Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)=[C:11]([F:22])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].N1C=CC=CC=1.[C:29](Cl)(=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:17][N:16]=2)=[C:11]([F:22])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-c2ncc(O)cn2)c(F)c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCC(=O)Oc1cnc(-c2ccc(OCCCCCCC)cc2F)nc1
Reaction time: 12 h

Procedure:
0.1 mol of 2-(4-heptyloxy-2-fluorophenyl)-5-hydroxypyrimidine (prepared from 4-heptyloxy-2-fluorobenzamidine in accordance with Example 1) is dissolved together with 0.12 mol of pyridine in toluene and 0.1 mol of nonanoyl chloride is then added at room temperature. Stirring is then carried out for 12 hours and standard working-up is carried out. 2-(4-Heptyloxy-2-fluorophenyl)-5-nonanoyloxypyrimidine is obtained, C 65 I, Δε=-0.2.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[N+:14]([O-])=O)[CH2:3][CH2:2]1>C(O)C>[CH:1]1([CH2:4][NH:5][C:6]2[C:7]([NH2:14])=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Solvent: CCO
Product: COc1ccc(NCC2CC2)c(N)c1
Temperature: 10 °C
Reaction time: 2.5 h

Procedure:
N-(Cyclopropylmethyl)-4-methoxy-2-nitroaniline (175 g) was dissolved in ethanol (1750 mL) and added to a 4.0 L Hast ‘C’ Shaker can. The mixture was cooled to 10° C. and treated with 3% Pt/0.6% VG/C, deGussa (4.5 g). The vessel was sparged under nitrogen and then sparged three times with hydrogen at a setting of 40 psi and agitated for 2.5 hours. To a pre-washed solka-flok with ethanol, the reaction mixture was filtered through solka-flok through a sintered glass funnel to have about a ½ inch depth of solka-flok. The solka -flok was then washed with 1 L ethanol and concentrated in vacuo, providing the titled compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].O1CCCC1>C(=O)([O-])[O-].[K+].[K+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Brc1cccc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc3[nH]ccc23)cc1OC
Temperature: 100 °C

Procedure:
In a microwave safe tube, 4-Bromoindole (1.383 g, 0.007054 mol), 3,4-dimethoxyphenyl boronic acid (3.21 g, 0.0176 mol), and Tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.00035 mol) were mixed in 1.00 M of Potassium carbonate in Water (21 mL) and Tetrahydrofuran (34 mL, 0.42 mol). The resulting mixture was heated at 100° Celsius in the microwave for 10 minutes. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layers were combined, washed with brine and dried over sodium sulfate. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to the yield 1.02 g of the titled compound as a light green solid. MS(ESI) [M+H+]+=254.20.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](=[CH2:11])[CH3:10]>>[C:9]([C:4]1[CH:5]=[CH:6][C:1]([SH:7])=[CH:2][CH:3]=1)([CH3:11])([CH3:10])[CH3:8]
Reactant: C=C(C)C
Reactant: Sc1ccccc1
Product: CC(C)(C)c1ccc(S)cc1
Temperature: 70 °C
Yield: 67.4 %

Procedure:
To a mixture of 1100 grams (10.0 moles) of thiophenol, and 300 grams of boron trifluoride-phosphoric acid complex was slowly added, with stirring, 620 grams (10.9 moles) of isobutylene at 0° C. After addition was complete the mixture was stirred at 0°-10° C. for two hours. The mixture was then heated to 70° C. and stirred at 70°-75° C. for two hours. The reaction mixture was cooled to 25° C. and the organic layer was separated from the lower catalyst layer and added to 500 ml of toluene. The toluene layer was washed four times with 1000-ml portions of water and then dried with magnesium sulfate. The toluene was evaporated from the mixture in vacuo and the residue was distilled in a 10-tray column to give 1120 grams of 4-(tert-butyl)thiophenol, b.p. 58°-60°/1.00 mm (yield 68%). The nmr spectrum agreed with the structure. The residue from the above distillation was 470 grams of tert-butyl 4-(tert-butyl)phenyl sulfide. Neuworth et al (1963) report b.p. 120°/20 mm for 4-(tert-butyl)thiophenol.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:9]2[C:8](Cl)=[N:7][C:6]([Cl:13])=[N:5][C:4]=2[CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:7][C:6]([Cl:13])=[N:5][C:4]=2[CH:3]=1
Reactant: Clc1nc(Cl)c2ncc(Br)cc2n1
Reactant: C1COCCN1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
To an ice cold solution of crude 7-bromo-2,4-dichloro-pyrido[3,2-d]pyrimidine (2.85 g, 0.0102 mol) in DCM (25 mL) at 0° C. was added morpholine (1.8 g, 0.0204 mol). The reaction was continued at 0° C. for 30 min. The volatiles were evaporated and subjected to column chromatography (60-120 silica gel, 0-12% ethyl acetate in hexane) to get the title compound as a light yellow solid [0.35 g, 26%]. 1H NMR (300 MHz, DMSO-d6): δ 8.68 (d, J=2.7 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 3.86-3.89 (m, 8H); LC-MS (ESI): Calculated mass: 328.0; Observed mass: 330.8 [M+H]+ (RT: 1.50 min).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[B-](F)(F)F.[CH2:20]([O+](CC)CC)[CH3:21].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:20]([O:1][C:2]1[CH2:3][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:6][N:7]=1)[CH3:21]
Reactant: CC[O+](CC)CC
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC1=NCCN(C(=O)OC(C)(C)C)C1

Procedure:
To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (1 g, 5 mmol) in DCM (15 mL) was added triethyloxonium tetrafluoroborate (2.9 g, 15 mmol). Stirred for 2 h and neutralized with sat. aq NaHCO3. Layers separated and aqueous layer extracted with DCM. Combined organic layers dried over Na2SO4, filtered, and concentrated to give the title compound, which was used directly without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH2:12]([O:14][C:15](=[O:23])/[CH:16]=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:23])[C@H:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])[CH3:13]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: CO[Si](CCCN)(OC)OC
Product: CCOC(=O)C[C@H](NCCC[Si](OC)(OC)OC)C(=O)OCC

Procedure:
179.0 g (1.0 mol) of 3-aminopropyl-trimethoxysilane and 172.0 g (1.0 mol) of maleic acid diethyl ester were reacted by the same procedure used Example 1. A clear, colorless product having a viscosity of about 30 mPa.s (23° C.) was obtained. The amine equivalent weight determined by base titration was about 359 g (theory: 351 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:30])([F:29])[CH:23]([F:28])[C:24]([F:27])([F:26])[F:25])[C:3]=1[Cl:31].[C:32](OC(=O)C)(=O)C>>[Cl:31][C:3]1[C:4]([O:21][C:22]([F:29])([F:30])[CH:23]([F:28])[C:24]([F:25])([F:26])[F:27])=[N:5][N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:16])([F:18])[F:17])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[C:2]=1[NH:1][CH3:32]
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CNc1c(Cl)c(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 3 h

Procedure:
0.8 g of 5-amino-4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole was dissolved in 20 mL of acetic anhydride. After stirring for 3 hours under reflux with heating, acetic anhydride was distilled off under reduced pressure, the obtained residue was dissolved in 20 mL of tetrahydrofuran, and 20 mL of a 25 mass % ammonia water was added under cooling with ice. After stirring for one hour under cooling with ice, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 5 mL of dimethylformamide, and the solution was dropwise added to a suspension having 50 mg of sodium hydride suspended in 10 mL of dimethylformamide under cooling with ice. After completion of the dropwise addition, stirring was carried out at room temperature for 30 minutes. The reaction solution was cooled with ice again, and 0.18 g of methyl iodide was added, followed by stirring at room temperature for one hour. Water was injected, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 10 mL of ethanol, and 10 mL of a 35 mass % hydrochloric acid aqueous solution was added, followed by stirring under reflux with heating for one hour. The reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.34 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)-5-methylaminopyrazole.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[CH2:7]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)[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][CH3:22]>CN(C)C=O>[CH2:7]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:29][N:3]=[N:2][N:1]=2)=[CH:26][CH:25]=1)[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][CH3:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCNc1ccc(-c2nnn[nH]2)cc1
Temperature: 120 °C

Procedure:
Sodium azide (0.98 g., 0.015 mole) and NH4Cl are added to a solution of p-hexadecylaminobenzonitrile (5.13 g., 0.015 mole) in dimethylformamide. The mixture is stirred and heated in an oil bath maintained at 120° C. for 42 hours. The reaction mixture is cooled and then poured into ice-water with vigorous stirring. The precipitate separated is filtered, washed thoroughly with water and dried. The dry precipitate is washed repeatedly with ether and dried; 1.7 g. of a pale brown powder is obtained as a homogeneous product, melting point 114°-116° C. (decomp.).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: FC(F)CCl
Solvent: CCN(CC)CC
Solvent: O
Product: FC(F)CNCc1ccccc1
Yield: 66 %

Procedure:
An amount of 10 g (92 mmol) of 2,2-difluoro-1-chloroethane, 5 g (46 mmol) of benzylamine and 5.2 g (51 mmol) of triethylamine are heated in 20 g of water in an autoclave at an internal temperature of 120° C. for 6 hours. The two-phase solution is twice extracted with 50 ml of dichloromethane each time and the combined organic phases are washed with 50 ml of water and subsequently distilled. An amount of 5.2 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 66%, based on benzylamine.
Reaction SMILES: [Br-].[C:2]1([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][O:10][C:9]2=[N+:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]2[N:30]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]3[C:36]([N:37]=2)=[CH:35][N:34]=[CH:33][N:32]=3)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:14][N:13]([CH3:15])[C:9](=[O:10])[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:11][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:29]2[N:30]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]3[C:36]([N:37]=2)=[CH:35][N:34]=[CH:33][N:32]=3)[CH2:26][CH2:27]1
Reactant: c1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)nc1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)C(=O)C(CCN1CCC(Nc2nc3cncnc3n2Cc2ccccn2)CC1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 3.46 parts of N-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide, 3.1 parts of N-(4-piperidinyl)-9-(2-pyridinylmethyl)-9H-purin-8-amine, 1.5 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 80° C. after cooling, the reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 4.1 parts (71%) of N,N-dimethyl-α,α-diphenyl-4-[[9-(2-pyridinylmethyl)-9H-purin-8-yl]amino]-1-piperidinebutanamide; mp. 191.6° C. (compound 122).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:25][C:26]3[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=3)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)c1
Temperature: 100 °C
Reaction time: 0.1 h

Procedure:
A mixture of 0.226 g (0.58 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.40 g (2.42 mmol) of 3-aminobenzoic acid, ethyl ester was fused in a 170° C. oil bath to give a clear melt. After 6 minutes, the melt was cooled to ca. 100° C. Glacial acetic acid (1 mL) was added to dissolve the melt. Water (5 mL) was added to precipitate a solid. The solid was filtered, washed well with water, and triturated with 2 mL of methanol. The mixture was filtered, and the cake was washed with 1 mL of methanol and then ether; wt 0.194 g. Recrystallization from ethyl acetate gave pure product; wt 0.075 g; mp 238°-240° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]C.[C:7]([O:12]CC)(=O)[CH:8]([CH3:10])O>>[OH:12][CH:7]=[CH:8][C:10]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CCOC(=O)C(C)O
Reactant: CCCCCC
Product: OC=Cc1ccccc1

Procedure:
A solution prepared by dissolving 10.0 g of a poly(hydroxystyrene) resin having a weight-average molecular weight of 20000 with a dispersion of the molecular weight distribution Mw /Mn of 1.1 (VP-20000, a product by Nippon Soda Co.), which contained a few % by weight or less of unpolymerized monomer and oligomers having a molecular weight smaller than 1000, in 40 g of ethyl lactate was taken in a separatory funnel and admixed with 150 g of n-hexane and the mixture was thoroughly shaken followed by standing to effect phase separation into an upper layer of the n-hexane solution and lower layer of the ethyl lactate solution. The n-hexane solution as the upper layer was discarded and the ethyl lactate solution as the lower layer was again admixed with 150 g of n-hexane followed by vigorous shaking of the mixture. This fractionating extraction with n-hexane was repeatedly undertaken four times and the finally obtained ethyl lactate solution was subjected to replacement of solvent with methyl alcohol by repeating evaporation of ethyl lactate and addition of methyl alcohol. The thus obtained methyl alcohol solution was added dropwise into a large volume of water to effect precipitation of the polymer which was collected, washed with pure water and dried to give a poly(hydroxystyrene) resin substantially free from unpolymerized hydroxystyrene monomer and oligomers having a molecular weight smaller than 1000 as confirmed by the GPC method. Since the content of the low molecular weight fractions in the starting resin was relatively low, no significant changes were found in the weight-average molecular weight and in the dispersion of the molecular weight distribution.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][OH:17])[C@@H:14]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:13]([C:27]([O:29][CH3:30])=[O:28])[C@@H:12]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:42](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16][O:17][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:14]([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:13]([C:27]([O:29][CH3:30])=[O:28])[C@@H:12]1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](CO)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Yield: 117.1 %

Procedure:
To a stirred and ice-cooled solution of crude (2R*,3S*,4S*,5S*)-1-benzyloxycarbonyl-4-benzyloxymethyl-5-hydroxymethyl-3-methoxycarbonyl-2-phenylpyrrolidine (15.9 g, ca.29.0 mmol) and imidazole (Im, 7.90 g, 116 mmol) in DMF (32.0 ml) was added t-butyldimethylsilyl chloride (8.74 g, 58.0 mmol)in one portion. The cooling bath was removed immediately after the addition, and the stirring was continued at room temperature for ca.5 hours. The reaction mixture was diluted with PhMe--AcOEt (2:1, 300 ml), washed with H2O (×3), and sat. NaCl aq. solution (×2), dried (MgSO4), and concentrated in vacuo to give a colorless oil (20.5 g). This was chromatographed over SiO2 (Merck Kieselgel 60, 200 g). Elution with n-hexane-AcOEt (50:1→20:1→15:1) gave title compound (16.8 g, 96%) as a colorless viscous oil: IR νmax (film): 1743(s), 1705(vs), 1495(m), 1100(s), 780(s), 745(s), 737(s), 700(s) cm-1 ; 1H-NMR δ: 7.48-7.37(m, 3H), 7.37-7.14(m, 11H), 6.90(br.s, 1H), 5.27(br.d,J=6.1 Hz, 1H), 5.02(br.s, 2H), 4.51-4.41(m, 1H), 4.47(s, 2H), 3.97(dd, J=10.3, 2.6 Hz, 1H), 3.94-3.83(m, 1H), 3.60(d, J=3.7 Hz, 2H), 3.54(dd, J=11.8, 9.5 Hz, 1H), 3.33-3.15(m,1H), 3.28(s, 3H), 0.90(br.s, 9H), 0.05(br.s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH3:12][CH:13](O)[CH2:14][CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:13]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[Cl:11])([CH2:14][CH3:15])[CH3:12]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCC(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
2,6-dichloropurine (5.3 mmol), 2-Butanol (9.01 mmol), triphenylphosphine (7.95 mmol) in 40 ml anhydrous tetrahydrofuran, to which was added drop-wise diisoproplyazidodicarboxylate (7.95 mmol) at room temperature over a period of 30 minutes. The reaction mixture was stirred at room temperature for 24 hrs. The reaction is monitored by TLC or LC/MS. The reaction mixture was poured in to a beaker containing ice-cold water. Extraction of the aqueous layer, using 3×100 ml portions of ethyl acetate, afforded the crude product. This was purified on the silica gel column (10-80% ethyl acetate in petroleum ether, gradient elution), to give the desired compound in a yield of 50%.
Reaction SMILES: [C:1]12([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[NH:7][C:6](=[O:14])[O:5]1)[CH2:4][CH2:3][CH2:2]2.C([O-])(=O)C.[K+].[Br:20]Br>C(O)(=O)C>[Br:20][C:11]1[CH:12]=[CH:13][C:8]2[NH:7][C:6](=[O:14])[O:5][C:1]3([CH2:4][CH2:3][CH2:2]3)[C:9]=2[CH:10]=1
Reactant: O=C1Nc2ccccc2C2(CCC2)O1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C2(CCC2)O1
Yield: 53 %

Procedure:
To a solution of spiro[3,1-benzoxazine-4,1′-cyclobutan]-2(1H)-one (0.36 g, 1.9 mmol) and potassium acetate (0.56 g, 5.7 mmol) in acetic acid was added a solution of bromine (0.09 mL, 1.95 mmol) in acetic acid (2 mL) at room temperature. Upon completion by TLC of the reaction, the acetic acid was removed. The residue was treated with saturated sodium bicarbonate (100 mL) and the product extracted with ethyl acetate (50 mL). The organics were dried over magnesium sulfate and concentrated. Trituration of residue with ether gave 6-bromospiro[3,1-benzoxazine-4,1′-cyclobutan]-2(1H)-one (0.27 g, 52%) as a white solid. 1H NMR (DMSO-d6): δ 10.37 (s, 1H), 7.65 (d, 1H, J=2.1 Hz), 7.47 (dd, 1H, J=8.5, 2.2 Hz) 6.86 (d, 1H, J=8.5 Hz), 2.52-2.47 (m, 2H), 2.04-1.98 (m, 2H), 1.87-1.80 (m, 2H). MS (ESI) m/z 268/270 ([M+H]+); MS (ESI) m/z 266/268 ([M−H]−).
Reaction SMILES: C(N(CC)CC)C.Br.[CH3:9][N:10]1[C:14]2[CH2:15][NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=[N:11]1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[N:27]=[C:28]([CH3:40])[N:29]2[C:34]=1[C:33](N1C=NC=N1)=[N:32][CH:31]=[N:30]2>ClCCl>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[N:27]=[C:28]([CH3:40])[N:29]2[C:34]=1[C:33]([N:16]1[CH2:17][CH2:18][C:13]3[CH:12]=[N:11][N:10]([CH3:9])[C:14]=3[CH2:15]1)=[N:32][CH:31]=[N:30]2
Reactant: Cn1ncc2c1CNCC2
Reactant: Cc1nc(-c2ccccc2F)c2c(-n3cncn3)ncnn12
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2F)c2c(N3CCc4cnn(C)c4C3)ncnn12
Temperature: 40 °C

Procedure:
Triethylamine (0.510 mL, 3.66 mmol) and C9 (0.333 g, 1.58 mmol) were added to a solution of C6 (0.360 g, 1.22 mmol) in dichloromethane (10 mL), and the reaction mixture was heated at 40° C. for 18 hours. The mixture was then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification was effected first via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane), then by reversed phase HPLC (Column: Phenomenex Gemini C18, 5 μm; Mobile phase A: 0.1% ammonium hydroxide in water; Mobile phase B: 0.1% ammonium hydroxide in methanol; Gradient: 5% to 100% B). The product was obtained as a solid. Yield: 202 mg, 0.556 mmol, 46%. LCMS m/z 364.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.63 (ddd, J=7.6, 7.5, 1.8 Hz, 1H), 7.52 (dddd, J=8.3, 7.5, 5.2, 1.8 Hz, 1H), 7.35 (ddd, J=7.6, 7.5, 1.1 Hz, 1H), 7.22 (br ddd, J=10.0, 8.3, 1.0 Hz, 1H), 7.16 (br s, 1H), 4.45 (br s, 2H), 3.76-3.84 (m, 2H), 3.43 (s, 3H), 2.67 (s, 3H), 2.35-2.41 (m, 2H).