N)NC(=N)NCc1ccc(NC(=O)OC(C)(C)C)cc1

Procedure:
In a similar manner 4-{[3-(N,N-Dimethylcarbamimidoyl)guanidino]methyl}phenyl-octanoate (Example 14) and 4-{[3-(N,N Dimethylcarbamimidoyl)guanidino]methyl}phenyl-diethylcarbamate (Example 15) were synthesized.
Reaction SMILES: Br[C:2](=[C:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][CH:39]=[CH:40][N:41]=1)CCC>C1COCC1.CCOC(C)=O>[C:3]1([C:2](=[C:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]3[C:26]4[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=4[O:27][CH3:28])[NH:20][CH:19]=3)=[O:17])[CH2:11][CH2:10]2)[C:37]2[S:38][CH:39]=[CH:40][N:41]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(Br)c4ccccc4)CC3)c[nH]c12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4nccs4)CC3)c[nH]c12
Temperature: 90 °C
Yield: 34.1 %

Procedure:
A mixture of 1-[4-(1-bromo-1-phenyl-methylene)-piperidin-1-yl]-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione (0.032 g, 0.066 mmol), 2-(tri-n-butylstannyl)thiazole (0.025 g, 0.066 mmol) and bistriphenylphosphinepalladium dichloride (0.001 g, 1 mol %) in THF (4 mL) was heated at 90° C. in a sealed tube under Ar for 15 h. The cooled mixture was then diluted with EtOAc, washed (1M KF, brine), dried (Na2SO4) and evaporated to give a clear yellow oil. Purification by preparative HPLC afforded the product (0.011 g, 34%) as a white solid:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH:5]=[C:4]([Br:13])[C:3]=1[OH:14].[Sn].O>CC(O)=O.Cl>[Br:13][C:4]1[C:3]([OH:14])=[CH:2][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2
Reactant: Oc1ccc2cc(Br)c(O)c(Br)c2c1
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2cc(Br)c(O)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,3-dibromonaphthalene-2,7-diol (48.76 g, 153.34 mmol) (Helv. Chim. Acta, 78, pp. 1037-1066, 1995) in AcOH/HCl is added tin (17.48 g, 147.21 mmol) in portions. The mixture is stirred vigorously at room temperature for 1 h. The reaction forms a paste and is stirred for an additional 4 h, at which point it becomes mobile again. Stirring is continued overnight. The mixture is poured into water (1 L) and extracted with EtOAc. The organic layer is dried over MgSO4, filtered and concentrated to afford a sticky beige solid. The solid is triturated with DCM and filtered to afford 3-bromonaphthalene-2,7-diol as a fluffy beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([N:12]=[C:13]=[O:14])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH:17][CH2:18][CH:19]=[O:20])[CH3:16]>C1C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH:19]=[O:20])[C:13]([NH:12][C:10]1[S:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14])[CH3:16]
Reactant: CCNCC=O
Reactant: COc1cccc2sc(N=C=O)nc12
Solvent: c1ccccc1
Product: CCN(CC=O)C(=O)Nc1nc2c(OC)cccc2s1
Reaction time: 1 h

Procedure:
4-Methoxybenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-ethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-ethyl-3-(4-methoxybenzothiazol-2-yl)ureido]acetaldehyde as the residue.