Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH:3]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=CC(F)(F)c1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(F)(F)c1ccccc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Intermediate 19 (0.88 g, 5.64 mmol) was dissolved in THF (12 mL) and (carbethoxymethylene) triphenylphosphorane (1.96 g, 5.64 mmol) was then added. The solution was stirred at 50° C. for 12 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel using n-hexane/AcOEt (5:1) as eluent. The title compound was obtained (1.10 g, 89%) as pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[N:30]=[C:31]=S.C(O)C.CC(N=C=NC(C)C)C>CN(C=O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[NH:30][C:31]1[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:3]2[C:2]([N:1]=1)=[CH:7][N:6]=[C:5]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([OH:15])[CH2:13][CH2:14]1)[N:4]=2
Reactant: Fc1cccc(F)c1N=C=S
Reactant: Nc1cnc(N[C@H]2CC[C@H](O)CC2)nc1NC1CCCC1
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H]1CC[C@H](Nc2ncc3nc(Nc4c(F)cccc4F)n(C4CCCC4)c3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-{[5-Amino-4-(cyclopentylamino)pyrimidin-2-yl]amino}trans-cyclohexan-1-ol (1.13 mmol, 330 mg) was dissolved in DMF (8.5 mL) and 2,6-difluorophenyl-isothiocyanate (1.13 mmol, 0.146 mL) was added. The reaction mixture was stirred at room temperature for about 90 minutes. Ethanol (2.5 mL) was added and the reaction mixture was stirred for about an additional 30 minutes. N,N-Diisopropylcarbodiimide (3.40 mmol, 0.532 mL) was added and the reaction mixture was stirred overnight. Solvent was removed and the residue was purified using column chromatography (SiO2, 1:1 n-hexanes/ethyl acetate→ethyl acetate→1% methanol/ethyl acetate) to give the desired product (222.5 mg, 46% yield). ES-MS: 429 (M+1). Tetrahydrofuran can also be used as solvent in this step.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CC#N>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:17]1[CH2:16][CH2:15][N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH3:6])[CH2:19][CH2:18]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: ClCC1CO1
Solvent: CC#N
Product: COc1ccccc1N1CCN(CC(O)CCl)CC1

Procedure:
To epichlorohydrin (3.9 ML, 50 mmol) in CH3CN (3 mL) at 0° C. was added 1-(2-methoxyphenyl)piperazine (9 mL, 50 mmol) in CH3CN (20 mL) dropwise over 5 minutes under a nitrogen atmosphere. After 16 hours the resultant white precipitate was filtered away, washed with CH3CN and acetone, dried at 30° C. in a vacuum oven and identified as pure product (7.28 g, 51.1%). mp 96°-98° C. DCI/MS M+1=285. (100 MHz) 1 H nmr (dmso-d6) δ:6.9 (m, 4H), 3.76(m, 1H), 3.76 (s, 3H), 3.62 (d of d, 2H), 2.96 (m, 4H), 2.56 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][C:18](Br)=[O:19].O>ClCCl>[Br:16][CH2:17][C:18]([NH:4][C:3]1[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=1[F:9])=[O:19]
Reactant: Nc1c(F)cccc1F
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2,6-difluoroaniline (1.12 g) and potassium carbonate (1.8 g) in 50 mL dichloromethane was added bromoacetyl bromide (1.5 mL) and the mixture was stirred at room temperature for 17 h. Water was added and the mixture stirred for several hours then the phases were separated on a hydrophobic frit and the organic layer was evaporated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane to give the sub-titled compound (0.92 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].Cl>O1CCCC1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2,6-dimethyl-3-nitrobenzoic acid (3.09 g) in tetrahydrofuran (5 ml) was added borane-methyl sulfide complex (2.41 g) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature, for 1 hour at ambient temperature, and then for 4 hours under heating. To the mixture was added 1N hydrochloric acid under ice-cooling, and the mixture was allowed to stand overnight. The mixture was extracted with ethyl acetate twice, and the combined organic layer was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The residue was recrystallized with diisopropyl ether to give 2,6- dimethyl-3-nitrobenzyl alcohol (2.296 g) as a pale yellow crystal.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[C:15]([C:22]([OH:24])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:15]3[C:16](=[O:21])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([OH:10])=[CH:20][CH:19]=4)=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: O=C(O)c1cc2cc(O)ccc2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(O)ccc2oc1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
DIEA (46.5 μL, 0.27 mmol) was added to 6-hydroxy-3-carboxy-coumarin (50.0 mg, 0.24 mmol) and HATU (101.4 mg, 0.27 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (50.8 mg, 0.24 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 81.1 mg of product in 85% yield: LCMS (ESI) m/z 398 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[CH2:19][C:10]2[O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[C:9]=2[CH2:8][CH2:7]1)[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[CH:19]=1)[CH3:2]
Reactant: CCOC(=O)CC1CCc2c(oc3ccc(Cl)cc23)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc2c(c1)oc1ccc(Cl)cc12

Procedure:
A mixture of 7.23 g. of 8-chloro-1,2-dihydro-3(4H)-dibenzofuranacetic acid ethyl ester, 11.8 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 150 ml. of benzene was stirred at reflux temperature for 18 hours under an atmosphere of nitrogen, and then cooled. The solid was removed by filtration and washed with benzene. The filtrate and washings were combined and concentrated under reduced pressure to yield 14.1 g. of dark oil, which was dissolved in methylene chloride and filtered through 143.5 g. of alumina II (neutral) in a column 60 mm. in width and 65 mm. in lenght. The eluate was evaporated to 3.28 g. of yellowish solid, which was crystallized first from a mixutre of ether-pentane, and then from ether alone to give 1.35 g. of 8-chloro-'-dibenzofuranacetic acid ethyl ester having a melting point of 90°-91°.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[C:3]=1Cl.[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23]>ClCCl>[CH3:5][C:4]1[CH:3]=[CH:2][C:14]2[C:5]3([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]4[C:4]3=[CH:3][CH:2]=[CH:14][CH:13]=4)[C:20]3[C:21]([O:22][C:13]=2[CH:12]=1)=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]=3
Reactant: Cc1cccc(O)c1
Reactant: Clc1ccc2c(c1Cl)Cc1ccccc1-2
Solvent: ClCCl
Product: Cc1ccc2c(c1)Oc1cc(C)ccc1C21c2ccccc2-c2ccccc21
Temperature: 40 °C

Procedure:
Dichlorofluorene (DCF) (35.27 g, 0.15 mole) is weighed into a powder addition funnel and dissolved in 20 mL of dry dichloromethane. Liquid m-cresol (64.88 g, 0.6 mole) is weighed into a 250 mL three-necked round-bottomed flask which is equipped with a stirrer, heating mantle, nitrogen inlet, condenser, thermometer, and drying tube. Dry dichloromethane (80 mL) is added and the mixture is heated to 40° C. with stirring. DCF solution is added slowly to the mixture as the temperature is maintained at about 40° C. The reaction is rapid as evidenced by copious production of HCl bubbles after each addition. After addition is complete, the reaction is stirred for an additional half hour and then checked by LC. The reaction is complete, and the chromatograph shows peaks for the desired bisphenol (9,9-bis(2-hydroxy-4-methylphenyl)fluorene) along with isomers. The mixture is dissolved in toluene and refluxed with 0.5 mL of methanesulfonic acid collecting water formed during the cyclization reaction in a Dean-Stark trap. The toluene is then removed by rotary evaporation and the residue is slurried with acetonitrile, chilled and filtered to yield the spiro-ether [3',6'-dimethylspiro[fluorene-9,9'-xanthene] as an off-white powder. The isomeric bisphenols formed in the alkylation reaction do not cyclize and remain dissolved in the acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[N:3]=1.[C:25]([NH2:28])(=[O:27])[CH3:26]>[Cu]>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:4]2[N:3]=[C:2]([NH:28][C:25](=[O:27])[CH3:26])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[CH:5]=2)[CH:21]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)cc(Cl)n1
Reactant: CC(N)=O
Agent: [Cu]
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)cc(NC(C)=O)n1
Temperature: 180 °C
Yield: 23.5 %

Procedure:
A mixture of [2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl]-p-tolyl-amine (60 mg, 0.167 mmol) prepared according to Example 1, copper powder (100 mg, 1.54 mmol) and acetamide (2.0 g, 33.9 mmol) was heated at 180° C. for 3 hours. The mixture was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:1 followed by 3:2) to provide title compound (15 mg, 23% yield). 1H NMR (acetone-d6) δ 2.19 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.91 (s, 3H, CH3), 7.12 (d, 1H, J=8.8 Hz, Ar), 7.19-7.25 (m, 4H, Ar), 7.35 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.47-7.48 (m, 1H, Ar), 7.86 (s, 1H, NH), 7.89 (d, 1H, J=2.8 Hz, Ar), 8.05 (s, 1H, NH).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:6]=1[C:15](=[O:17])[CH3:16])(=O)C.[OH-].[K+].O>C(O)C>[NH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:6]=1[C:15](=[O:17])[CH3:16]
Reactant: COc1cc(NC(C)=O)c(C(C)=O)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(C(C)=O)c(OC)c1
Yield: 58.4 %

Procedure:
A mixture of (2'-acetylamino-4',6'-dimethoxyphenyl)ethanone (compound 75-3, prepared in Preparation 75) (0.237 g, 1.0 mmol), potassium hydroxide (0.2 g, 3.57 mmol), water (0.2 ml), and ethanol (2 ml) is heated to reflux for one hour. The solvent is distilled under reduced pressure, and the residue is extracted with dichloromethane. The extract is washed with water, dried, and the solvent is removed to yield a crystalline residue. Recrystallization from ethyl acetate gives (2'-amino-4',6'-dimethoxyphenyl)ethanone as a crystalline solid (0.114 g, 58%, m.p.=104°-105° C.).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][N:23]=[C:24]=S)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:24]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:2][C:3]=2[CH:7]=1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: S=C=NCCCCc1ccccc1
Agent: Cl
Product: O=S1(=O)N=C(NCCCCc2ccccc2)Nc2cc(Cl)sc21

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and 4-phenylbutyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 201°-205° C.; 1H-NMR (DMSO-d6): δ 1.55 (m, 4H), 2.6 (t, 2H), 3.2 (q, 2H), 7.04 (s, 1H), 7.1-7.4 (m, 6H), 10.94 (br. s, 1H).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[N:10][C:9]=2[CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]=1[CH3:26].[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[CH:32][CH:31]=1.C(N(CC)CC)C>CN(C=O)C.[O-]S(C(F)(F)F)(=O)=O.[Zn+2].[O-]S(C(F)(F)F)(=O)=O>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:2]2[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]3[N:12]([C:13]4[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=4[Cl:20])[N:11]=[N:10][C:9]=3[CH:21]([CH3:22])[CH3:23])=[CH:4][C:3]=2[CH3:26])=[CH:32][CH:31]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1Br
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a room temperature solution of 5-(4-bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-[1,2,3]triazole (50 mg, 0.110 mmol) in DMF (1 mL) are added 4-ethynyl-benzoic acid methyl ester (18 mg, 0.110 mmol) and triethylamine (107 μL, 0.770 mmol). The reaction mixture is degassed for 20 minutes with nitrogen. To the reaction mixture are added dichloro(bistriphenylphosphine) palladium (II) (8 mg, 0.011 mmol, 10 mol %) and zinc (II) triflate (40 mg, 0.110 mmol). The reaction mixture is heated to 80° C. After 3 h, the reaction is concentrated and the residue is chromatographed (40 g SiO2, 0% to 5% EtOAc/Hexanes) to yield 4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenylethynyl}-benzoic acid methyl ester (38 mg, 64%). LC/MS m/e 534.2 (M+1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=1)[O:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1.[NH2:45][C:46]1[N:55]=[C:54]([N:56]2[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]2)[C:53]2[C:48](=[CH:49][C:50]([C:63](O)=[O:64])=[CH:51][CH:52]=2)[N:47]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:45][C:46]1[N:55]=[C:54]([N:56]2[CH2:57][CH2:58][N:59]([CH3:62])[CH2:60][CH2:61]2)[C:53]2[C:48](=[CH:49][C:50]([C:63]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=3)[O:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[O:64])=[CH:51][CH:52]=2)[N:47]=1
Reactant: COC(=O)c1ccc(Oc2cccc(CN)c2)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccc(CNC(=O)c3ccc4c(N5CCN(C)CC5)nc(N)nc4c3)c2)cc1
Reaction time: 1 h
Yield: 73 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of methyl 4-[3-(aminomethyl)phenoxy]benzoate-HCl (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-Dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified without workup by RP-HPLC (pH=10) to give the desired product (0.020 g, 50%) as a white amorphous solid. 1H NMR (400 MHz, DMSO): δ 9.16 (m, 1H), 7.89 (d, 2H), 7.70 (m, 2H), 7.36 (m, 2H), 7.14 (d, 1H), 6.99 (d, 2H), 6.95 (m, 2H), 6.39 (bs, 2H), 4.44 (d, 2H), 3.75 (s, 3H), 3.50 (bs, 4H), 3.29 (s, 4H), 2.18 (s, 3H); Analytical LCMS (M+H)+: m/z=527.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:21]>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:16]([F:21])=[O:18])[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)F
Reaction time: 8 h
Yield: 120.1 %

Procedure:
Formula 502 where R6 is Isopropyl and R6′ is H: To a solution of dichloromethane (100 mL) and N-benzyloxycarbonyl D-valine (9 g, 35.8 mmol) was added cyanuric fluoride (2.4 mL, 26.1 mmol). The reaction mixture was stirred overnight and then filtered through Celite. The remaining solution was washed with ice-water and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the substantially pure acid fluoride product of Formula 502, (1-fluorocarbonyl-2-methyl-propyl)-carbamic acid benzyl ester (7.94 g, 87.6%).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][C@H:9]([NH:13][C:14](=[O:33])[C@@H:15]([NH:26][C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=1)[C:10]([OH:12])=O)(C)(C)C.[ClH:35].[NH2:36][C@@H:37]([CH2:49][C:50]([NH2:52])=[O:51])[C:38]([NH:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C=O)C>[ClH:35].[CH2:30]([O:29][C:27]([NH:26][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=1)[C:14]([NH:13][C@H:9]([C:10](=[O:12])[NH:36][C@H:37]([C:38](=[O:39])[NH:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:49][C:50](=[O:51])[NH2:52])[CH2:8][CH2:7][C:6]([OH:5])=[O:34])=[O:33])=[O:28])[CH:31]=[CH2:32]
Reactant: NC(=O)C[C@H](N)C(=O)NCCc1ccccc1
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(S)-[2-(S)-allyloxycarbonylamino-3-(4-carbamimidoyl-phenyl)-propionylamino]-pentanedioic acid 5-tert-butyl ester (48 mg, 0.1 mmol) and 2-(S)-amino-N1-phenylethyl-succinamide hydrochloride (27 mg, 0.1 mmol) in 5 ml of DMF were added at 0° C. HATU (39 mg, 0.1 mmol) and collidine (24.2 mg, 0.2 mmol). The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation the residue was purified by chromatography on Sephadex LH20 employing n-butanol/glacial acetic acid/water (17/1/2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water and the aqueous solution was freeze-dried. Yield: 45 mg (66%). MS: m/z=638.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]([C:19]2[C:20]([OH:34])=[N:21][C:22]([C:25]([NH:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:26])=[N:23][CH:24]=2)=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>[OH-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]([C:19]2[C:20]([OH:34])=[N:21][C:22]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[N:23][CH:24]=2)=[O:18])[C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNC(=O)c1ncc(C(=O)NC(c2ccc(F)cc2)c2ccc(F)cc2)c(O)n1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1ncc(C(=O)NC(c2ccc(F)cc2)c2ccc(F)cc2)c(O)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a 10% KOH solution (30 mL) was added compound 2-18 (53 mg, 0.11 mmol), and the mixture was stirred at 50° C. for 30 min, then cooled to room temperature. The cooled mixture was washed with DCM (30 mL×2). The aqueous phase was acidified with 5% HCl to about a pH 2˜3, filtrated and dried to afford compound 2-19 as a white solid (42 mg, 85%). 1H NMR (300 MHz, DMSO-d6): δ 3.92-3.95 (d, J=9.0 Hz, 2H), 6.28-6.31 (d, J=9.0 Hz, 2H), 7.18-7.34 (m, 8H), 8.47 (s, 1H), 9.36-9.39 (m, 1H), 10.33 (br s, 1H). LC-MS: (M+Na)+ 465.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][CH2:8][CH:9]([N:17]=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:44][CH2:45][CH2:46][CH2:47][B:48]1[O:52][C:51]([CH3:54])([CH3:53])[C:50]([CH3:56])([CH3:55])[O:49]1.O>O1CCCC1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][CH2:8][C:9]([N:17]=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:44][CH2:45][CH2:46][CH2:47][B:48]2[O:52][C:51]([CH3:54])([CH3:53])[C:50]([CH3:55])([CH3:56])[O:49]2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(CCCCI)OC1(C)C
Reactant: CC(C)(C)OC(=O)C(CCOc1ccc(Cl)cc1)N=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCOc1ccc(Cl)cc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
While under a nitrogen atmosphere, a solution of tert-butyl 4-(4-chlorophenoxy)-2-(diphenylmethyleneamino)butanoate (450 mg, 1.0 mmol) in tetrahydrofuran (7 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (2.0 mL, 1.0 M in tetrahydrofuran, 2.0 mmol) in a dropwise manner. After the addition was complete, stirring was continued for 30 minutes and 2-(4-iodobutyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (931 mg, 3.0 mmol) was slowly added to the reaction mixture. Stirring was continued for 2 more hours, and then slowly warmed to room temperature overnight. The resulting solution was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 0-15% ethyl acetate in heptane) gave tert-butyl 2-(2-(4-chlorophenoxy)ethyl)-2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (486 mg. 77%); 1H NMR (CDCl3, 300 MHz) δH 7.54 (d, J=7 Hz, 2H), 7.36 (m, 4H), 7.18-7.32 (m, 6H), 6.82 (d, J=9 Hz, 2H), 4.19 (m, 1H), 4.04 (m, 1H), 2.39 (ddd, J=14 Hz, J2=9.5 Hz, J3=5.0 Hz, 1H), 2.22 (ddd, J1=13.5 Hz, J2=9.5 Hz, J3=5.0 Hz, 1H), 1.73 (m, 2H), 1.14-1.46 (m, 4H), 1.34 (s, 9H), 1.18 (s, 12H) and 0.76 (t, J=7 Hz, 2H); MS (+CI): m/z for C37H47BClNO5: expected 631.3. found 632.3 (M+H)+, 576.3 (M+H-isobutene)+.