Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:12])[O:2][CH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1.[OH:14][C:15]1[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])[O:17][N:16]=1.[OH-].[Na+].Cl>C(Cl)Cl.CCOC(C)=O>[OH:14][C:15]1[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([NH:24][CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([C:1]([O:2][CH2:3][C:4]3[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=3)=[O:12])[CH2:30][CH2:31]2)=[O:23])[O:17][N:16]=1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: O=C(CCc1cc(O)no1)NCC1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CCc1cc(O)no1)NCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3,5-dichlorobenzyl carbonochloridate (331 mg, 1.380 mmol) and 3-(3-hydroxyisoxazol-5-yl)-N-(piperidin-4-ylmethyl)propanamide (step 2) (200 mg, 0.690 mmol) in DCM (7 ml) was added 2M NaOH solution (6.90 ml, 13.80 mmol) and the mixture stirred vigorously at RT for 16 hrs. The mixture was diluted with EtOAc (50 ml) and acidified with 2M HCl. The organics were dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in MeOH/EtOAc and dry loaded onto silica (10 g). This was applied to a 12 g silica cartridge, eluting with 1% AcOH/EtOAc. The product fractions were combined and concentrated under reduced pressure and the residue was triturated with diethyl ether to afford 3,5-dichlorobenzyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: IC.C[N:4]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=S)[NH:22][CH3:23])[CH2:17][CH2:16]1)[C:5](=O)OCC1C=CC=CC=1.C(O[CH:28](OCC)[CH2:29][NH2:30])C>CO>[CH3:5][NH:4][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[N:22]([CH3:23])[CH:28]=[CH:29][N:30]=2)[CH2:19][CH2:20]1
Reactant: CCOC(CN)OCC
Reactant: CNC(=S)N1CCC(N(C)C(=O)OCc2ccccc2)CC1
Solvent: CI
Solvent: CO
Product: CNC1CCN(c2nccn2C)CC1
Reaction time: 20 h

Procedure:
A solution of iodomethane (0.22 ml, 3.4267 mmol, 1.1 eq) in methanol (5 ml) was added dropwise over a period of 5 min to a solution of benzyl methyl(1-(methylcarbamothioyl)-piperidin-4-yl)carbamate (1 g, 3.115 mmol, 1 eq) in methanol (10 ml). Stirring was then carried out for 20 h at room temperature. When the reaction was complete according to TLC monitoring, the reaction mixture was concentrated under reduced pressure. The residue was taken up in pyridine (15 ml); aminoacetaldehyde-diethylacetal (455 mg, 3.4267 mmol, 1.1 eq) was added and refluxing was carried out for 10 h. The reaction mixture was concentrated under reduced pressure, 2 N HCl solution (20 ml) was added, and the mixture was refluxed for 5 h. The reaction mixture was concentrated under reduced pressure and dried by removal of toluene by distillation. The crude product was used in the next stage without being purified further. Yield: 1.1 g (5.67 mmol)
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]([CH:10]([OH:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8].[CH3:20]O>>[NH2:5][C@@H:6]([C@H:10]([OH:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: CO
Reactant: COc1ccc(C(O)C(N)C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)[C@H](O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Thionyl chloride (12.3 mL, 169 mmol) was added dropwise to methanol (250 mL) at 0° C. followed by addition of 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoic acid (25.0 g, 118 mol). The reaction mixture was stirred at ambient temperature for 1 h and heated under reflux for 3 h. The mixture was cooled to ambient temperature and then concentrated to dryness. The residue was purified by flash column chromatography on silica gel (DCM/methanol=60:1) to afford (2S,3R)-methyl 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoate (15.7 g, 59% yield, threo-) as a colorless oil. Further separation by chiral preparative HPLC afforded (2S,3R)-methyl 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoate (7.0 g, 45% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].CS(O[CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:48][O:47][CH2:46][CH2:45][CH2:44][CH2:43][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11]
Reactant: COCCCCOS(C)(=O)=O
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of tert-butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (200 mg), 4-methoxybutyl methanesulfonate (107 mg) and cesium carbonate (254 mg) in N,N-dimethylacetamide (5 ml) was stirred at 60° C. for 15 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (10 ml×2). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (190 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29]>>[C:28]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:29])[CH2:27][C:26]([O:25][CH3:24])=[O:31]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: COC(=O)CC(=O)O
Product: COC(=O)CC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethyny-octahydro-indole-1-carboxylic acid methyl ester and malonic acid monomethyl ester to yield (3aR,4S,7aR)-1-(methoxycarbonyl)-4-(m-tolylethynyl)octahydro-1H-indol-4-yl methyl malonate. MS [M+H]=414; RT=1.24 min; UPLC Method I
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[N:8]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12][CH2:11][CH:10]([C:14](OCC)=O)[CH2:9]1.C[Al](C)C.O>C1(C)C=CC=CC=1>[CH2:6]1[N:7]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:9]2)[N:1]2[CH2:5][CH2:4][CH2:3][CH:2]12
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: NCC1CCCN1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C2=NCC3CCCN23)C1
Temperature: 110 °C
Yield: 43.2 %

Procedure:
To a solution of pyrrolidin-2-ylmethanamine (250 mg, 2.5 mmol) in toluene (8.5 mL) was added 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (635 mg, 2.5 mmol) under nitrogen. The solution was cooled with an ice-water bath and trimethylaluminum (2M in toluene, 2.2 mL, 4.4 mmol) was added. The resulting solution was transferred to a pressure tube and heated to 110° C. for 18 h. The reaction mixture was cooled to room temperature and water was added (10 mL). The mixture was extracted with dichloromethane (40 mL×2). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford tert-butyl 3-(5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-3-yl)piperidine-1-carboxylate as a colorless oil (317 mg, 43.8%). MS (ES+) (M+H) 294.2; LCMS retention time: 1.03 minutes (Method M).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31][CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31][CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=1
Reactant: C[Si](C)(C)CCOCSc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: C[Si](C)(C)CCOCSc1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (2-(((2-bromophenyl)thio)methoxy)ethyl)trimethylsilane. MS (ESI): mass calcd. for C22H26FN3OSSi, 427.16; m/z found, 428.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=1.4, 2H), 7.69 (dd, J=7.7, 1.1, 1H), 7.44 (m, 1H), 7.34-7.15 (m, 5H), 4.86 (s, 2H), 3.60-3.47 (m, 2H), 0.88-0.76 (m, 2H), 0.06 (s, 9H)
Reaction SMILES: CN1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)=[N:5][CH2:4][C:3]1=[O:23].[CH2:24]([O:26]C(=O)OCC)[CH3:25].[H-].[Na+]>>[CH2:24]([O:26][C:3]([C:4]1[NH:5][C:6]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)=[C:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:23])[CH3:25]
Reactant: CN1C(=O)CN=C(c2cccc(C(F)(F)F)c2)c2ccccc21
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1[nH]c(-c2cccc(C(F)(F)F)c2)c2ccccc12

Procedure:
According to the procedure described in Example 1, 1,3-dihydro-1-methyl-5-(α, α, α-trifluoro-m-tolyl)-2H-1,4-benzodiazepin-2-one is reacted with diethylcarbonate in the presence of sodium hydride, and there is obtained 3-(α, α, α-trifluoro-m-tolyl)-isoindole-1-carboxylic acid ethyl ester, having a melting point of 155°-157° C. Recrystallization from ethanol does not increase the melting point.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=1[O:30]C)(=[O:21])=[O:20])[CH3:2].[Cl-].[Li+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=1[OH:30])(=[O:20])=[O:21])[CH3:2]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Temperature: 140 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a solution of 148 mg of ethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate in 3 mL of N,N-dimethylformamide was added 41 mg of lithium chloride, and the mixture was stirred at 140° C. for 3 hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added aqueous 10% citric acid solution to adjust pH4, and the mixture was extracted with 100 mL of ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 139 mg of ethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[I-:10].[Na+].[OH-].[Na+].Cl[O-].[Na+]>CO>[Cl:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:9])=[C:5]([I:10])[CH:6]=1
Reactant: [I-]
Reactant: Oc1ccc(Cl)c(F)c1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Product: Oc1cc(F)c(Cl)cc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
3-Fluoro-4-chlorophenol (1.78 g, 12.1 mmol) was dissolved in methanol (40 mL). Sodium iodide (3.63 g, 24.2 mmol) and sodium hydroxide (0.97 g, 24.2 mmol) was added, and the solution was cooled to 0° C. Aqueous sodium hypochlorite (6.0% NaOCl, 24.2 mmol) was added dropwise over 75 minutes at 0-3° C. The resulting slurry was stirred for 1 h at 0-2° C. and allowed to warm up to room temperature overnight. White precipitates were observed. The mixture was adjusted to pH 7 using 1M aqueous HCl while stirring. The aqueous layer was extracted with ether for three times and the ether layer was washed with aq sodium thiosulfate, brine, the organic layers were dried with MgSO4. The solvent was removed under reduced pressure to afford the residue which was purified by flash column chromatography on silica gel (Hexanes:Ethyl acetate 1:1 to afford the desired product (1.60 g, 64% yield). 1H NMR: 6.84 (d, 1H, J=9.9 Hz), 7.67 (d, 1H, J=8.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:10]=[C:11]([CH2:18][OH:19])[N:12]([CH3:17])[C:13]=2[CH:14]([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.ClC(Cl)(Cl)[C:22]([N:24]=C=O)=[O:23].C(=O)([O-])O.[Na+]>O1CCCC1>[C:22]([O:19][CH2:18][C:11]1[N:12]([CH3:17])[C:13]([CH:14]([CH3:16])[CH3:15])=[C:9]([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:10]=1)(=[O:23])[NH2:24]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)c1c(Sc2cccc(Cl)c2)nc(CO)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1c(Sc2cccc(Cl)c2)nc(COC(N)=O)n1C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
In 5 ml of dry tetrahydrofuran was dissolved 200 mg (0.67 mmol)of [4-(3-chlorophenylthio)-5-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (Compound I-38), and 190 mg (1.0 mmol) of trichloroacetylisocyanate was added to the mixture with cooling at -40° C. After 10 minutes, the mixture was warmed to 0° C., and stirred at the same temperature for 10 minutes To the reaction mixture, ice-water was added, and then, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and to the residue was added 5 ml of methanol, 0.5 ml of water and 0.5 ml of triethylamine. The mixture was stirred at 50° C. for 30 minutes. To the reaction mixture was added water, extracted with methylene chloride, the extract was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate). The product was recrystallized from ethyl acetate/isopropyl ether to give 180 mg of the target compound (Compound I-59)(yield 79%). mp 145-146° C.
Reaction SMILES: [N:1]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][CH2:4][C:3]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:6]2)[CH2:2]1.[Br:30]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(C)(C)C.O>[Br:30][C:11]1[CH:12]=[C:13]2[C:3]3([CH2:4][CH2:5][N:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2]3)[CH2:6][N:7]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])=[O:15])[C:8]2=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(Br)cc12
Temperature: 60 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (15.2 g, 36.5 mmol) was dissolved in t-butanol (240 mL) and water (40 mL). Thereafter, N-bromosuccinimide (7.9 g, 44.4 mmol) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred at 60° C. for 15 hours. Thereafter, an aqueous solution of sodium thiosulfate was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (12.9 g, 71%) in the form of a white amorphous product.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[C:15]([C:48]([F:51])([F:50])[F:49])=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]([NH:40]C(=O)OC(C)(C)C)([CH3:39])[CH2:25][O:26][P:27]([O:34]C(C)(C)C)([O:29]C(C)(C)C)=[O:28])[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.Cl.O>>[P:27]([OH:34])([OH:29])([O:26][CH2:25][C@:24]([NH2:40])([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][C@H:10]3[CH2:11][CH2:12][C@H:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:8][CH2:9]3)[C:15]=2[C:48]([F:49])([F:51])[F:50])[CH:20]=1)[CH3:39])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C4CCCCC4)CC3)ccc2c1
Agent: Cl
Solvent: O
Solvent: CO
Product: C[C@](N)(COP(=O)(O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C4CCCCC4)CC3)ccc2c1
Temperature: 80 °C

Procedure:
tert-Butyl (R)-2-(6-(trans-4-cyclohexylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-1-(di-tert-butoxyphosphoryloxy)propan-2-ylcarbamate was then dissolved in methanol (2 mL, 0.06 mol) followed by 6 M of hydrogen chloride in water (1 mL, 0.007 mol). The reaction mixture was then heated at 80° C. for 3 hours. All solvents were removed, the crude product was then purified via reverse chromatography (4.3 g, 10-90% acetonitrile with 0.1% TFA/water with 0.1% TFA 7.2 mg, 17%). 1H NMR (MeOD) δ: 8.24 (d, J=8.8 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.98 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.57 (d, J=9.3 Hz, 1H), 4.43-4.56 (m, 1H), 4.33 (d, J=8.3 Hz, 1H), 4.19 (d, J=7.0 Hz, 1H), 2.18 (d, J=10.5 Hz, 2H), 1.81-1.91 (m, 5H), 1.71-1.79 (m, 4H), 1.67 (d, J=11.5 Hz, 1H), 1.40-1.57 (m, 2H), 1.10-1.32 (m, 7H), 0.97-1.08 (m, 2H). MS (M+1): 530.0
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[O:4][CH2:3]1.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:12][CH3:13])[O:4][CH2:3]2)[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: COc1cccc2c1CC(N)CO2
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Temperature: 60 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
In a round bottomed flask, 2.2 mmol of 3-amino-5-methoxychroman (described in Patent EP 279,150) are dissolved in 6 ml of dimethylformamide in the presence of 2.4 mmol of N-(4-bromobutyl)phthalimide, 6.6 mmol of potassium carbonate and a catalytic amount of potassium iodide. The mixture is left stirring at 60° C. for 6 hours. After cooling, the solvent is evaporated off and, after aqueous hydrolysis, the crude reaction mixture is extracted with dichloromethane. After washing, drying and evaporation of the organic phase, the expected product is obtained after purification by chromatography on a silica column (elution solvent: ether/petroleum ether, 5:95).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:21].O>O1CCOCC1>[I:11][C:10]1[C:3]2[C:2]([NH2:21])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[CH:9]=1
Reactant: N
Reactant: O=[N+]([O-])c1cccc(-n2cc(I)c3c(Cl)ncnc32)c1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2c1c(I)cn2-c1cccc([N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
A suspension of 4-chloro-5-iodo-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (16) (4.0 g, 10.0 mmol) in dioxane (80 mL) and NH3.H2O (40 mL) was sealed in a reaction vessel and heated to 120° C. for 1 hr. After cooling to r. t., the reaction mixture was concentrated under reduced pressure to afford 5-iodo-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (17) (quant. yield) as a yellow solid which was directly used in next step. LC-MS (ESI): m/z (M+1) 381.6.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[CH2:37][C:36](O)([C:38]([O:40][CH2:41][CH3:42])=[O:39])[O:35][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[CH:37]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[O:35][N:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(O)CC(c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)=NO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)no1
Yield: 79.4 %

Procedure:
A stirred solution of ethyl 3-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]-5-hydroxy-4,5-dihydroisoxazole-5-carboxylate (8.5 g, 14 mmol) and tosic acid hydrate (5.5 g, 29.5 mmol, 2.1 eq.) in toluene (150 mL) was refluxed for 6 hours. After cooling, the solution was washed with 1 M Na2CO3 solution then with brine. The solvent was removed and the residue was columned over a small pad of silica gel eluting with hexane/ethyl acetate 5/1 to provide the title compound (6.3 g, 79% yield).
Reaction SMILES: [SH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl>C(O)(=O)C>[C:13]([S:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(C(=O)O)c1S
Agent: Cl
Solvent: CC(=O)O
Product: COc1cccc(C(=O)O)c1SC(C)=O

Procedure:
A solution of 2-mercapto-3-methoxybenzoic acid (14.6 g, 79 mmol), acetic anhydride (9.7 g, 95 mmol) and glacial acetic acid (35 ml) was refluxed 15 minutes, then cooled and poured into dilute hydrochloric acid. The product was vacuum-filtered.
Reaction SMILES: [BrH:1].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4]>CCOCC>[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Br:1])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)Cc1ccc(CO)cc1
Reactant: Br
Solvent: CCOCC
Product: CC(C)Cc1ccc(CBr)cc1
Reaction time: 1 h

Procedure:
HBr gas was bubbled through a solution of (4-isobutyl-phenyl)-methanol (5 g, 28 mmol) in Et2O (50 mL) for 10–15 minutes. The reaction was stirred for 1 h and was poured onto ice (100 g). Et2O was added and the organic solution was washed with brine (2×). The organic solution was dried (MgSO4), filtered, and concentrated to provide the title compound (6 g). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H), 7.10 (d, 2H), 4.49 (s, 2H), 2.45 (d, 2H), 1.84 (m, 1H), 0.89 (d, 6H).