Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:35]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:6][C:5]([CH2:12][Br:35])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1
Reactant: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-3′-tert-butyl-5′-bromomethyphenyl)-5-chlorobenzotriazole was prepared from the bromination of 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)-5-chlorobenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 7.042 g (0.0223 mol) 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)-5-chlorobenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)-5-chlorobenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy3′-tert-butyl-5′-bromomethyphenyl)-5-chlorobenzotriazole was 7.2 g (81%).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)=[O:4].[NH2:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20].C[O-].[Na+].Cl>COCCO>[Cl:16][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:18][C@@H:19]([CH3:20])[C:21]([OH:23])=[O:22])=[O:4])[C:6](=[O:17])[S:7]2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1c(O)c2ccc(Cl)cc2sc1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2ccc(Cl)cc2sc1=O)C(=O)O
Temperature: 115 °C
Yield: 67.7 %

Procedure:
A mixture of 7-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Compound 60 (f)) (125 mg, 0.46 mmol), L-alanine (494 mg, 5.55 mmol) and NaOMe (249 mg, 4.62 mmol) in 2-methoxyethanol (5 mL) was heated in a 115° C. sand bath for 24 h. 1 N HCl aq. solution was added to precipitate the product. The solid was collected and rinsed with water. It was dried in vacuo and then triturated with MeOH to provide the title compound (102 mg). MS ESI(−) m/e: 327.96, 325.97 (M−1).
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.[CH:9]([N:12]1[C:17](=[O:18])[CH2:16][O:15][CH:14]([C:19]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[CH2:27][CH2:26][CH2:25]3)=[O:20])[CH2:13]1)([CH3:11])[CH3:10]>O.C(OCC)(=O)C>[OH:20][C:19]([O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH2:26][CH2:25]2)([CH:14]1[O:15][CH2:16][C:17](=[O:18])[N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13]1)[CH3:5]
Reactant: CC(C)N1CC(C(=O)Oc2ccc3c(c2)CCC3)OCC1=O
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N1CC(C(C)(O)Oc2ccc3c(c2)CCC3)OCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
After adding dropwise a solution of 5 g. of methyl magnesium bromide in 27 ml. of tetrahydrofuran to a mixture of 4.0 g. of 4-isopropyl-5-oxo-2-(1-oxo-5-indanyloxymethyl)morpholine and 100 ml. of tetrahydrofuran with stirring at room temperature, the mixture was stirred for 3 hours at room temperature. Then, after adding a small amount of water to the reaction mixture, the solvent was distilled off under reduced pressure. To the residue formed were added 50 ml. of ethyl acetate and 50 ml. of water to dissolve the residue and they were filtered. The ethyl acetate filtrate (100 ml.) was recovered, washed twice each with 50 ml. of saturated sodium chloride aqueous solution, and condensed under reduced pressure, the obtained residue was adsorbed on a silica gel column prepared from 100 ml. of silica gel in chloroform, and then eluted using ethyl acetate as the eluting solution. After removing the first 30 ml. of the ethyl acetate eluting solution emerging from the column, 300 ml. of the subsequent ethyl acetate eluting solution was collected and dried to provide 2.5 g. (yield 59.3%) of oily 2-(1-hydroxy-1-methyl-5-indanyloxymethyl)-4-isopropyl-5-oxomorpholine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12]O.[ClH:14]>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][Cl:14]
Reactant: COc1cc(Br)c(CO)cc1OC
Reactant: Cl
Product: COc1cc(Br)c(CCl)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Bromo-4,5-dimethoxy-phenyl)-methanol (25.09 g, 0.1015 mol) was added as a solid to a vigorously stirred solution of concentrated aqueous HCl (75 mL). The resulting white suspension was stirred at room temperature for 30 min. The resulting mixture was then extracted with CH2Cl2 (3×) and the combined extracts dried over MgSO4, filtered and concentrated in vacuo to yield 1-bromo-2-chloromethyl-4,5-dimethoxy-benzene as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH2:4][C@H:3]1[OH:16].[Li][CH2:18]CCC.CI>C1COCC1>[CH3:18][C@H:4]1[CH:5]=[C:6]([S:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][C@H:2]([CH3:1])[C@@H:3]1[OH:16]
Reactant: [Li]CCCC
Reactant: C[C@H]1C=CC(Sc2ccccc2)=CC[C@H]1O
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H]1C=CC(Sc2ccccc2)=C[C@H](C)[C@H]1O
Temperature: -100 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A solution of alcohol 29 (887 mg, 3.82 mmol) in THF (50 mL) was cooled to −78° C., and 3.20 mL of n-BuLi (2.5 M in hexanes, 8.00 mmol) was added dropwise. The mixture was slowly brought to −7° C. over 1 h, and stirred at this temperature for 10 min. It was then cooled to −100° C. in a THF-liquid N2 bath. To this cold dark orange solution was slowly added a solution of MeI (0.72 mL, 11.56 mmol) in THF (5 mL) over 30 min via syringe pump. The resulting light yellow solution was warmed to −60° C. prior to quenching with saturated aqueous NH4Cl. After warming to room temperature, the two layers were separated, and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, and dried over Na2SO4. Flash column chromatography (EtOAc/hexanes; 1:4) afforded 660 mg (70% yield) of 31 as a white solid. mp 81.5-83.5° C.; [α]20D=+407.8 (c=0.55CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.20-7.35 (m, 5H), 6.27 (d, J=5.4 Hz, 1H), 5.98 (br d, J=10.8 Hz, 1H), 5.75 (dd, J=4.5 Hz, 10.8 Hz), 3.79 (dd, J=2.7 Hz, 6.0 Hz, 1H), 2.55 (m, 1H), 2.45 (m, 1H), 1.65 (br s, 1H), 1.25 (d, J=7.5 Hz, 3H), 1.20 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 140.9, 138.7, 136.1, 130.5, 130.2, 129.9, 129.2, 126.7, 84.7, 43.5, 38.1, 19.4, 17.6; Analytical. Calculated for C15H18OS: C, 73.13; H, 7.36. Found: C, 72.42; H, 7.22.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1.[N:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36][CH:35]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:16](=[CH:15][C:14]([S:18]([NH:40][C:37]4[CH:38]=[CH:39][N:34]=[CH:35][N:36]=4)(=[O:19])=[O:21])=[CH:13][CH:12]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: Nc1ccncn1
Reactant: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(4-chloro-2-methylphenyl)isoquinoline-6-sulfonate (INTERMEDIATE DDDDD, 189 mg, 0.378 mmol), pyrimidin-4-amine (39.6 mg, 0.416 mmol), and THF (1891 μl) to give a clear, lightly-colored solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (794 μl, 0.794 mmol) was added drop wise over 30 s to give a yellow suspension. After 15 min, the mixture was quenched by the addition of TFA (0.3 mL), and then concentrated. The residue was concentrated from DCM then from MeOH. The residue was then purified by chromatography on silica gel (12-g Redi-Sep Gold column, 5-10% MeOH/DCM). Fractions containing product were combined and concentrated. The residue was taken up in DCM and filtered. The collected solid was washed with DCM (3×), then dried under a stream of N2 (g) for 20 min to give 1-(4-chloro-2-methylphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (70.2 mg, 0.171 mmol, 45.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 2H), 8.58 (br. s., 1H), 8.26 (br. s., 1H), 8.16 (d, J=5.4 Hz, 1H), 8.00-7.94 (m, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.46-7.40 (m, 1H), 7.36-7.30 (m, 1H), 7.05 (s, 1H), 1.98 (s, 3H). m/z (ESI) 411.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@@H:49]([CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CN(C=O)C>[CH:62]1([C@H:49]([NH:48][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[N:5][CH:6]=2)=[O:10])[C:50]2[CH:51]=[CH:52][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:54][CH:55]=2)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCOP(C)(=O)c1ccc([C@@H](N)C2CCCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(C)(=O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.1 %

Procedure:
To a stirred solution of 8-b (2.6 g, 12.6 mmol) and Et3N (3.8 g, 37.8 mmol) in DMF (50 mL) was added HATU (5.8 g, 15.2 mmol). The mixture was stirred for 5 min at room temperature and then ethyl 4-((S)-amino(cyclohexyl)methyl)phenyl(methyl)phosphinate hydrochloride, 27-d, (4.2 g, 12.6 mmol) was added. The resulting mixture was stirred at room temperature for 15 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (ethyl acetate:MeOH=10/1) to provide the product, 27-e, (3.3 g, 54.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.CI.[CH3:16]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:16])[CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=1
Reactant: CN(C)C=O
Reactant: OCc1cc(Cl)nc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COCc1cc(Cl)nc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
To a solution of [2-chloro-6-(trifluoromethyl)pyridin-4-yl]methanol (130 mg, 0.614 mmol, from Step A) and methyl iodide (42 μL, 0.68 mmol) in N,N-dimethylformamide (0.65 mL, 8.4 mmol) was added potassium carbonate (250 mg, 1.8 mmol). The mixture was sealed and stirred at room temperature for 24 hours. Additional methyl iodide (42 μL, 0.68 mmol) was added. The mixture was stirred again for 24 hours, then was diluted with water and extracted with EtOAc. The extract was washed with water (3×), followed by brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-20% EtOAc in Hexanes, afforded product as a colorless oil (56 mg, 40%). 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 7.50 (s, 1H), 4.53 (s, 2H), 3.48 (s, 3H); 19F NMR (282 MHz, CDCl3) δ−68.45 (s); LCMS (M+H)+: 226.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]2[CH2:11][CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCC1CCCCN1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCC1CCCCN1c1ccc(Br)cc1C=O
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (20 g, 99 mmol) in DMSO (230 mL) and water (70 mL) were added 2-ethylpiperidine (14.4 mL, 108 mmol) and sodium carbonate (20.9 g, 197 mmol). The resulting mixture was heated at 110° C. for 30 hours. The reaction mixture was cooled at RT, diluted with water (1000 mL) and extracted with MTBE (2×500 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether), the title compound was obtained as a yellow oil. 1H NMR (DMSO-d6, 400 MHz) δ 10.15 (1H, s), 7.72 (2H, d), 7.24 (1H, m), 3.11 (2H, m), 2.85 (1H, m), 1.84 (1H, m), 1.34-1.67 (7H, m), 0.64 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH:19](O)=[O:20]>C1(C)C=CC=CC=1>[NH:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:19]=[O:20])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]([CH3:12])[CH3:13]
Reactant: O=CO
Reactant: CN(C)CCC(c1ccc(N)cc1)c1ncc[nH]1
Solvent: Cc1ccccc1
Product: CN(C)CCC(c1ccc(NC=O)cc1)c1ncc[nH]1

Procedure:
A mixture of 3-(4-aminophenyl)-N,N-dimethyl-3-(imidazol-2-yl)propanamine (0.8 g), formic acid (2 ml) and toluene (50 ml) was boiled under reflux for 2 days in a Dean and Stark apparatus. Solvent was removed and the residue partitioned between 2 N sodium carbonate (25 ml) and ethyl acetate (3×50 ml). The extracts were dried (Na2SO4) and concentrated to a white solid. Recrystallisation from ethyl acetate gave the title compound, m.p. 142°-144°, (0.46 g). ν max (CHBr3) 3445, 3420,3390 (NH), 1690(CO), 1500, 2780 and 2820 cm-1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:25][C@H:24]([CH2:26][O:27]C(=O)C3C=CC(Cl)=CC=3)[C@@H:13]([O:14]C(=O)C3C=CC(Cl)=CC=3)[CH2:12]2)=[C:4]([NH:37][Si](C)(C)C)[N:3]=1.CO[Na].CO>CO>[CH:7]1[N:8]([C@@H:11]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:13]([OH:14])[CH2:12]2)[C:9]2[C:5](=[C:4]([NH2:37])[N:3]=[C:2]([Cl:1])[N:10]=2)[N:6]=1
Reactant: C[Si](C)(C)Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Agent: CO[Na]
Solvent: CO
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
To the above prepared mixture of 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofuranosyl]-purine (IVa) and 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2′-deoxy-β-D-ribofuranosyl]-purine (IVb) (179 g, >95.4% HPLC purity) in MeOH (895 mL, 5 P) was added 29% MeONa/MeOH solution (5.25 g, 0.1 eq.) at 20-30° C. The mixture was stirred at 20-30° C. for 6 hours, the solid was filtered, washed with MeOH (60 mL, 0.34 P) and then dried in vacuo at 50° C. for 6 hour to give 72 g white to off-white crude cladribine with 98.9% HPLC purity in ca. 93% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:19])[O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16].N1C=CC=CC=1>ClCCl>[Cl:16][C:15]([Cl:18])([Cl:17])[CH2:14][O:13][C:12](=[O:19])[NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][O:7][C:8]2=[O:11]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)C(=O)OC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2c(c1)C(=O)OC2)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a suspension of 6-aminoisobenzofuran-1(3H)-one 1 (Maybridge, 13.43 g, 90 mmol) in dichloromethane (DCM, 200 mL) at 0° C. was added 2,2,2-trichloroethyl carbonochloridate 1a (18.23 mL, 135 mmol) and pyridine (17.79 mL, 180 mmol). The reaction mixture was stirred at room temperature (RT, ca. 25° C.) for 1 h. Thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) showed the reaction was complete. The reaction mixture was filtered and washed with DCM (2×30 mL) to afford carbamate 2 as a white solid (17.03 g, 58%). LCMS: [M+1]=324.
Reaction SMILES: C(OC([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C.CCOCC.[ClH:42]>CCOC(C)=O>[ClH:42].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](Oc1ccc2cccc(N)c2c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 1-(tert-butoxycarbonylamino)-7-(tert-butyldiphenylsilyloxy)naphthalene, as described above in Step B, (1.54 g, 3.09 mmol) in EtOAc (80 mL) and Et2O (20 mL) at ambient temperature was saturated with HCl (g). After 1 hr, the mixture was concentrated in vacuo to yield the desired product as a pale solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([NH:13]C(OC(C)(C)C)=O)[CH2:8]2)=[CH:4][CH:3]=1.[ClH:23].CCOCC>CO>[ClH:1].[ClH:23].[NH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1-(4-chlorobenzyl)-3-{(tert-butoxycarbonyl)amino}piperidine (2.55 g, 7.85 mmol) in CH3OH (25 mL) was treated with 1 N HCl-Et2O (50 mL). The reaction mixture was stirred at 25° C. for 15 h. The solvent was removed under reduced pressure to afford 3-amino-1-(4-chlorobenzyl)piperidine dihydrochloride as an amorphous solid (2.49 g, quant). The purity was determined by RPLC/MS (>95%),; ESI/MS m/e 225.2 (M++H, C12H18ClN2).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:10][CH:9]=1.[C:26](OCC)(=[O:28])[CH3:27]>CCCCCC.O1CCCC1>[C:20]1([N:17]2[CH2:18][CH2:19][C:15]([N:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=3)[C:26](=[O:28])[CH3:27])=[N:16]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(N(C(C)=O)C2=NN(c3ccccc3)CC2)cc1
Reaction time: 2 h

Procedure:
1.7M n-butyl lithium in hexane (7.0 ml) was added dropwise to a solution of 4,5-dihydro-N-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-amine (2.67 g) in tetrahydrofuran (150 ml) at -25° under N2. After 40 minutes ethyl acetate was added and the solution was allowed to reach room temperature. After being stirred for 2 hours, the solution was evaporated to dryness and the residue chromatographed on silica gel eluting with ethyl acetate in dichloromethane to give an oil which crystallised on trituration with ether. The solid was recrystallised from ether and hexane to give the title compound (0.82 g) mp 83°-5° (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O.[F:17][C:18]([F:29])([F:28])[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.O.[Sn](Cl)Cl>C1(C)C=CC=CC=1>[F:17][C:18]([F:28])([F:29])[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][C:24]2([NH:8][C:6](=[O:7])[C:5]3[C:4](=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:9]=3)[NH:1]2)[CH2:23][CH2:22]1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(OCC(F)(F)F)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC2(CCC(OCC(F)(F)F)CC2)Nc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 39.7 %

Procedure:
2-Nitro-4-trifluoromethylbenzamide (347 mg, 1.47 mmol), 4-(2,2,2-trifluoroethoxy)cyclohexanone (303 mg, 1.54 mmol) and tin(II) chloride hydrate (663 mg, 2.94 mmol) were added to toluene (5 ml) under argon and stirred under reflux conditions for 10 h. After cooling to room temperature, filtration with suction and thorough drying of the solid which precipitated gave 4′-(2,2,2-trifluoroethoxy)-7-(trifluoromethyl)-1H-spiro[quinazolin-2,1′-cyclohexan]-4(3H)-one (223 mg, 36% of theory) as a colorless solid. 1H NMR (400 MHz, d6-DMSO δ, ppm) 8.23 (br. 5, 1H, NH), 7.73 (d, 1H), 7.21 (br. s, 1H, NH), 7.19 (s, 1H), 6.90 (d, 1H), 4.06 (q, 2H), 3.51 (m, 1H), 1.90 (m, 4H), 1.62 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH:24]([NH2:26])[CH2:23][CH2:22]2.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH:24]([NH:26][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=1)[CH2:23][CH2:22]2
Reactant: COc1cccc2c1C(N)CC2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1C(Nc1ccc3cc([N+](=O)[O-])ccc3n1)CC2
Temperature: 140 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (1.8 g, 8.62 mmol) in 1-methyl-2-pyrrolidone (5 mL) with the above described 7-methoxy-indan-1-ylamine (1.69 g, 10.35 mmol) and N-ethyldiisopropylamine (2.22 mL, 12.94 mmol) was stirred at 140° C. for 2 h. Cooled to 23° C., poured onto water and extracted twice with ethyl acetate, dried over Na2SO4 and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as a yellow solid (2.3 g, 80%); MS: m/e=336.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](Cl)(=[O:13])=[O:12])[C:7](=[O:15])[CH2:6][CH2:5]2.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CC(C)=O>[CH2:16]([NH:23][S:11]([C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:15])=[CH:3][C:2]=1[Cl:1])(=[O:13])=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCc2cc(Cl)c(S(=O)(=O)Cl)cc21
Reactant: NCc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(Cl)c(S(=O)(=O)NCc3ccccc3)cc21

Procedure:
According to Example 2(a), 13.26 g (50 mmoles) of 5-chloro-6-chlorosulfonyl-1-indanone, 5.89 g (55 mmoles) of benzylamine and 5.05 g (50 mmoes) of triethylamine in a total of 100 ml of acetone yield 6-benzylsulfamoyl-5-chloro-1-indanone having a melting point of 203° to 205° C., from which the pure product is obtained after a recrystallization from ethanol, said product having a melting point of 228° to 231° C.