Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH2:7].[C:9](Cl)(=[O:11])[CH3:10]>>[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH:7][C:9](=[O:11])[CH3:10]
Reactant: COC(=O)CCN
Reactant: CC(=O)Cl
Agent: Cl
Product: COC(=O)CCNC(C)=O

Procedure:
According to scheme II, β-alanine methyl ester hydrochloride 4 is reacted with acetyl chloride giving N-acetyl-β-alanine methyl ester 5 which is reacted with disulfide cystamine 6 upon heating neat at 80° C. giving the tetraamide disulfide product N, N - (Dithiodi-2, 1-ethanediyl bis [3-(acetylamino) propanamide 7. Reductive cleavage of the disulfide bond of 7 with sodium borohydride in methanol gives the unstable thiol 8 which is reacted in situ with an excess of oleoyl chloride 1, giving the thioester product S-[2-[[3-(acetylamino)-1-oxopropyl]amino]ethyl]-9(Z)-octadecenethioate 9. ##STR11##
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][CH2:26][N:27]=[C:28]=[O:29]>C1(C)C=CC=CC=1>[Cl:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:21][CH:22]=1
Reactant: O=C=NCCCCl
Reactant: Cc1cccc(N2CCN(CCc3ccc(N)cc3)CC2)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCN(CCc3ccc(NC(=O)NCCCCl)cc3)CC2)c1

Procedure:
11.3 gm (38.5 millimols) of N-(p-amino-phenethyl)-N'-(m-tolyl)-piperazine, 4.6 gm (38.5 millimols) of 3-chloropropyl-isocyanate and 120 ml of toluene were admixed with each other, accompanied by gentle agitation, and the mixture was allowed to react for two hours and was then vacuum-filtered, yielding as the filter cake 90% of theory of N-[p-(3-chloropropyl-ureido)-phenethyl]-N'-(m-tolyl)-piperazine, m.p. 168° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][F:21].BrC(F)C>O.CS(C)=O>[F:21][CH2:20][CH2:19][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][NH:10][N:9]=[CH:8]1
Reactant: c1ccc(-c2cn[nH]c2)cc1
Reactant: FCCBr
Agent: CC(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: FCCC1(c2ccccc2)C=NNC1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To 2.0 grams of 4-phenyl-1H-pyrazole, 10 mL of dimethyl sulfoxide and 1.5 g of potassium carbonate were added and the solution was stirred at room temperature. Then, 1.5 grams of 1-bromo-2-fluoroethane was added dropwise. After addition of the bromofluoroethane, the mixture was stirred at room temperature for 24 hours, then poured into 100 mL of water. The precipitated product was filtered off, washed with water, and air-dried. There was obtained 2.0 grams of 4-(2-fluoroethyl)-4-phenyl-1H-pyrazole. The compounds summarized in Table 1 were prepared using essentially the same procedure as shown above. Each of the compounds so formed is characterized by its NMR characteristics.
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[S:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH2:27])(=[O:26])=[O:25])(=[O:16])=[O:15])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.CO.[H][H].C(OCC)(=O)C.CO>CCOC(C)=O>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH2:27])(=[O:25])=[O:26])(=[O:15])=[O:16])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(C2=CCCC2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(C2CCCC2)cc1
Yield: 57.1 %

Procedure:
(E)-2-(2-(4-Cyclopentenylphenyl)vinylsulfonamido)benzenesulfonamide (25.00 mg, 0.06 mmol) was dissolved in EtOAc (1.6 mL) and MeOH (1.6 mL) and hydrogenated under continuous flow hydrogenation conditions (full hydrogen, flow 1 ml/min, ethyl acetate/methanol 1:1 as eluent) at 50° C. using an H-Cube system. The solvent was removed in vacuo and the residue was purified by column chromatography on silica using heptane/ethyl acetate gradient mixtures as eluent (0-100% ethyl acetate) to give the product as a solid (14 mg, 55%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:12]=[O:13])[NH:6]2.[C:14](OCC)(=[O:16])[CH3:15]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:16][CH2:14][CH3:15])=[O:13])[NH:6]2
Reactant: O=Cc1cc2c(F)ccc(F)c2[nH]1
Reactant: CCOC(C)=O
Product: CCOC(=O)c1cc2c(F)ccc(F)c2[nH]1

Procedure:
The cooled mixture was dissolved in ethyl acetate, washed with sodium bicarbonate and brine, dried and evaporated. Chromatography on silica gel (1:1 dichloromethane/petrol) followed by recrystallization (dichloromethane/hexane) gave the indole ester (0.75 g). (f) 4,7-Difluoroindole-2-carboxaldehyde
Reaction SMILES: [CH:1]1([C:4]2[NH:8][C:7]3=[CH:9][S:10][CH:11]=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.Br[CH2:13][C:14]1[CH:33]=[CH:32][C:17]2/[C:18](=[C:28](/[CH3:31])\[C:29]#[N:30])/[C:19]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=3[O:21][CH2:22][C:16]=2[CH:15]=1>>[CH:1]1([C:4]2[N:8]([CH2:13][C:14]3[CH:33]=[CH:32][C:17]4/[C:18](=[C:28](/[CH3:31])\[C:29]#[N:30])/[C:19]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=5[O:21][CH2:22][C:16]=4[CH:15]=3)[C:7]3=[CH:9][S:10][CH:11]=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: c1scc2[nH]c(C3CC3)nc12
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CC4)nc4cscc43)cc2COc2cc(F)ccc21
Yield: 94 %

Procedure:
[step 2] Using 2-cyclopropyl-1H-thieno[3,4-d]imidazole (65 mg, 0.40 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (145 mg, 0.40 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (166 mg, 95%) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]([C:5]=23)=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16](Br)[C:17]#[CH:18]>CN(C)C=O>[CH2:18]([C:3]1[CH:2]=[CH:1][C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]=1[C:5]=23)[C:17]#[CH:16]
Reactant: C#CCBr
Reactant: C1=Nc2noc3cccc(c23)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCc1ccc2onc3c2c1OCC=N3
Temperature: 80 °C
Yield: 53 %

Procedure:
A solution of 4,5-dihydroisoxazolo[3,4,5-ef][1,4]benzoxazepine of Example 7(b ) (3.9 g; 22.1 mmoles) in 120 ml dimethylformamide was added to a suspension of sodium hydride (1.4 g; 27.7 mmoles). This was followed by a solution of propargyl bromide (2.7 ml of 80% solution; 24.4 mmoles). The reaction was heated at 80° C. for 1.5 hours and then quenched into water (400 ml). The resulting precipitate was filtered, rinsed and dried, then passed through a column of florisil (ethyl acetate/dichloromethane). This gave 3.5 g of a solid, mp 100°-104° C., which was recrystallized from isopropanol to give 2.5 g (53%) of 4,5-dihydro-3-(2-propynyl)isoxazolo[3,4,5-ef][1,4]benzoxazepine, mp 104°-106° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:23](OC1C=CC=CC=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:23]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)Oc1ccccc1
Reactant: C1CCNCC1
Product: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)N1CCCCC1
Yield: 66.5 %

Procedure:
Working again according to a protocol identical to the one used in step 1.1 of Example 1, followed by treating, under the same conditions as those of step 1.2 of Example 1, 1 g of 1,4-dibenzyl-2-phenoxycarbonyloxymethylpiperazine with 10 ml de piperidine, 0.68 g of 1,4-dibenzyl-2-(1′-piperidinocarbonyloxymethyl)piperazine is obtained in the form of a viscous product. Yield: 66.5%. Rf=0.09 (70/30 v/v ether/petroleum ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[CH2:5]2.N1C=CC=CC=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>O1CCCC1>[F:1][C:2]1[C:10]([NH:11][C:22](=[O:23])[CH2:21][O:20][CH3:19])=[CH:9][C:8]2[C:4](=[CH:5][C:6](=[O:12])[N:7]=2)[CH:3]=1
Reactant: COCC(=O)Cl
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc2c(cc1F)=CC(=O)N=2
Temperature: 25 °C
Yield: 40.9 %

Procedure:
5-Fluoro-6-Amino-indol-2-one 9d (2.028 g, 12.2 mmol) was dissolved in 30 mL of tetrahydrofuran under stirring at room temperature, and 1.3 mL of pyridine was then added to the solution. The reaction system was cooled down to −50° C. in a dry ice-ethanol bath. Methoxy-acetyl chloride (1.35 g, 12.5 mmol) was dissolved in 20 mL of tetrahydrofuran under stirring, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the dry ice-ethanol bath was removed. The reaction system was allowed to warm up to room temperature and stirred overnight until TLC showed the disappearance of starting materials. The resulting solid was filtered, washed with water (10 mL ×3) and recrystallized from methanol to give the title compound 5-fluoro-6-methoxyacetamido-2-oxoindole 13a (1.18 g, yield 40.6%) as a gray solid.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:2]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:3]2[CH:2]=[C:1]([CH3:12])[CH:6]=[CH:5][CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C2CCCN2)c1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2cccc(C)c2)cc1

Procedure:
The title compound, off-white solid, m.p. 79° C. and MS: m/e=315 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-m-tolyl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33].[NH:36]1[CH:40]=[CH:39][N:38]=[N:37]1>CN(C=O)C>[N:36]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21](=[O:24])[CH:20]=[C:19]3[NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=2[Cl:33])[CH:40]=[CH:39][N:38]=[N:37]1
Reactant: c1c[nH]nn1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCn1ccnn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Potassium carbonate (350 mg, 2.54 mmol) was added to a solution of 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (1.0 g, 2.0 mmol, Example 28), 1H-1,2,3-triazole (210 mg, 3.04 mmol), and DMF (15 mL) at rt. After 3.5 h at 80° C., the mixture was allowed to cool to rt, quenched with water (10 mL), and then extracted with ethyl acetate (20 mL×3). The combined extracts were washed with brine, dried, filtered, concentrated, and then purified by silica gel chromatography (dichloromethane:methanol) to give 8-(5-(1H-1,2,3-triazol-1-yl)pentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.81 (s, 2H), 8.13 (s, 1H), 7.94 (d, 1H), 7.69 (s, 1H), 7.19 (d, 1H), 4.63 (s, 1H), 4.40 (t, 2H), 3.97 (t, 2H), 3.90 (s, 3H), 1.88 (m, 2H), 1.75 (m, 2H), 1.45 (m, 2H); MS (ESI): 490.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([CH2:29][NH2:30])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([CH2:29][NH:30][C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:13])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCn1c2ccccc2c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(CNC(=O)C(C)NC(=O)OC(C)(C)C)ccc21
Yield: 77.3 %

Procedure:
A solution of 2-((tert-butoxycarbonyl)amino)propanoic acid (200 mg, 1.06 mmol), (9-ethyl-9H-carbazol-3-yl)methanamine (237 mg, 1.06 mmol), HATU (522 mg, 1.37 mmol) and TEA (0.442 mL, 3.17 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 60% ethyl acetate/hexane), and crystallized from ethyl acetate and hexane to give tert-butyl (1-(((9-ethyl-9H-carbazol-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (324 mg, 0.819 mmol, 78%) as a white powder.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:3]1=[O:30].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>O1CCCC1>[C:24]1([CH2:23][O:22][C:20](=[O:21])[CH2:19][N:4]2[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[N:8][CH:2]([NH:1][C:39]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)=[O:40])[C:3]2=[O:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(RS)-amino-1,3-dihydro-1-phenylmethyloxycarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 220°-222° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:20])=[CH:7][CH:8]=2)[CH2:3]1.Br[C:22]1[CH:27]=[C:26]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN1CCCC1>>[CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:20][C:24]3[CH:25]=[C:26]([CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[CH:27]=[CH:22][N:23]=3)=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CSc1ccc(C2CN(C)Cc3cc(O)ccc32)cc1
Reactant: Brc1cc(CN2CCCCC2)ccn1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CSc1ccc(C2CN(C)Cc3cc(Oc4cc(CN5CCCCC5)ccn4)ccc32)cc1
Temperature: 150 °C
Yield: 49.2 %

Procedure:
To a Smith-process vial were added 2-methyl-4-(4-methylsulfanyl-phenyl)-1,2,3,4-tetrahydro-isoquinolin-7-ol (305.8 mg, 1.051 mmol), 2-bromo-4-piperidin-1-ylmethyl-pyridine (338.7 mg, 1.314 mmol), Cs2CO3 (684.9 mg, 2.102 mmol) and N-methylpyrrolidine (2.10 mL). The vial was purged with N2, the cap sealed, and the reaction mixture heated at 150° C. in a microwave reactor for 2 h. The mixture was diluted with Et2O, washed with 1 N NaOH, water and brine, dried, and concentrated. Purification by FCC gave the desired product (237.5 mg, 48%). MS (ESI): mass calcd. for C28H33N3OS, 459.23; m/z found, 460.3 [M+H]+. 1H NMR (acetone-d6): 8.03 (d, J=5.1, 1H), 7.23-7.19 (m, 4H), 7.04 (d, J=5.1, 1H), 6.94 (s, 1H), 6.90-6.89 (m, 1H), 6.88-6.83 (m, 2H), 4.19 (t, J=6.2, 1H), 3.63 (q, J=15.1, 2H), 3.46 (s, 2H), 2.92-2.88 (m, 1H), 2.62-2.58 (m, 1H), 2.47 (s, 3H), 2.41-2.35 (m, 4H), 2.35 (s, 3H), 1.56 (quintet, J=5.5, 4H), 1.46-1.40 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:26]=[C:25](Cl)[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)=[CH:16][CH:15]=1)(=[O:12])[O:7][CH2:8][CH2:9][O:10][CH3:11].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH2:46][CH2:45]2)=[C:37]2[C:41]=1[C:40](=[O:42])[N:39]([CH3:43])[CH2:38]2>>[CH3:1][O:2][CH2:3][CH2:4][O:5][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:26]=[C:25]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C@H:44]4[CH2:45][CH2:46][C@H:47]([OH:50])[CH2:48][CH2:49]4)=[C:37]4[C:41]=3[C:40](=[O:42])[N:39]([CH3:43])[CH2:38]4)[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)=[CH:16][CH:15]=1)(=[O:12])[O:7][CH2:8][CH2:9][O:10][CH3:11]
Reactant: COCCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCCOC
Reactant: CN1Cc2c(C3CCC(O)CC3)ccc(N)c2C1=O
Product: COCCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCCOC

Procedure:
The title product was prepared according to the procedure for Example 102 using bis(2-methoxyethyl)(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 189A, 39.5 mg, 0.0816 mmol) and 7-amino-4-(4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (24.7 mg, 0.0949 mmol). The reaction mixture concentrated and purified by MDP [under basic conditions; ammonium bicarbonate basic buffer (pH 9)]. The title compound was obtained as a white solid, 36.2 mg (61%). 1H NMR (400 MHz, DMSO-d6) δ 10.58 (br s, 1H), 9.89 (s, 1H), 8.46 (s, 1H), 8.65 (br s, 1H), 7.57 (br s, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.26 (dd, J=8.6, 2.0 Hz, 2H), 4.56-4.65 (m, 1H), 4.52 (s, 2H), 3.94-4.09 (m, 4H), 3.49-3.55 (m, 1H), 3.44-3.49 (m, 4H), 3.27 (d, J=13.4 Hz, 2H), 3.24 (s, 6H), 3.08 (s, 3H), 1.93 (d, J=9.9 Hz, 2H), 1.70-1.80 (m, 2H), 1.47-1.66 (m, 2H), 1.22-1.38 (m, 2H). MS (ES+): m/z 708.26 (100) [MH+]. HPLC: tR=3.61 min (ZQ3, polar—5 min).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1.S(Br)([Br:20])=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Br:20])=[CH:12][CH:11]=1
Reactant: OCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=S(Br)Br
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: BrCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
To 4-(benzoxazol-2-yl)benzyl alcohol (20.9 g; 100 mmol) dissolved in CH2Cl2 (330 ml) and cooled to 0°-5° C. is added thionyl bromide (9.2 ml; 120 mmol) and allowed to warm to room temperature after removing the bath. After 11/2 hours, 2,6-lutidine (11.6 ml; 100 mmol) is added to the mixture and warmed to 30° C. The reaction mixture is then diluted with CH2Cl2, washed with H2O 1x , 0.2M HCl 1x, NaHCO3 2x, brine, dried (MgSO4) and concentrated to dryness. The residue is recrystallized from EtOAc to obtain 4-(benzoxazol-2-yl)benzyl bromide as white-orange needles which is used directly in Step C.
Reaction SMILES: C(S([C:11]1[N:16]=[C:15]2[N:17]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[CH2:20][C:14]2=[CH:13][N:12]=1)(=O)=O)C1C=CC=CC=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1>CN1CCCC1=O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:19]1[CH2:20][C:14]2[C:15](=[N:16][C:11]([NH:34][C@H:35]3[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]3)=[N:12][CH:13]=2)[N:17]([CH2:29][C:30]([F:32])([F:31])[F:33])[C:18]1=[O:28]
Reactant: O=C1N(c2ccccc2Cl)Cc2cnc(S(=O)(=O)Cc3ccccc3)nc2N1CC(F)(F)F
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN1CCCC1=O
Product: O=C1N(c2ccccc2Cl)Cc2cnc(N[C@H]3CC[C@H](O)CC3)nc2N1CC(F)(F)F
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
7-Benzylsulfonyl-3-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (300 mg, 0.604 mmol), trans-4-aminocyclohexanol (208 mg, 3 equivalents) and 1-methyl-2-pyrrolidinone (0.3 mL) were heated with stirring at 110° C. for 20 minutes, at which time it was cooled to room temperature. The residue was purified using preparative thin layer chromatography using ethyl acetate as eluant, to give 155 mg of 3-(2-chlorophenyl)-7-(trans4-hydroxycyclohexylamino)-1-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([N:24]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:2].C(O)C.[ClH:42]>C1COCC1>[ClH:42].[NH2:24][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:3][CH2:1][CH3:2])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCC(N)C(=O)OCC
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred solution of ethyl-N-(diphenylmethylene)-2-aminoeicosanoate prepared as in Example 28A (104 g, 0.200 mol) in a 1:1 mixture (300 ml) of absolute ethanol and THF was added 0.5N hydrochloric acid (1.0 l) at room temperature over 10 min. The resulting solution was stirred for 30 min. Ethanol and THF were removed in vacuo and the aqueous slurry was extracted with CH2Cl2 (4×1 l). The extracts were combined and dried (MgSO4). The solvent was removed in vacuo and the crude product was recrystallized from hexane to give 74.3 g (95% yield) of colorless needles: mp 91°-4° C.; 1H NMR (CDCl3) δ 0.88 (t, J=6.6 Hz, 3 H), 1.26 (m, 33 H), 1.43 (m, 1 H), 1.56 (m, 1 H), 2.03 (quart, J=7.4 Hz, 2 H), 4.03 (m, 1 H), 4.27 (m, 2 H), 8.84 (br s, 3 H).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36]Cl.P([O-])([O-])([O-])=O>CN(C=O)C.O>[C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:21][CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:39])([CH3:38])[CH3:31])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CNc1cc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cc1NC=O
Reaction time: 0.17 h

Procedure:
A solution of (5-{(1R)2-[bis(phenylmethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)formamide (354 mg) in DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 38 mg) and the mixture stirred at 20° for 10 min. 2-(Trimethylsilyl)ethoxymethyl chloride (0.17 ml) was added and the mixture was stirred at 20° for 3 h. Phosphate buffer solution (pH 6.5) and water were added and the mixture was extracted with EtOAc. The extract was washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified on a silica SPE bond elut cartridge (20 g) using a gradient of 0% to 2% MeOH in DCM (Gradmaster™). The appropriate fractions were evaporated in vacuo to give the title compound (286 mg). LCMS RT=3.08 min.