Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[S:44][CH:45]=[CH:46][N:47]=1)CCC.O>COCCOC.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>[S:44]1[CH:45]=[CH:46][N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:27][CH2:28][CH2:29]2)=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nccs4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (300 mg, 0.54 mmol), 2-(tributylstannyl)thiazole (337 μA, 1.1 mmol), and PdCl2(PPh3)2 (38 mg, 0.047 mmol) in 1,2-dimethoxyethane (10 ml) was added to a crimp top microwave vial, which was then sealed and heated under microwave irradiation conditions at 130° C. for 60 min. After cooling to room temperature the mixture was poured into water and extracted into ethyl acetate. The organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography (hexane/ethyl acetate; 0-100% ethyl acetate over 60 min) to give a yellow amorphous (quant.). 1HNMR (CDCl3) 400 MHz δ: 8.18 (1H, dd, J=7.7, 1.4 Hz), 8.02 (1H, d, J=4.0 Hz), 7.75 (1H, d, J=2.9 Hz), 7.44-7.37 (3H, m), 7.32 (1H, td, J=7.5, 1.7 Hz), 7.24 (1H, d, J=2.9 Hz), 7.15 (1H, td, J=7.4, 1.2 Hz), 6.97 (1H, d, J=8.0 Hz) 6.89-6.81 (1H, m), 6.61 (1H, dd, J=7.7, 4.9 Hz), 6.48 (1H, s), 5.18 (1H, s), 2.60-2.32 (4H, m), 2.17-2.08 (1H, m), 1.93-1.84 (1H, m), 1.48-1.21 (9H, m); LC/MS [M+H]: 563.
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O.C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1ccc(C=O)cc1O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1O
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Piperidine (0.25 mL, 2.5 mmol) was added to a suspension of 3-hydroxy-4-methoxybenzaldehyde (0.39 g, 2.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.50 g, 2.2 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 3 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5.0 mL) and water (2.0 mL) at 40° C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(3-hydroxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.53 g, 76%) as a yellow crystalline solid; mp 215-216° C., lit.5 219-222° C.; δH (500 MHz, DMSO-d6) 3.81 (s, 3H, OCH3), 6.59 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6=8.5 Hz, 1H, H5′), 7.10-7.13 (m, 2H, H2′, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.47 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.99 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.58 (d, J5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.56 (br s, 1H, CO2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([C:22]1[NH:32][C:25]2=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]2[N:23]=1)[CH3:21].O[CH:34]1[C:42]2[C:37](=[CH:38][C:39]([C:43]3[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=3[C:45]#[N:46])=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>C1(C)C=CC=CC=1>[CH2:20]([C:22]1[N:32]([CH:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43]4[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=4[C:45]#[N:46])=[CH:40][CH:41]=3)[CH2:36][CH2:35]2)[C:25]2=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]2[N:23]=1)[CH3:21]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: N#Cc1ccccc1-c1ccc2c(c1)CCC2O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1C1CCc2cc(-c3ccccc3C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of triphenylphosphine (393 mg, 1.5 mmol) in toluene was slowly added diethylazadicarboxylate (261 mg, 1.5 mmol). After 1 hour, this solution was added to a mixture of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (350 mg, 2.0 mmol) and 2-(1-hydroxy-indan-5-yl)-benzonitrile (246 mmol, 1.01 mmol). The reaction mixture was stirred for 17 hours at room temperature and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 30% ethyl acetate/hexanes. The residue was dissolved in CHCl3, hexanes were added to precipitate out a white solid. The mixture was filtered and the filtrate was concentrated in vacuo to give a yellow oil which solidified upon standing.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][N:6]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([CH:3]2[CH2:2][O:4]2)=[N:6][CH:7]=1)[CH3:12]
Reactant: CCc1ccc(C(O)CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1ccc(C2CO2)nc1
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a stirred solution of 10 g (0.0426 mol) of 2-bromo-1-(5-ethyl pyridin-2-yl)-ethanol dissolved in 50 mL of methanol, 6.86 g (0.0511 mol) potassium carbonate was added at 25-30° C. and stirring was continued for 1 hr. Subsequently filtered and methanol was concentrated to furnish 5.8 g (90%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([F:18])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:19])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[C:12]([F:18])[CH:11]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(Oc1ccc(C#N)c(F)c1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Yield: 94.8 %

Procedure:
(±)-2-(4-Cyano-3-fluoro-phenoxy)-propionic acid tert-butyl ester (1.77 g, 6.7 mmol) was shaken on a Parr shaker under 40 psi hydrogen for 30 min, using palladium hydroxide on carbon (1 g, 30% Pd by wt) in 200 mL anhydrous methanol. The reaction mixture was filtered through sintered glass, and solvents removed in vacuo to afford 1.71 g colorless oil (95% yield).
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C=O)C.O>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:29][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35])[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 78 %

Procedure:
8-Bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,71-1)-dione (33.4 g, 90.4 mmol, intermediate 8), potassium carbonate (25.0 g, 180.8 mmol) and TBAI (0.225 g) were combined in DMF (460 mL). To the mixture was added (3-bromopropoxy)(tert-butyl)dimethylsilane (25.17 g, 99.4 mmol) and the reaction was heated at 100° C. for 4 h. The reaction was cooled to room temperature, diluted with water (1.2 L) and extracted with ethyl acetate (3×400 mL). The combined organic extracts were washed with 1N lithium chloride (2×500 mL), dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give a light golden oil. The oil was purified using 2×120 g silica gel columns eluted with 10% ethyl acetate/hexanes to yield 8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (38.3 g, 78% yield) as an off-white solid. LCMS retention time=5.083 min and 99% purity, LCMS MH+ 543. 1H NMR (CDCl3) δ 7.29-7.34 (m, 4H), 5.50 (s, 2H), 4.08 (t, 2H, J=8 Hz), 3.70 (t, 2H, J=8 Hz), 3.53 (s, 3H), 1.83-1.90 (m, 2H), 0.86(s, 9H), 0.02 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2nc3ccccc3s2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C=Cc2nc3ccccc3s2)cc1
Yield: 9.3 %

Procedure:
A mixture of 2-(4-nitrophenylethenyl)benthiazole 11 (500 mg, 1.7 mmol) and tin (II) chloride dihydrate (1.18 g, 5.2 mmol) in anhydrous ethanol (20 ml) was refluxed under N2 for 4 hrs. Ethanol was removed by vacuum evaporation. The residue was dissolved into ethyl acetate (20 ml), washed with NaOH solution (1 N, 3×20 ml) and water (3×20 ml), and dried over MgSO4. Evaporation to dryness gave 40 mg (8.0%) of product 12.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][CH2:14]2)=[C:6]([CH3:25])[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][C:6]=2[CH3:25])[CH2:14][CH2:15]1
Reactant: COC(=O)c1ccc(OCCN2CCN(CCC(C)(C)C)CC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1OCCN1CCN(CCC(C)(C)C)CC1
Yield: 100 %

Procedure:
4-{2-[4-(3,3-Dimethyl-butyl)-piperazin-1-yl]-ethoxy}-3-methyl-benzoic acid methyl ester from Example E40.3 (42 mg, 0.12 mmol) was dissolved in dioxan (5 ml) and 1M NaOH (1 ml) was added. The mixture was heated at reflux for 2 h then solvents were concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3, water then brine, dried and concentrated in vacuo to yield the title compound (40 mg, 100%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C@@:20]([O:24]C(C1C(C(O)=O)=CC=CC=1)=O)([C:22]#[CH:23])[CH3:21])(=[O:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C@@:20]([CH3:21])([OH:24])[C:22]#[CH:23])(=[O:3])[CH3:2]
Reactant: C#C[C@@](C)(CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O)OC(=O)c1ccccc1C(=O)O
Solvent: ClC(Cl)Cl
Product: C#C[C@](C)(O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O

Procedure:
By the same procedure as described above (example 11), this compound was prepared from (R)-1,2-benzenedicarboxylic acid[3-[2,5-bis(acetyloxy)-3,4,6-trimethylphenyl]-1-ethynyl-1-methylpropyl]ester, as white crystals=mp 100°-103° C., [α]D25 -17.38° (CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C@@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]2[NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:23][CH:22]=1)(=[O:26])[CH3:25]
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1c1ccccc1)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc([C@@H]2CCCC[C@H]2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 42.5 %

Procedure:
To a mixture maintained at 0° C. of 4.0 g (12 mmoles) of trans-4-chloro-N-(2-phenylcyclohexyl)-benzenesulfonamide (prepared according to Das P. C. et al., Indian J. Chem. (1974), 12, 1139-40), 80 ml of anhydrous dichloromethane and 2.4 g (31 mmoles) of acetyl chloride, 5.3 g (40 mmoles) of aluminum chloride are added by fractions. After 4 hours at 0° C., the reaction mixture is thrown onto an ice-HCl mixture before being extracted with dichloromethane. The organic phase is washed with water to neutrality, dried over Na2SO4 and concentrated. The residue is purified by chromatography on a column of silica (eluant:hexane-ethyl acetate 4/1) to give 2 g of a colorless oil (yield:42.5%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]CC5C=CC(OC)=CC=5)=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[CH:3]=[N:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[CH:3]=[N:2]1
Reactant: COc1ccc(COC(=O)c2ccc3nc(-c4ccc5oncc5c4)c(N(C)C(C)C)nc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2oncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To a solution of (4-methoxyphenyl)methyl 2-(1,2-benzoxazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (50 mg, 0.10 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The solution was stirred for 30 min at room temperature. Then the reaction was quenched by the addition of water (100 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 5% dichloromethane in methanol to afford 2-(1,2-benzoxazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a yellow solid (12.3 mg, 33%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1.[O:19]1[CH2:23][CH2:22][NH:21][C:20]1=[O:24]>>[O:17]=[S:13]1(=[O:18])[CH2:14][CH2:15][CH2:16][N:12]1[C:4]1[CH:3]=[C:2]([N:21]2[CH2:22][CH2:23][O:19][C:20]2=[O:24])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1NCCO1
Reactant: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Product: COC(=O)c1ccc(N2CCOC2=O)cc1N1CCCS1(=O)=O
Yield: 37.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using methyl 4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)benzoate (2 g) described in Preparation Example 116 and oxazolidin-2-one (515 mg), the title compound (758 mg) was obtained.
Reaction SMILES: CO[C:3](=[O:69])[C@H:4]([CH2:60][O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:5][C:6](=[O:59])[C@H:7]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:47][CH:46]=1)[NH:8][C:9](=[O:43])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:42])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:41])[C@H:22]([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[NH3:70]>CO>[C:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([NH2:70])=[O:69])[CH2:60][O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:59])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:47][CH:46]=1)=[O:43])=[O:42])=[O:41])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: N
Reactant: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](COCc1ccccc1)C(N)=O
Reaction time: 72 h

Procedure:
Nα -t-Butoxycarbonyl-L-tryptophyl-L-prolyl-L-prolyl-O-benzyl-L-tyrosyl-O-benzyl-L-serine methyl ester (0.5 g.) is dissolved in methanol, 25 ml., and the solution saturated with gaseous ammonia. The reaction is let stand for three days at room temperature, and the solvent then removed by evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:26]([O-:28])=[O:27])[CH2:13][CH2:14][C:15](=[O:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:40](O)[CH2:41][OH:42]>C1CCCCC1>[CH2:41]1[O:42][C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH2:14][CH2:13][CH:12]([N+:26]([O-:28])=[O:27])[CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:25][CH2:40]1
Reactant: COc1ccc(CC(CCC(=O)CCc2ccc(F)cc2)[N+](=O)[O-])cc1OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: COc1ccc(CC(CCC2(CCc3ccc(F)cc3)OCCO2)[N+](=O)[O-])cc1OC

Procedure:
Into a 1 l. r.b. flask equipped with a Dean-Stark trap was placed 79 g (0.2 mole) of 1-(3',4'-dimethoxyphenyl)-7-(4'-fluorophenyl)-2-nitro-5-heptanone, 38 g p-toluenesulfonic acid, 120 ml ethylene glycol and 400 ml cyclohexane. The mixture was allowed to reflux overnight, then concentrated in vacuo. Dil NaHCO3 solution was added to the residue and extracted with methylene chloride. The organic layer was backwashed with water, dried over anh MgSO4, filtered and concentrated under reduced pressure to obtain 84.8 g of oily product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]([CH3:35])[C:32]([NH2:34])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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]>[CH3:30][N:31]([CH3:35])[C:32](=[O:33])[NH:34][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(N)=O
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)C(=O)Nc1cc(Oc2ccc(NC(=O)N3CCN(C4CCOCC4)C3=O)nc2)ccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A mixture of Example C1 (0.150 g, 0.359 mmol), N,N-dimethyl urea (0.190 g, 2.154 mmol), Cs2CO3 (0.292 g, 0.897 mmol) and Xantphos (0.062 g, 0.108 mmol) in dioxane (7 mL) was sparged with Ar, treated Pd2(dba)3 (0.043 g, 0.047 mmol), sparged again with Ar and heated at 100° C. overnight. The mixture was cooled to RT, treated with aqueous saturated NaHCO3, and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The yellowish solid was re-purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue neutralized with satd. NaHCO3 and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness and dried in vacuo. The residue was dissolved in 4:1 MeCN/water, frozen and lyophilized overnight to afford N-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (110 mg, 54%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.90 (s, 1 H), 8.20 (d, J=2.5 Hz, 1 H), 8.10 (J=5.7 Hz, 1 H), 8.06 (d, J=9.0 Hz, 1 H), 7.69 (dd, J=9.0, 2.9 Hz, 1 H), 7.37 (d, J=2.4 Hz, 1 H), 6.60 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.77 (m, 5 H), 3.47-3.35 (m, 4 H), 2.87 (s, 6 H), 1.76-1.65 (m, 2 H), 1.62-1.56 (m, 2H); MS (ESI) m/z: 470.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:21])[O:13]3)[O:10][N:9]=2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:27]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]([O:13][CH3:27])=[O:21])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C1OC2(CC(c3ccc(Cl)cc3)=NO2)c2ccccc21
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1-c1cc(-c2ccc(Cl)cc2)no1
Temperature: 0 °C

Procedure:
A solution of 6.3 g. (0.020 mole) of 3'-(p-chlorophenyl)-spiro[isobenzofuran-1(3H),5'(4'H)-isoxazol]-3-one, 2 ml. of concentrated H2SO4 and 300 ml. of methanol was stirred at reflux for 20 hours. The cooled solution was poured into ice water (3 liters) and extracted with ether. The combined organic extracts were washed twice with water, dried over CaSO4 and concentrated under vacuum to yield 5.8 g. of colorless crystals (88%) of product. Recrystallization from hexane afforded 5.4 g. of an analytically pure sample; m.p. 89.5°-91° C.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:7][CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][CH3:1])=[O:15]
Reactant: NCC(=O)CCC(=O)O
Reactant: CCCC(O)CC
Agent: Cl
Product: CCCC(CC)OC(=O)CCC(=O)CN
Reaction time: 48 h

Procedure:
From 3-hexanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 100° C. The reaction was complete after 2 days. The yield was 0.87 g (58%) of amber oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32][NH2:33])=[CH:31][C:26]=2[N:25]=[CH:24]1.CCN(C(C)C)C(C)C>CCO>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:33][CH2:32][C:30]4[CH:29]=[CH:28][C:27]5[N:23]([CH:18]6[CH2:19][CH2:20][CH2:21][CH2:22][O:17]6)[CH:24]=[N:25][C:26]=5[CH:31]=4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: NCc1ccc2c(c1)ncn2C1CCCCO1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2ccc3c(c2)ncn3C2CCCCO2)n1
Temperature: 120 °C
Yield: 81.3 %

Procedure:
A microwave vial was charged with 53 (750 mg, 3.20 mmol), 28 (740 mg, 3.20 mmol), DIPEA (2.0 mL) and EtOH (10.0 mL), sealed and heated at 120° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by SiO2 chromatography eluting with DCM:MeOH (8:1) to afford 1.12 g (81%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4-diamine (32) as white solid: MS (ESI) m/z=431.2 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:29])([F:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:27]([CH:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:28])[F:29])=[CH:24][CH:23]=3)[CH3:26])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)cc1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1ccc(OCC(F)(F)F)cc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (131 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (124 mg, 0.57 mmol, Amine-10, single enantiomer) in a similar manner to Intermediate-2.