Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:54]=[C:55]([Cl:57])[CH:56]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29]([N:33](C(OC(C)(C)C)=O)[NH:34]C(OC(C)(C)C)=O)=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:49]1[O:50][CH:51]=[N:52][N:53]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:58][CH2:59]CC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(O)(=O)C>[Cl:57][C:55]1[CH:56]=[C:20]([CH2:19][OH:18])[CH:21]=[C:22]([CH2:23][N:24]2[C:32]3[CH:31]=[CH:30][C:29]4[N:28]([C:58]([CH3:59])=[N:34][N:33]=4)[C:27]=3[CH:26]=[C:25]2[C:49]2[O:50][CH:51]=[N:52][N:53]=2)[CH:54]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3nnco3)n2Cc2cc(Cl)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1nnc2ccc3c(cc(-c4nnco4)n3Cc3cc(Cl)cc(CO)c3)n12

Procedure:
A solution of di-tert-butyl 1-[1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-2-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (0.26 g, 0.32 mmol, from Step 3) in acetic acid (15 mL) was heated at 180° C. for 5 minutes in the microwave. Acetic acid was removed in vacuo. The residue was partitioned between an additional NaHCO3 and EtOAc. The aqueous layer was further extracted with two portions of EtOAc. The combined organic layers were dried over sodium sulfate, decanted and concentrated. The product was dissolved in THF (5 mL) and was treated with 1.0 M TBAF in THF (0.64 mL, 0.64 mmol, Aldrich). When the reaction was complete as determined by LCMS, the reaction mixture was poured into pH 7 buffer and extracted with three portions of EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-10% MeOH in DCM was used to purify the product. Yield: (0.045 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][CH:6]([C:9]#[N:10])[C:7]#[N:8].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][C:6]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:7]#[N:8])[C:9]#[N:10]
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Cl)c(Cl)c1
Yield: 14.7 %

Procedure:
Using 2.00 g of (3,4-dichlorobenzyl)malononitrile, 20 ml of N,N-dimethylformamide, 0.36 g of sodium hydride (60% in oil), and 2.37 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.42 g of 2-(3,4-dichlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (21)).
Reaction SMILES: [N:1]([C@H:4]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:5]1[O:10][CH:8]([OH:9])[C@H:7]([OH:11])[C@H:6]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N+:2]=[N-:3].[CH3:29]O>C(Cl)Cl>[N:1]([C@H:4]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:5]1[O:10][CH:8]([O:9][CH3:29])[C@H:7]([OH:11])[C@H:6]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H](COCc1ccccc1)[C@H]1OC(O)[C@H](O)[C@H]1OCc1ccccc1
Reactant: CO
Solvent: ClCCl
Product: COC1O[C@H]([C@@H](COCc2ccccc2)N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 5-azido3,6-di-O-benzyl-5-deoxy-D-glucofuranose (10.23 g, 26.5 mmol) in methylene chloride (170 ml) was added methanol (11 ml) and borontrifluoroetherate (1.5 ml). The mixture was stirred 24 h at room temperature. The reaction mixture was successively washed with a saturated aqueous solution of sodium bicarbonate and then with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silica gel and elution with a 1:1 mixture of hexane and ethyl acetate afforded methyl 5-azido-3,6-di-O-benzyl-5-deoxy-D-glucofuranoside as a colorless oil (9.15 g, 85%).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([CH3:15])=[N:8]1)([CH3:6])[C:3]([OH:5])=O.[C:16]([NH:19][NH2:20])(=[O:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:16]([NH:19][NH:20][C:3](=[O:5])[C:2]([CH3:1])([N:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([CH3:15])=[N:8]1)[CH3:6])(=[O:18])[CH3:17]
Reactant: Cc1nn(C(C)(C)C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NNC(=O)C(C)(C)n1cc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a mixture of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propanoic acid (500 mg, 2.38 mmol) in DCM (20 ml) was added acetohydrazide (211 mg, 2.86 mmol), HATU (1.8 g, 4.76 mmol), and DIPEA (618 mg, 4.76 mmol). The mixture was stirred at room temperature for 1 h. After concentration, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (1/3) to give the title product (600 mg, 95%) as light yellow oil. LC-MS (ESI): m/z=270.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:5]=[C:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[OH:21]O.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:6]3([C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])[O:21]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C1C(=Cc2ccc(Cl)c(Cl)c2)C(=O)c2ccccc21
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2C(=O)C12OC2c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of 2-(3,4-dichloro-benzylidene)-indane-1,3-dione (1c) (1.6 g, 5.2 mmol) in MeOH (13 mL) was added hydrogen peroxide (30% solution, 3 mL). The mixture was cooled to 0° C. and sodium hydroxide (1N, 300 μL) was added dropwise. After addition was completed, stirring was continued at room temperature for 1 h. The mixture was then poured into water (5 mL) and the resulting solid was collected by filtration and washed with water and MeOH. After drying under high vacuum 3-(3,4-dichlorophenyl)-spiro (oxirane-2,2′-indan)-1′,3′-dione (Id) (1.6 g, 95% yield) was obtained.
Reaction SMILES: [BH3-]C#N.[Na+].C(OC([NH:12][C:13]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:20])=[O:16])=O)(C)(C)C.[OH:35][C:36]1[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O.CO>C(O)(=O)C>[NH2:12][C:13]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:43]([CH3:44])[C:36]=2[OH:35])[CH2:27][CH2:28]1)=[O:20])=[O:16]
Reactant: Cc1cccc(C=O)c1O
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH3CN (0.40 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 2-hydroxy-3-methylbenzaldehyde (0.25 mmol), methanol (1.0 mL) and acetic acid (0.040 mL). The resulting mixture was stirred at 50 overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated. The residue was dissolved in ethyl acetate/methanol=5:1 (1 mL), loaded onto a Varian™ SCX column, eluted with ethyl acetate/methanol=5:1 (5 mL) and concentrated. The residue was dissolved in methanol (2 mL), and a 4 M dioxane solution of HCl (0.50 mL) was added to the resulting solution. The obtained mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL), concentrated and purified by preparative TLC to thereby provide 4-[[N-(2-amino-4,5-difluorobenzoyl) glycyl]aminomethyl]-1-(2-hydroxy-3-methylbenzyl)piperidine (Compd. No. 2106). The purity was determined by RPLC/MS (97%). ESI/MS m/e 447.0 (M++H, C23H28F2N4O3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:28][CH2:27][CH:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]2[OH:29])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]([O:16][C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:29][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC2C(=CC=CC2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2cc(Cl)ccc2[N+](=O)[O-])C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (1.93 g, 11 mmols), 2-tert-butoxycarbonyl-5-hydroxy-tetrahydroisoquinoline (2.74 g, 11 mmols), potassium carbonate (1.53 g, 11 mmols) and N,N-dimethylformamide (20 ml) was stirred at 60° C. for 24 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an oil of 2-tert-butoxycarbonyl-5-(5-chloro-2-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline (4.35 g, 97.7%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:13]=[C:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:11][N:10]=1.Cl.C([O-])([O-])=O.[K+].[K+]>CO>[N:15]1([CH2:14][C:12]2[O:11][N:10]=[C:9]([CH2:8][OH:7])[CH:13]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: c1c(COC2CCCCO2)noc1CN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1cc(CN2CCOCC2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
[5-((morpholin-4-yl)methyl)isoxazol-3-yl]methyl 2-tetrahydropyranyl ether (1.0 g) was dissolved in methanol (2 mL) and treated with 1 M HCl (aq. 10 mL). The mixture was stirred at room temperature for 1 h, then basified with K2CO3, and extracted with dichloromethane. The organic layers were dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH4OH 92/7.5/0.5) to afford [5-((morpholin-4-yl)methyl)-isoxazol-3-yl]methanol (53%). MH+ 199, Rf 0.24 (CH2Cl2/MeOH/NH4OH 92/7.5/0.5).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:28])=[CH:7][C:8]([CH3:27])=[C:9]([C:11]2[NH:26][C:14]3[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][C:13]=3[N:12]=2)[CH:10]=1)=[O:4].[OH-].[Na+]>CO.O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]2[N:12]=[C:11]([C:9]3[C:8]([CH3:27])=[CH:7][C:6]([CH3:28])=[C:5]([CH:10]=3)[C:3]([OH:4])=[O:2])[NH:26][C:14]=2[CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)cc1C(=O)O
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of tert-butyl 2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound 2.6, 300 mg, 0.70 mmol, 1.00 equiv, 90%) and sodium hydroxide (62 mg, 1.55 mmol, 2.00 equiv) in 15 mL methanol/H2O (2:1) was stiffed for at 40° C. in an oil bath. After 2 h, the reaction mixture was concentrated to about ⅓ of the volume under reduced pressure. The pH value of the remaining mixture was adjusted to 3-4 with hydrogen chloride (aq., 1 M). The resulting solids were collected by filtration and dried in an oven under reduced pressure to yield 0.2 g (69%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][C:9](=[CH:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[C:8](=[O:22])[C:7]2=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[C:8](=[O:22])[C:7]2=1
Reactant: Cc1[nH]cnc1C=C1CCc2[nH]c3c(F)cccc3c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]cnc1CC1CCc2[nH]c3c(F)cccc3c2C1=O
Yield: 46.7 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-3-[(5-methyl-1H-imidazol-4-yl) methylene]-4H-carbazol-4-one (728 mg) in absolute ethanol (30 ml) was added to a suspension of 5% palladium on charcoal (100 mg) in ethanol (30 ml), and the resulting mixture was hydrogenated at room temperature and atmospheric pressure until hydrogen uptake had ceased. The mixture was filtered, and the filtrate was evaporated in vacuo to leave an oil which was purified by FCC eluting with ethanol:ethyl acetate (1:5) to give the title compound (342 mg), m.p. 135°-140°, t.l.c. (ethanol:ethyl acetate, 1:5) Rf 0.175.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C-:14]#[N:15].[Na+]>CN(C)C=O>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:14]#[N:15]
Reactant: [C-]#N
Reactant: OCCCCCCCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCCCCCCCCCO
Temperature: 0 °C

Procedure:
A solution 4.6 g. of 11-bromoundecanol and 1.6 g. of sodium cyanide in 40 ml. of dimethylformamide is heated at 80° C. for 18 hours, cooled, and poured into ice-water. The mixture is extracted with methylene chloride and the extract is dried over anhydrous magnesium sulfate. Evaporation of the solution affords 12-hydroxydodecanonitrile as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:30])[CH2:22][NH:23][C:24](=[O:29])[CH2:25][N:26]([CH3:28])[CH3:27])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:30])[CH2:22][NH:23][C:24](=[O:29])[CH2:25][N:26]([CH3:27])[CH3:28])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=1
Reactant: C[C@H](CNC(=O)CN(C)C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: ClCc1ccccn1
Agent: Cl
Product: C[C@H](CNC(=O)CN(C)C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 59 %

Procedure:
The procedure described in Example 3 was repeated using N1-[(2R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)propyl]-N2,N2-dimethylglycinamide and picolyl chloride hydrochloride to give the title compound in 59% yield; NMR spectrum (CDCl3) 1.47 (d, 3H), 2.11 (s, 6H), 2.88 (s, 2H), 3.50-3.63 (m, 1H), 3.64-3.78 (m, 1H), 4.76-4.90 (m, 1H), 5.23 (s, 2H), 6.92-7.00 (m, 2H), 7.13-7.19 (m, 1H), 7.36-7.49 (m, 2H), 7.52-7.72 (m, 4H), 7.90 (d, 1H), 8.55 (m, 2H), 9.82 (s, 1H); Mass spectrum MH+ 521.0.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([C:10]2[NH:11][C:12]([CH3:29])=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[Cl:23])[N:15]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([C:10]2[NH:11][C:12]([CH3:29])=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[Cl:23])[N:15]=2)=[CH:8][N:9]=1
Reactant: CCOC(=O)C1=C(C)NC(c2cnc(NC(C)=O)s2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(c2cnc(N)s2)=NC1c1ccc(F)cc1Cl

Procedure:
Ethyl 2-(2-acetylaminothiazol-5-yl)-4-(2-chloro-4-fluorophenyl)-6-methyl-1,4-dihydro-pyrimidin-5-carboxylate (Example 43) was refluxed with 6 mol/L HCl in ethanol to obtain 0.15 g a yellowish solid with mp 132-135° C.; 1H-NMR (400 MHz, DMSO-d6) δ 1.0-1.05 (3H, m); 2.50 (3H, s); 3.90-3.93 (2H, m); 5.82 (1H, s); 7.13-7.50 (5H, m); 7.69 (1H, s); 9.19 (1H, s); MS (EI) 394.0 (M+).
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.CO>N1C=CC=CC=1>[I:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(I)c(N)nc3=O)C[C@@H]2O)cc1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a suspension of 5-iodo-2'deoxycytidine (17.65g, 50.00 mmol) in 250 ml of dry pyridine at 0° (ice bath) is added p-toluenesulfonyl chloride (11.50g, 60.00 mmol). The reaction mixture is stirred at 0° for 1 h and then stored at 3° in the dark with stirring for an additional 23 h. At the end of the reaction a clear solution is obtained, to which 15 ml of methanol is added. After standing for 30 min, the solvent is removed under diminished pressure at room temperature to afford a syrup which is coevaporated several times with methanol. The residue is triturated with icecooled water to give a crystalline mass which is broken down to the fine particles with a spatula. The solid material is collected by filtration, washed thoroughly with water, a small amount of ice-cooled ethanol, ether, and dried in vacuo to yield 20.24 g (80%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])[CH3:17].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:13][C:10]2[S:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[N:12][CH:11]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2cnc(NC(=O)OC(C)(C)C)s2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
To a single necked round bottom flask (5-Formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1 g, 4.38 mmol) was dissolved in 20 ml methanol. To it piperidine-4-carboxylic acid ethyl ester (2.02 ml, 13.15 mmol) and 4-drops of glacial acetic acid was added and reaction mixture was stirred at room temperature for 2.5 hr. To it sodium cyanoborohydride (550 mg, 8.76 mmol) was added in portions and stirred for 12 hrs. Methanol was removed under reduced pressure using rotavapour. The residue was taken in water (15 ml) and ethyl acetate (25 ml), layers were separated, and aq. layer was re-extracted with ethyl acetate (25 ml). The combined organic layer was washed with brine (25 ml) and dried over anhydrous sodium sulfate. Solvent was evaporated on rotavapour, to get the yellow solid product. The crude material was purified by silica-gel column chromatography, eluting with 30-50% ethyl acetate in hexane. (0.98 g, 60% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17][C:18](O)([CH3:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17][C:18]([F:29])([CH3:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Product: CC(C)(F)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-3-methyl-butan-1-one (2.5 g) in dry methylene chloride (30 mL) cooled to -78° C. is added diethylaminosulfur trifluoride (Aldrich Chemical Co.) (1.2 mL) and the stirring is continued for an additional 45 minutes. The mixture is washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The crude product is purified by silica gel column chromatography (hexane:ethyl acetate, 9:1) followed by crystallization from petroleum ether to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-fluoro-3-methyl-butan-1-one as a white solid, mp 94° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:25]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:14]([I:25])=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: OCc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1I
Yield: 84 %

Procedure:
The dibenzyloxybenzyl alcohol 28 (21.44 mmol) and silver trifluoroacetate (21.44 mmol) were suspended in 100 mL of dry chloroform and stirred under argon. A solution of iodine (21.44 mmol) in dry chloroform (50 mL) was added to the suspension dropwise at room temperature. The reaction mixture was then stirred for a further period of 2 h and filtered. The filtrate was washed with 20% sodium thiosulfate solution in water. The organic layer was separated and dried over anhydrous Na2SO4. Filtration was followed by evaporation of the chloroform solution resulting in the pure iodo compound, 3,4-Dibenzyloxy-6-iodobenzyl alcohol (29), as a pale yellow solid in 84% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:44]1[CH2:50][CH2:49][CH2:48][C@H:45]1[CH2:46][OH:47]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([N:44]1[CH2:50][CH2:49][CH2:48][C@H:45]1[CH:46]=[O:47])=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: OC[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 28.1 g of t-butyloxycarbonyltyrosine. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from chloroform to obtain a white solid substance which was then dissolved in 500 ml of THF. To this solution was added 6.0 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 200 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 20.3 g of WSCD.HCl and 90 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 3.9 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 300 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 200 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 200 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 0.8 g (2.2%).