Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[C:5]([N:8]1[C:16]2[C:11](=[C:12]([CH3:20])[C:13]([O:18]C)=[C:14]([CH3:17])[CH:15]=2)[CH:10]([CH3:21])[CH2:9]1)(=[O:7])[CH3:6]>C(Cl)Cl>[C:5]([N:8]1[C:16]2[C:11](=[C:12]([CH3:20])[C:13]([OH:18])=[C:14]([CH3:17])[CH:15]=2)[CH:10]([CH3:21])[CH2:9]1)(=[O:7])[CH3:6]
Reactant: COc1c(C)cc2c(c1C)C(C)CN2C(C)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)N1CC(C)c2c1cc(C)c(O)c2C
Temperature: -78 °C
Reaction time: 17 h
Yield: 0.9 %

Procedure:
Boron tribromide (1.4 mL of 1M solution in methylene chloride, 1.4 mmol) was added to a cooled (-78° C.) solution of indoline 9 (110 mg, 47 mmol) dissolved in methylene chloride (2 mL). The resulting solution was maintained at -78° C. (1 h), then slowly warmed to room temperature and held there for 17 h. The cooled reaction mixture was quenched with a few drops of methanol followed by cold water. The solution was extracted with methylene chloride and the combined organic layers were washed with brine and dried (MgSO4). Removal of solvents gave a solid, which was recrystallized from methylene chloride-hexanes to afford the indoline 11a (95 mg, 92% yield) as a colorless solid, mp 204°-205° C. Spectral data: 13C NMR (CD3SOCD3): δ 12.3, 17.2, 20.7, 23.7, 33.4, 56.4, 115.3, 120.7, 122.6, 133.9, 134.3, 149.1, 167.4; HRMS: calcd. for C13H17NO2 219.1259, fnd. 219.1261. Anal: calcd. for C13H17NO2C, 71.21, H, 7.81, N, 6.39, fnd. C, 71.06,H, 7.84, N, 6.33.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][F:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1.[CH3:14][N:15]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>>[F:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=[C:2]1[C:30]#[C:29][C:26]1[CH:25]=[CH:24][C:23]([N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:28][CH:27]=1
Reactant: FCCn1c(Br)nc2ccccc21
Reactant: C#Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C#Cc2nc3ccccc3n2CCF)cc1
Yield: 35.3 %

Procedure:
T534 was prepared using general procedure B from 2-bromo-1-(2-fluoroethyl)-1H-benzo[d]imidazole and tert-butyl methyl-4-(ethynyl)phenylcarbamate. Reaction was performed on a 53 mgs scale of 2-bromo-1-(2-fluoroethyl)-1H-benzo[d]imidazole. The crude product was purified by ISCO column to afford tert-butyl 4-((1-(2-fluoroethyl)-1H-benzo[d]imidazol-2-yl)ethynyl)phenyl(methyl)carbamate (0.03 g, 35.3%). It was dissolved in acetonitrile (0.5 mL). To this solution was added a solution of 20% sulfuric acid (1.5 mL, 5.63 mmol). The resulting mixture was stirred at room temperature for 20 minutes, diluted with water (2.0 mL) and purified by preparative HPLC to afford T534 as TFA salt (0.004 g, 12.88%). 1H NMR (400 MHz, CD3CN) δ 7.81-7.79 (m, 1H), 7.67-7.65 (m, 1H), 7.52-7.48 (m, 4H), 6.66-6.64 (m, 2H), 4.95-4.93 (m, 1H), 4.83-4.478 (m, 2H), 4.74-4.73 (m, 1H), 2.82 (s, 3H); MS (ESI): 294.1 (M+H+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32]C(OC(C)(C)C)=O)=[C:28]([NH:40][CH:41]=O)[CH:27]=2)=[CH:21][CH:20]=1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:51]>>[ClH:51].[ClH:51].[NH:32]1[C:29]2[CH:30]=[CH:31][C:26]([O:25][C:22]3[CH:23]=[CH:24][C:19]([CH2:18][NH:10][CH:2]4[CH2:3][C:4]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:1]4)=[CH:20][CH:21]=3)=[CH:27][C:28]=2[N:40]=[CH:41]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(CN(C(=O)OC(C)(C)C)C3Cc4ccccc4C3)cc2)cc1NC=O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1ccc2c(c1)CC(NCc1ccc(Oc3ccc4[nH]cnc4c3)cc1)C2

Procedure:
1,1-Dimethylethyl 2,3-dihydro-1H-inden-2-yl[(4-{[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(formylamino)phenyl]oxy}phenyl)methyl]carbamate (365 mg, 0.637 mmol) was dissolved in 20 mL of methylene chloride and stirred with 4 mL trifluoroacetic acid for approximately 18 hours. The reaction was concentrated and purified using preparative HPLC. Pure fractions were combined, diluted with ethyl acetate and washed with 1N NaOH. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in ethyl acetate. 4N HCl in dioxane was added and N-{[4-(1H-benzimidazol-5-yloxy) phenyl]methyl}-2,3-dihydro-1H-inden-2-amine dihydrochloride was collected by filtration as a white precipitate. The solid was dissolved in methanol, concentrated onto basic alumina and purified by column chromatography using an ISCO™ amine functionalized silica column. (dichloromethane to 5% methanol). The purified material was dissolved in minimal methanol. HCl (4N in dioxane) was added to the solution which was concentrated to give N-{[4-(1H-benzimidazol-5-yloxy)phenyl]methyl}-2,3-dihydro-1H-inden-2-amine dihydrochloride. (Example No. 26)
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=O)=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[CH3:14][NH:15][C:16]([C:18]1[N:19]([CH3:24])[N:20]=[CH:21][C:22]=1[NH2:23])=[O:17]>>[CH3:24][N:19]1[C:18]([C:16](=[O:17])[NH:15][CH3:14])=[C:22]([NH:23][C:11]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH:8]([CH3:9])[CH3:10])[N:4]=2)=[O:13])[CH:21]=[N:20]1
Reactant: CC(C)c1ncc(Br)c(C(=O)O)n1
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(C(C)C)ncc2Br)cnn1C

Procedure:
The product was obtained starting from 5-bromo-2-isopropyl-pyrimidine-4-carboxylic acid (intermediate A-4, step 1; 300 mg, 1.22 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (245 mg, 1.59 mmol) according to the method described in example 64, step 6 after extraction with ethyl acetate and purification by silica gel chromatography using ethyl acetate as light brown solid (472 mg, 96%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][S:32]([CH3:31])(=[O:34])=[O:33])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)n2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(NS(C)(=O)=O)c3)n2)n1
Yield: 47.5 %

Procedure:
To a stirred and cooled solution of 3-{4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-phenylamine (example 326) (0.150 g, 0.369 mmol) in EtOAc (2 mL) and sat. NaHCO3-sol. (1 mL) was added methanesulfonyl chloride (1.0 mL, 13.6 mmol) and the mixture was stirred at 23° C. for 2 h. Diluted with EtOAc, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with EtOAc, followed by trituration with diethyl ether to give the title compound as a white solid (0.085 g, 47%). MS (ISP) 485.3 [(M+H)+].
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]([C:29](=O)[CH3:30])=[CH:20][C:21]([Cl:28])=[C:22]4[C:27]=3[N:26]=[CH:25][CH:24]=[CH:23]4)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:38].[Na+].O1CCCC1>CO.C(#N)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]([CH:29]([NH2:38])[CH3:30])=[CH:20][C:21]([Cl:28])=[C:22]4[C:27]=3[N:26]=[CH:25][CH:24]=[CH:23]4)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCN(C(C)=O)CC2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)N2CCN(c3c(C(C)N)cc(Cl)c4cccnc34)CC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-(8-{4-[(1-acetylpiperidin-4-yl)carbonyl]piperazin-1-yl}-5-chloroquinolin-7-yl)ethanone (0.030 g, 0.068 mmol) and ammonium acetate (0.0522 g, 0.677 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.17 mL, 0.17 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C23H31ClN5O2 (M+H)+: m/z=444.2; Found: 444.2.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[N:7]=1)=[O:5].[N:14]([Si](C)(C)C)=[N+:15]=[N-:16]>CN(C=O)C.ClCCl>[CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:14]=[N+:15]=[N-:16])[N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1cccc(F)n1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(N=[N+]=[N-])n1
Temperature: 110 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
A mixture of 6-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide (1.19 g, 6.47 mmol) and azido-trimethylsilane (2.0 g, 16.8 mmol) in DMF (10 mL) was stirred at 110° C. for 72 h. The reaction mixture was diluted with 50 mL of dichloromethane and washed with water (3×50 mL). The organic layer was separated, evaporated to dryness, and subjected to column chromatography (SiO2, 40% EtOAc-hexanes) to obtain 6-azido-pyridine-2-carboxylic acid methoxy-methyl-amide (0.335 g) in 25% yield. ESMS m/z (relative intensity): 208 (M+H)+ (100).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.Cl.[CH2:12]([NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl)[CH:13]([CH3:15])[CH3:14].C(OCC)C>C(O)C>[CH2:12]([NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][S:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:13]([CH3:15])[CH3:14]
Reactant: Sc1nc2ncccc2[nH]1
Reactant: CC(C)CNc1ccccc1CCl
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CC(C)CNc1ccccc1CSc1nc2ncccc2[nH]1
Yield: 49.3 %

Procedure:
To a dispersion of 0.96 of 2-mercaptoimidazo[4,5-b]pyridine in 30 ml of ethanol was added at once 1.5 g of 2-(isobutylamino)benzyl chloride hydrochloride at room temperature under stirring. The resulting mixture was further stirred for one hour. To the mixture was added 30 ml of diethyl ether, and the precipitated crystals were collected by filtration and washed with a mixture of ethanol and diethyl ether (1/1 in volume). The obtained powdery product was added portionwise to a mixture of 30 ml o fchloroform and 30 ml of a saturated NaHCO3 solution for neutralization. The organic phase was separated, washed with a saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was crystallized by addition of diethyl ether and hexane. The crystalline product was collected by filtration, washed with a mixture of diethyl ether and hexane (1/1 in volume) and dried to give 985 mg (yield: 49.3%) of 2-[2-(isobutylamino)benzylthio]imidazo[4,5-b]pyridine as a white crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23].[OH-].[K+]>CO>[F:11][C:12]1[C:17]([CH:18]([OH:19])[C:10]2[C:3]3[C:2]([CH3:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23]
Reactant: Cc1ncnc2[nH]ccc12
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncnc(C)c23)c1F
Temperature: 25 °C
Reaction time: 30 h
Yield: 37.7 %

Procedure:
To 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (42, 0.192 g, 1.44 mmol), propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (9, 0.456 g, 1.73 mmol), potassium hydroxide (0.263 g, 4.69 mmol) and 1.0 mL of methanol were added to provide a solution. The reaction was allowed to stir at room temperature for 30 hours, then quenched with water and adjusted to pH ˜5 with acetic acid and sodium bicarbonate and extracted with ethyl acetate and saturated sodium chloride. The organic layer was washed with water and brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane with 4% acetic acid. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as an off-white solid (P-0055, 215 mg). 1H-NMR(dmso-d6) showed it contains about >80% of the desired compound, used in the next step without further purification. MS(ESI) [M+H−]+=397.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:26]1[CH:27]=[N:28][CH:29]=[C:30]([O:32]C)[CH:31]=1)[N:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])[CH3:2].C(S)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:26]1[CH:27]=[N:28][CH:29]=[C:30]([OH:32])[CH:31]=1)[N:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cncc(OC)c1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)C[C@@H](c1cncc(O)c1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 16-3 (200 mg, 0.4278 mmol) and ethanethiol (0.5 ml) and CH2Cl2 (3 ml) was added AlCl3 (570 mg, 4.28 mmol). After 1.0 hour, the reaction was quenched with sat. NaHCO3. Ethyl acetate was added, and the reaction mixture was then purged with argon for 1.0 hour. The organic layer was separated, washed with brine, dried (MgSO4) and then concentrated to give the phenol 16-4 as a yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15](N(OC)C)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.[Li]CCCC>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CON(C)C(=O)CC1c2ccccc2-c2ccccc21
Reactant: Ic1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC1c2ccccc2-c2ccccc21)c1ccncc1

Procedure:
In analogy to example 55, step 2, from 2-(9H-fluoren-9-yl)-N-methoxy-N-methyl-acetamide and 4-iodopyridine using isopropylmagnesium chloride lithium chloride complex in THF at rt (instead of n-BuLi at −70° C.) was prepared the title compound as yellow oil, MS (ESI+): m/z=286.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6](F)[C:5]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[NH4+:20].[NH4+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([NH2:20])[C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc(N)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
6.0 g (27.5 mmol) of 3,5-difluoro-2-nitro-benzoic acid methyl ester was dissolved in DMF and treated with 2.9 g (30.25 mmol) of ammonium carbonate. The reaction was heated at 60° C. for 6 h. Water was added to the reaction mixture. The solid produced was collected by filtration and washed with water to produce 3-amino-5-fluoro-2-nitro-benzoic acid methyl ester. LCMS: 215 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9]CC(C)(C)N=2)=[C:4]([S:15][CH3:16])[C:3]=1[O:17][CH3:18].Cl.[OH2:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])=[O:20])=[C:4]([S:15][CH3:16])[C:3]=1[O:17][CH3:18]
Reactant: O
Reactant: COc1c(Cl)ccc(C2=NC(C)(C)CO2)c1SC
Agent: Cl
Product: COc1c(Cl)ccc(C(=O)O)c1SC

Procedure:
A mixture of 2-[4-chloro-3-methoxy-2-(methylsulphenyl)-phenyl]-4,4-dimethyloxazoline (9.0 g) and hydrochloric acid (5M) was stirred and heated at reflux for 5 hours. After cooling, the mixture was diluted with water and extracted with dichloromethane. It was dried (MgSO4), filtered and the filtrate was evaporated to dryness to give 4-chloro-3-methoxy-2-(methylsulphenyl)benzoic acid as a white solid, m.p. 98°-99° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Br[Mg]c1ccccc1
Product: OC(c1ccccc1)c1cccc(Br)c1

Procedure:
Prepared according to the procedure described in Example 16, Step 1, using 3-bromobenzaldehyde and phenylmagnesium bromide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)=[O:4].[CH2:23]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH2:30]([N:29]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:16](=[O:18])[CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]1[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=1[C:3]([O:2][CH3:1])=[O:4])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccccc1COc1cccc(CC(=O)O)c1
Reactant: CCCCCCNCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1cccc(OCc2ccccc2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-{[2-(Methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (60 mg, 0.2 mmol) was dissolved in DCM (2 ml), N-hexylbenzylamine (46 mg, 0.24 mmol) was added, then EDC (46 mg, 0.24 mmol) was added and then DMAP (29.3 mg, 0.24 mmol) was added. The mixture was stirred at room temperature overnight. 1% hydrochloric acid (1 ml) and water (1 ml) were added into the mixture. The two phases were separated by using a Whatman Filter Tube. The obtained organic portion was evaporated in vacuum and 59 mg crude oil product was left. It was then used directly in next step.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.NC[CH2:40][CH2:41][NH2:42].Cl.[N:44]1([C:49](N)=[NH:50])C=CC=[N:45]1.N1C=CN=C1>CS(C)=O.CO>[NH2:45][N:44]=[CH:49][NH:50][CH2:40][CH2:41][NH:42][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: NCCCN
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: N=C(N)n1cccn1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CS(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCNC=NN)nc32)[C@H](O)[C@@H]1O
Reaction time: 24 h
Yield: 58 %

Procedure:
A solution of 1-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-1-deoxy-N-ethyl-β-D-ribofuranuronamide (0.310, 0.592 mmol) in dimethylsulphoxide (2 ml) was heated with 1,3-diaminopropane (0.542 g, 7.31 mmol) at 1200 for 24 h. The cooled mixture was partitioned between ethyl acetate (50 ml) and water (50 ml) and the aqueous phase was separated and extracted with ethyl acetate (20 ml). The combined ethyl acetate solution was washed with water (20 ml), dried (MgSO4) and evaporated to leave a froth (0.302 g). This froth (0.3 g)was dissolved in 50% aqueous methanol (20 ml) and the solution was heated at reflux with pyrazole-1-carboxamidine hydrochloride (0.099 g, 0.675 mmol) and imidazole (0.05 g, 0.734 mmol) for 18 h. More pyrazole-1-carboxamidine hydrochloride (0.099 g, 0.675 mmol) was added and heating was continued for a further 24 h. The mixture was evaporated to leave a solid which was purified by preparative HPLC (20-60% acetonitrile) to give the title compound (0.202 g) as a solid from ether. The product had MH+ =603, nmr(δ,DMSO-d6) includes 1.02(t,3H), 1.7-1.9(m,2H), 3.05-3.25(m,4H), 3.3-3.5(m,2H), 4.15-4.25(m,1H), 4.8(s,1H), 4.5-4.7(m,2H), 5.85(d,1H), 7.15-7.4(m,10H), 7.5-7.65(m,1H), 8.12(s,1H), 8.1-8.25(m,1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:38]1[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][N:39]=1.C(OC(C)C)(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][N:39]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Solvent: CC(=O)OC(C)C
Product: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-5-cyanopyridine following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.301, m/z=416; 1H NMR (CDCl3) 1.09 (d, 6H), 1.49 (d, 3H), 2.09-2.22 (m, 4H), 2.37 (m, 1H), 2.87 (m, 1H), 5.68 (m, 1H), 6.92-7.01 (t, 2H), 7.06 (m, 2H), 7.23 (m, 2H), 7.71 (d, 1H), 7.78 (d, 2H), 7.91 (d, 1H), 8.88 (s, 1H). The compound was dissolved in refluxing isopropyl acetate and allowed to cool slowly to afford a solid with mp 155-157° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:18]=[O:19].[H-].[Na+]>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]([N:12]1[CH2:16][CH2:15][N:14]([CH2:18][OH:19])[C:13]1=[O:17])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: C=O
Reactant: CCOP(=O)(CC(=O)N1CCNC1=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)N1CCN(CO)C1=O)OCC

Procedure:
264 Gm (1 mol) of 1-(Diethylphosphonoacetyl)-imidazolidin-2-one and 33 gm of paraformaldehyde (1.1 mol) were dissolved in 2.5 liters of tetrahydrofuran; and after the addition of about 0.3 gm of sodium hydride, the solution was refluxed for one hour. After the solvent had been distilled off, there remained 1-(diethylphosphonoacetyl)-3-hydroxymethylimidazolidin-2-one as a yellowish, viscous liquid. The determination of the total formaldehyde and the free formaldehyde gave a degree of hydroxymethylation amounting to 100%. The compound had the formula ##EQU12##