Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1c(F)cccc1F
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2c(F)cccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(2,6-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14](=[O:31])[CH:15]([NH2:30])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14](=[O:31])[CH:15]([NH:30][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)C(N)Cc1ccc(-c2cccc(O)c2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[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: COC(=O)C(Cc1ccc(-c2cccc(O)c2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 36 %

Procedure:
A solution of 2-amino-5-chloro-benzoic acid (1.95 g, 11.38 mmol) in DMF (10.0 mL) was reacted with 2-amino-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester (3.50 g, 11.38 mmol), HBTU (3.98 g, 10.50 mmol), and DIEA (6.08 mL, 34.15 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silical gel using DCM (+15% hexane) and increasing the gradient to DCM and finally DCM (+0.25% methanol) to give 1.75 g, (36%) of 2-(2-amino-5-chloro-benzoylamino)-3-(3′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester as a white solid. LCMS: 425 (M+1)+.
Reaction SMILES: N[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[NH:6]2.N(OCCC(C)C)=O.C(Br)(Br)[Br:36]>>[Br:36][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[NH:6]2
Reactant: CCOC(=O)Nc1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]1
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Product: CCOC(=O)Nc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1

Procedure:
The product of example 5, step (d) (1 g) was dissolved in bromoform (14 ml) and iso-amyl nitrite (0.1 ml) and heated at 40° C. for 5 hr. The reaction mixture was then evaporated to dryness and purified by flash chromatography on silica gel with 20% ethyl acetate in dichloromethane, yielding the subtitled compound as a yellow solid (208 mg).
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.CO.[O:21]=[O+][O-]>ClCCl>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:21])[C:17]=2[N:16]=1
Reactant: Cc1ccc2c(n1)C(=Cc1ccccc1)CCC2
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(n1)C(=O)CCC2

Procedure:
Intermediate 200A2 in dichloromethane (100 mL)/methanol (200 mL) was cooled to −78° C. Ozone was passed through the mixture for 1-2 h until the mixture had a light blue color. The reaction mixture was purged with nitrogen followed by the addition of dimethyl sulfide (10 mL). The mixture was stirred for 30 m and evaporated. The residue was partitioned between ether and 1M HCl. The organic layer was extracted with 1N HCl (2×) and the acidic, aqueous layers were pooled, washed with ether (3×), cooled with crushed ice, and carefully basified with solid NaOH. The basic layer was extracted with chloroform, freed of solvent, and the residue was passed through a column of SiO2 with 80% ethyl acetate/hexane to give impure Intermediate 200A3 as a yellow solid. Further purification of this mixture was conducted by oxidation of the minor product: (˜3%) 8-oxo-5,6,7,8-tetrahydro-quinoline-2-carbaldehyde in formic acid (15 mL) at 0° C. by dropwise addition of H2O2 (2.1 mL, 30% solution). The mixture was stirred for 1.5 h, quenched with crushed ice, diluted with chloroform, and basified with 2 M NaOH to pH>8. The chloroform layer was dried, filtered and evaporated to give pure 2-methyl-6,7-dihydro-5H-quinolin-8-one (Intermediate 200A3), 15.1 g (˜50% over two steps).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=[O:8])=[CH:2]1.[CH3:10]O>>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:2]1
Reactant: O=C(O)Cc1ccsc1
Reactant: CO
Product: COC(=O)Cc1ccsc1

Procedure:
Methyl 3-thienylacetate was prepared by heating 3-thienylacetic acid in acidic methanol. It is an oil, 1H nmr:delta 3.71 (2H, s), 3.76 (3H, s) ppm.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:21][O:20][CH2:19][CH2:18][CH2:17][N:8]1[C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=[C:9]1[C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2cccc(Cl)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21

Procedure:
((R)-7-chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (0.111 mmol max, about half of crude oil from Step E) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.122 mmol, 0.040 g) and N-methylmorpholine (0.555 mmol, 0.061 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.122 mmol, 0.046 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (20-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (30F) as a clear oil that was used directly onto the next step. ESI-ESI-MS: m/z 619.5 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[N:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:36])[CH2:15][C@H:16]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:6][O:7][C:8]1[N:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:36])[CH2:15][C@H:16]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:31][CH2:32][N:33]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:34][CH2:35]2)=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1nnccc1C(=O)C[C@H](c1ccc(C2CCNCC2)cc1)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1nnccc1C(=O)C[C@H](c1ccc(C2CCN(S(C)(=O)=O)CC2)cc1)c1ccccc1C
Yield: 78.9 %

Procedure:
Methanesulfonyl chloride (35 mg, 0.31 mmol) was added at 0° C. to a solution of (R)-1-(3-methoxypyridazin-4-yl)-3-(4-(piperidin-4-yl)phenyl)-3-o-tolylpropan-1-one (64 mg, 154 μmol) and N,N-diisopropylethylamine (79.6 mg, 0.62 mmol) in dichlormethane (2.5 mL). The ice bath was removed, then after 1 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2, heptane/ethyl acetate gradient) produced the title compound (60 mg, 79%). Light yellow gum, MS: 494.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C@@H:17]2[NH:21][C@@H:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[C@H:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])=[C:10]([O:45][CH3:46])[CH:9]=1)(=O)=[O:3].CO>CCOC(C)=O>[CH3:1][S:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C@@H:17]2[NH:21][C@@H:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[C@H:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])=[C:10]([O:45][CH3:46])[CH:9]=1)=[O:3]
Reactant: COc1cc(OCCS(C)(=O)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(OCCS(C)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In the preparation of chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-methanesulfonyl-ethoxy)-2-methoxy-phenyl]-amide in Example 170, the second product chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-methanesulfinyl-ethoxy)-2-methoxy-phenyl]-amide was obtained by chromatography (10% MeOH in EtOAc) as a yellow solid (Yield 63 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:32])[N:27]3[CH2:30][OH:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:45]([NH:48][CH2:49][CH2:50][CH2:51][C:52](O)=[O:53])(=[O:47])[CH3:46]>ClCCl>[C:45]([NH:48][CH2:49][CH2:50][CH2:51][C:52]([O:31][CH2:30][N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH2:10][CH2:11]3)[CH:29]=2)[CH2:24][CH2:25][C:26]1=[O:32])=[O:53])(=[O:47])[CH3:46]
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1CO
Reactant: CC(=O)NCCCC(=O)O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Reaction time: 0.42 h

Procedure:
To a suspension of hemiaminal A1 (2.6 g, 5.5 mmol) in dichloromethane (30 mL) was added triethylamine (2.3 mL, 16.4 mmol), followed by addition of methanesulfonyl chloride (0.47 g, 6.0 mmol) over 3 min. The reaction mixture was stirred for 25 min and then N-acetyl-4-aminobutyric acid (1.6 g, 10.1 mmol) added. The reaction mixture was then heated at reflux for 18 h, cooled and washed with sat. NaHCO3 (aq). The organic phase was dried over MgSO4, filtered and evaporated. The residue was further purified on silica eluting with 1:1:0.1 to 1:1:0.2 dichloromethane/ethyl acetate/methanol to give the title compound as an off white solid (1.1 g, 34%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:27])[C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][CH2:24][CH3:25].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>>[CH3:1][O:2][N:3]([CH3:27])[C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:15]([O-:36])=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:23][CH2:24][CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N(C)OC
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCC(=O)N(C)OC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate N-methoxy-N-methyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide (4.01 g, 10.9 mmol) by reaction with m-CPBA (6.13 g) to provide N-methoxy-N-methyl-6-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide followed by reaction with p-toluenesulfonyl chloride (2.53 g, 13.3 mmol) and ammonium hydroxide solution (40 mL) to provide 6-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methoxy-N-methylhexanamide) as an off-white solid after recrystallization from a mixture of ethyl acetate and hexane, mp 134-135° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:7][CH:6]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-n2ccc3ccccc32)cc1
Temperature: 120 °C
Yield: 21.1 %

Procedure:
Ethyl-4-fluorobenzoate (4 mL, 27.3 mmol) and indole (3.51 g, 30 mmol) were dissolved in 50 mL of dimethylsulfoxide (DMSO). Potassium fluoride (37% on basic alumina, 12.8 g) and 18-crown-6 (720 mg, 2.73 mmol) were added and the mixture was heated to 120° C. for 24 hours. The reaction was diluted with ethyl acetate and washed with hydrochloric acid (1.0 M, aq.), sodium bicarbonate (sat'd., aq.) and sodium chloride (sat'd., aq.). The organic layer was dried over magnesium sulfate, filtered and the solvent removed. Purification by flash chromatography on silica gel eluted with 5% ethyl acetate, hexane provided 1.45 g (20%) of a white solid
Reaction SMILES: [Cl:1][C:2](Cl)([P:13](=[O:22])([O:18][CH:19]([CH3:21])[CH3:20])[O:14][CH:15]([CH3:17])[CH3:16])[P:3](=[O:12])([O:8][CH:9]([CH3:11])[CH3:10])[O:4][CH:5]([CH3:7])[CH3:6].S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[Cl:1][CH:2]([P:3](=[O:12])([O:4][CH:5]([CH3:7])[CH3:6])[O:8][CH:9]([CH3:11])[CH3:10])[P:13](=[O:22])([O:18][CH:19]([CH3:20])[CH3:21])[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)OP(=O)(OC(C)C)C(Cl)(Cl)P(=O)(OC(C)C)OC(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)OP(=O)(OC(C)C)C(Cl)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.25 h

Procedure:
Into a solution containing 8.2 g (0.02 moles) of tetraisopropyl (dichloromethylene)bisphosphonate in 70 ml of ethanol, 9.0 g of sodium sulphite in 250 ml of water are added while stirring during 15 minutes at 10° to 15° C., whereafter the mixture is stirred for 1 h. The mixture is extracted with chloroform and the extract is dried (MgSO4) and filtered. The filtrate is evaporated under a vacuum, whereby about 7.6 g (100% of the theor.) of tetraisopropyl (monochloromethylene)bisphosphonate (31P-NMR (CDCl3 : δ 12.04 ppm) are obtained as a colourless oil, at a concentration of 98%.
Reaction SMILES: C([C:5](C1C=CC=CC=1)(C1C=CC=CC=1)[C@@:6](O[SiH3])([N:8]1[C:13]2=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:17]=[C:12]2[CH2:11][N:10]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:9]1=[O:33])[CH3:7])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:66]1CCCC1>>[OH:66][CH2:5][C@H:6]([N:8]1[C:13]2=[N:14][C:15]([NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:16][CH:17]=[C:12]2[CH2:11][N:10]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:9]1=[O:33])[CH3:7]
Reactant: C1CCOC1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@](C)(O[SiH3])C(c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@H](C)CO)C2=O)cc1
Reaction time: 2 h

Procedure:
(R)-1-(2-tert-Butyl-diphenyl-silanyloxy-1-methyl-ethyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.55 g, 0.80 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL) and treated with tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 3.2 mL, 3.20 mmol) (Aldrich) at 40° C. for 3 hours and then at room temperature for 2 hours. The reaction was concentrated. The residue was redissolved in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (Biotage 40M, ethyl acetate-hexanes gradient [75–85% ethyl acetate]) followed by crystallization from ethyl acetate-hexanes gave (R)-(−)-1-(2-hydroxy-1-methyl-ethyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 0.26 g, 79.9%). Melting Point: 156–163° C.
Reaction SMILES: [C:1]([S@@:5]([NH:7][C@H:8]([C:12]1([C:17]([O:19]CC)=O)[S:16][CH2:15][CH2:14][S:13]1)[CH2:9][CH2:10][CH3:11])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:22][NH2:23].C(O)C>>[C:1]([S@@:5]([NH:7][C@H:8]([C:12]1([C:17]([NH:23][CH3:22])=[O:19])[S:16][CH2:15][CH2:14][S:13]1)[CH2:9][CH2:10][CH3:11])=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC[C@H](N[S@@](=O)C(C)(C)C)C1(C(=O)OCC)SCCS1
Reactant: CN
Solvent: CCO
Product: CCC[C@H](N[S@@](=O)C(C)(C)C)C1(C(=O)NC)SCCS1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
A heavy-walled glass tube was charged with ethyl (S,SS)-2-[1-(tert-butylsulfinylamino)butyl]-1,3-dithiolane-2-carboxylate (0.50 g, 1.4 mmol) and a chilled 8.0 M solution of methylamine in ethanol (5 mL, 40 mmol). The mixture was allowed to warm to room temperature and was allowed to stand for 72 hours. Distillation of the solvent at reduced pressure afforded (S,SS)-2-[1-(tert-butylsulfinylamino)butyl]-N-methyl-1,3-dithiolane-2-carboxamide (0.47 g, 98%) as a viscous amber-colored oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=1>>[C:20]([CH:19]=[CH:18][C:14]1[CH:13]=[C:12]([NH:11][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:17]=[CH:16][CH:15]=1)#[N:21]
Reactant: N#CC=Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: N#CC=Cc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (350 mg, 1.73 mmol) was coupled to aniline (88) (250 mg, 1.74 mmol) using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1)[CH3:13]>C(O)(=O)C.CCO>[CH2:12]([C:14]1[S:18][C:17]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CCc1ccc(C=O)s1
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1ccc(C=NNC(=O)c2ccc(O)cc2)s1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 5-ethyl-2-thiophenecarboxaldehyde (0.28 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.53 g, in 96% yield, mp: 194.5° C. 1H NMR (CD3OD) δ 8.39 (s, 1H), 7.79 (d, 2H), 7.19 (s, 1H), 6.86 (d, 2H), 6.80 (s, 1H), 2.86 (q, 2H), 1.31 (t, 3H). 13C NMR (CDCl3) δ 166.5, 162.7, 153.1, 144.9, 137.7, 132.3, 130.8, 125.3, 124.8, 116.3, 24.7, 16.2. Anal. Calcd for C14H14N2O2S : C, 61.29; H, 5.14; N, 10.21. Found: C, 61.00; H, 5.18; N, 10.00.
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([OH:33])[CH:5]=1)([CH3:3])[CH3:2].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.O[CH2:66][CH2:67][CH2:68][C:69]([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:70]>C1COCC1>[CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:29])([F:30])[F:31])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:33][CH2:66][CH2:67][CH2:68][C:69]([O:71][CH2:72][C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)=[O:70])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(CCCO)OCc1ccccc1
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(OCCCC(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.6 %

Procedure:
To a solution of 4-isopropyl-6-hydroxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1 g; 2.08 mmol) in THF containing (Ph)3P (550 mg; 2.09 mmol) and DEAD (360 mg; 2.07 mmol) was added benzyl 4-hydroxybutyrate (410 mg;2.099 mmol) and the resulting mixture was stirred at room temperature for 15 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) to afford 870 mg (64%) of 4-isopropyl-6-[3-(phenylmethyloxycarbonyl)propoxy]-2-(1-phenyl-3-trifluoro methylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CH3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)3CO2CH2Ph) as a solid, m.p. 99°-101° C.
Reaction SMILES: [F:1][C:2]([F:58])([F:57])[C:3]1[CH:4]=[C:5]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:43][CH2:44][O:45][C:46](C)(C)[CH3:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.C(=O)(O)[O-:60].[Na+]>Cl.C(OCC)(=O)C>[C:46]([O:45][CH2:44][CH2:43][N:31]([C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:29])([F:30])[F:28])=[CH:26][C:21]=1[CH2:20][N:7]([CH2:6][C:5]1[CH:50]=[C:51]([C:53]([F:55])([F:54])[F:56])[CH:52]=[C:3]([C:2]([F:58])([F:1])[F:57])[CH:4]=1)[C:8]1[N:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:12][N:13]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(=[O:60])[CH3:47]
Reactant: CCOC(=O)CCCCCCN(CCOC(C)(C)C)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(CCOC(C)=O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-(2-tert-butoxy-ethyl)-amino]-heptanoate (which is prepared by treating the corresponding starting compound in a same manner as in Example 12(1)-(4)) (260 mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (4 ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:2) to give ethyl 7-[(2-acetoxy-ethyl)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-amino]-heptanoate (162 mg). MS (m/z): 822 [M+H]+