Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][C@H:8]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH3:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH:21]=O>O.CO.[Pd]>[CH3:17][O:16][C:14](=[O:15])[C@H:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[NH:7][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[CH3:18]
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: COC(=O)C[C@H](NCCC(C)(C)C)C(=O)OC
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
Sodium hydrogen carbonate (1.68 g, 0.02 mol) was added to a Parr bottle containing a solution of dimethyl L-aspartate hydrochloride (3.94 g, 0.02 mol) in water (10 mL), followed by addition of 3,3-dimethylbutyraldehyde (2.2 g, 0.02 mol) in methanol (100 mL) and Pd/C (4% palladium on carbon, 50% wet), 10% by weight of substrate. The mixture was hydrogenated at 50 psi at room temperature for 1.5 hrs then filtered through a Celite® bed and the bed washed with methanol (10 mL). The filtrate and washings were concentrated under reduced pressure. The residual aqueous solution was extracted with diethyl ether (2×100 mL). The organic layer was washed with aqueous saturated sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give N-neohexyl-L-aspartic acid dimethyl ester (4.65 g, 95%) as an oil. NMR (CDCl3) δ3.67 (s, 3H); 3.50 (s, 3H); 3.57(t, 3H); 2.37-2.70 (m, 4H); 1.20-1.40 (m, 2H); 0.80 (s, 9H).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]=[CH:16][N:17]=[C:18](OC3CCOCC3)[C:19]=2[N:20]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>O1CCOCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH:41][CH:38]3[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:40][CH2:39]3)[C:19]=2[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Hunig's base (6.53 mL, 37.5 mmol) was added to a suspension of 4,6-dichloropyrido[3,2-d]pyrimidine (intermediate 1, 5.00 g, 25.0 mmol) and tert-butyl-4-aminopiperidine-1-carboxylate (6.00 g, 30.0 mmol) in 1,4-dioxane (250 mL) at room temperature. The reaction mixture was refluxed for 1 h, and cooled to room temperature. The solvent was removed under reduced pressure, EtOAc and water were poured into the residue, and the separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc) to give a pale yellow solid which was washed with MeOH afforded tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (8.72 g, 96%) as a off white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.49 (9H, s), 1.50-1.62 (2H, m), 2.10-2.15 (2H, m), 2.98-3.01 (2H, m), 4.01-4.25 (2H, m), 4.25-4.40 (1H, m), 6.86 (1H, d, J=7.6 Hz), 7.62 (1H, d, J=8.8 Hz), 8.04 (1H, d, J=8.8 Hz), 8.62 (1H, s).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH:22]=O)[CH2:20][C@H:19]2[C@@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:20][C@H:19]2[C@@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)C[C@@H]2C[C@@H]21
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](CNCc2ccccc2)C[C@@H]2C[C@@H]21
Reaction time: 14 h

Procedure:
Benzylamine (17.5 mmol, 1.0 eq) is added to a solution of (1S,3S,5S)-3-formyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (17.5 mmol, 1.0 eq) in DCM (100 mL). The mixture is treated with sodium triacetoxyborohydride (24.5 mmol, 1.4 eq), stirred for additional 14 h, poured into water (200 mL) and stirred vigorously for 10 min. The layers are separated and the aqueous layer is extracted twice with DCM (2×100 mL). The combined organic layers are washed with sat. NaHCO3 solution (100 mL) and water (100 mL), dried over Na2SO4 and concentrated in vacuo to give the desired benzylamine as a brownish oil which is used without further purification. LC-MS (basic): tR=0.96 min; [M+H]+=303.3.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][C:42]([F:43])=[C:16]23)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:62]([O:65][CH2:66][CH3:67])(=[O:64])[CH3:63].[Cl-].[NH4+]>O1CCCC1>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:19]2[C:20](=[O:21])[N:15]([C@H:12]3[CH2:11][CH2:10][C@H:9]([O:8][CH2:63][C:62]([O:65][CH2:66][CH3:67])=[O:64])[CH2:14][CH2:13]3)[C:16]3[N:17]([N:40]=[CH:41][C:42]=3[F:43])[C:18]=2[CH2:37][CH2:38][CH3:39])=[CH:24][CH:25]=1)#[N:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c2c(F)cnn12
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2c(F)cnn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[4-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-3-fluoro-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.24 g) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride (1 mL), and the mixture was stirred at 70° C. for 2 hr. Ethyl acetate and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in toluene (2 mL), rhodium acetate (dimer, 0.016 g) was added, ethyl diazoacetate (0.19 mL) was added dropwise at 100° C., and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.087 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:41][CH2:40][C:17]3[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=[N:20][C:16]=3[CH2:15]2)=[O:11])=[CH:4][CH:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:41][CH2:40][C:17]3[NH:18][CH:19]=[N:20][C:16]=3[CH2:15]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccc(Cl)cc1)NCC1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCc1ccc(Cl)cc1)NCC1CCc2[nH]cnc2C1
Temperature: 90 °C

Procedure:
A solution of a mixture of 3-(4-chlorophenyl)-N-((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methyl)propionamide and 3-(4-chlorophenyl)-N-((3-triphenylmethyl-4,5,6,7-tetrahydro-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methyl)propionamide (0.69 g, 1.23 mmol) in acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 1.5 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.42 g of the title compound.
Reaction SMILES: I[CH3:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:14])=[S:13])=[CH:7][CH:6]=1)#[N:4]>CC(C)=O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]=[C:12]([S:13][CH3:2])[NH2:14])=[CH:9][CH:10]=1)#[N:4]
Reactant: N#Cc1ccc(NC(N)=S)cc1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(N)=Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Iodomethane (1.76 ml) was added to 4-cyanophenyl-thiourea (5.0 g) in acetone (100 ml). The reaction mixture was stirred overnight at RT. The precipitate was filtered off, dried and dissolved in DCM. The organic solution was washed with NH3 (aq.) (excess), dried with potassium carbonate, filtered, and the solvent was evaporated, yielding 4.53 g (84%, white solid) of methyl N′-(4-cyanophenyl)carbamimidothioate (intermediate 6).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[CH2:10][C:4]=2[CH:3]=1.[N:18]1([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][O:28][C:27]2=[O:31])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:21]3[CH2:22][CH2:23][N:18]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][O:28][C:27]4=[O:31])[CH2:19][CH2:20]3)=[CH:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: O=C1Cc2cc(Cl)ccc2Sc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C1OCCN1CCN1CCN(C2=Cc3cc(Cl)ccc3Sc3ccccc32)CC1
Reaction time: 1 h

Procedure:
8.5 g of 2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-one, 30 g of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and 100 ml of benzene are treated dropwise under an argon atmosphere at 20° C with 5.2 g of titanium tetrachloride in 25 ml of benzene. The mixture is heated under reflux for 20 hours and subsequently poured on to a mixture of ice and aqueous sodium bicarbonate solution. The mixture is stirred for 1 hour and filtered through diatomaceous earth. The aqueous phase is separated and washed successively with benzene and chloroform. The organic phases are combined and washed successively with aqueous sodium chloride solution and water, dried, filtered and evaporated under reduced pressure. There is obtained 3-[2-[4-(2-chloro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone as a red-brown viscous oil which, for the purpose of purification, is chromatographed on 100 g of silica dioxide [elution agent ethanol: methanol: concentrated ammonia (100:50:10)]. There is obtained a red-brown oil which is crystallised from acetone with the aid of active carbon. There are obtained beige-coloured crystals which are converted into the corresponding maleate (beige-coloured crystals) of melting point 232°-233° C (decomposition) by treatment with maleic acid in acetone.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]2[CH:33]=[CH:32][CH:31]=[N:30][C:29]=2[F:34])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CN([CH:39]=[O:40])C.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH:39]([OH:40])[C:33]3[CH:32]=[CH:31][N:30]=[C:29]([F:34])[C:28]=3[C:27]2=[O:35])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2F)cc1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(N2C(=O)c3c(ccnc3F)C2O)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To the solution of 2,2,6,6-tetramethylpiperidine (5.0 ml, 30.0 mmol) in 60 mL of anhydrous THF at −78° C. was added n-BuLi (2.5 M solution in hexanes, 16 mL, 40.0 mmol) under N2. The resulting mixture was stirred at −78° C. for 30 min, and a solution of N-(4-tert-butyl-phenyl)-2-fluoro-nicotinamide (2.72 g, 10.0 mmol, Step A) in 20 mL of THF was added dropwise. The mixture was stirred at −78° C. for 2 h, DMF (4.6 mL, 60.0 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min, then gradually warmed to RT. 1N HCl was added to bring pH to 2, then Na2CO3 was added to bring pH to 10. The mixture was extracted with EtOAc, the combined organic portions were dried with MgSO4, filtered, and condensed. The titled compound was obtained as a light-yellowish solid after column chromatography. MS (ES+): 301.2 (M+H)+. Calc'd for C17H17FN2O2-300.33.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](B2OC(C)(C)C(C)(C)O2)=[CH2:9])=[CH:4][CH:3]=1.Br[C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C@H:27]2[CH2:39][OH:40])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C@H:27]3[CH2:39][OH:40])=[N:24][CH:25]=2)=[CH2:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)[C@H](CO)C1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=C(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)nc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
2-(1-(4-Fluorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (138 mg, 0.556 mmol), (S)-tert-butyl 4-(5-bromopyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (103 mg, 0.276 mmol), 2 M sodium carbonate (0.35 mL, 0.700 mmol), and PdCl2(dppf)-DCM adduct (17.3 mg, 0.021 mmol) were taken up in 1,4-dioxane (2 mL) in a 2-5 mL microwave vial. The reaction was stirred at 100° C. for 18 hours. Room temperature was attained, the reaction mixture was filtered through a plug of Celite eluting with MeOH, and the filtrate was concentrated in vacuo while loading onto Celite. The residue was purified by MPLC (0-100% EtOAc-hexanes) to give (S)-tert-butyl 4-(5-(1-(4-fluorophenyl)vinyl)pyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (107 mg, 0.258 mmol, 94% yield) as an orange gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][CH:11]=1)=[O:8].S(Cl)([Cl:23])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]([Cl:23])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)O)cn1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1

Procedure:
A mixture of 6.2 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carboxylic acid and 23 ml of thionyl chloride is refluxed for 1 hour. An additional 12 ml of thionyl chloride is added and the mixture refluxed for 0.5 hour. The mixture is concentrated to dryness under vacuum and 30 ml of toluene added to the residue. The toluene is removed under vacuum and the process (add toluene and remove) is repeated to give 7.7 g of crude product as a solid.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[C:6]([O:20][CH3:21])[CH:5]=1.C[O:24][C:25]([C:27]1([NH2:36])[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)=[O:26]>>[CH3:21][O:20][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)[C:3]([NH:36][C:27]1([C:25]([OH:26])=[O:24])[CH2:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35]1)=[O:22]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COC(=O)c1ccc(OCCc2cccc(C)c2)c(OC)c1
Product: COc1cc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)ccc1OCCc1cccc(C)c1

Procedure:
The compound of step 3 was hydrolyzed in analogy to example 2, the obtained carboxylic acid reacted with 2-amino-indane-2-carboxylic acid methyl ester in analogy to step 1 of example 15, and the obtained ester hydrolyzed in analogy to example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C([O:16]O)(C)(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:6]2[O:16][C@H:7]2[CH2:8][OH:9])=[CH:10][CH:11]=1
Reactant: OCC=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OO
Agent: [Fe+2]
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Product: OC[C@@H]1O[C@@H]1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To 520 ml of a methylene chloride solution of 10.98 g of titanium tetraisopropoxide cooled to -70° C., 12 ml of a methylene chloride solution of 12.07 g of D-(-)-diethyl tartarate was added dropwise, and the resulting mixture was stirred for 20 minutes. Then, 25 ml of a methylene chloride solution of 12.9 g of p-chlorocinnamyl alcohol was added dropwise, and the resulting mixture was stirred for 20 minutes. Then, 42.0 ml of t-butyl hydroperoxide (3.67 mol/l methylene chloride solution) was added dropwise, and the resulting mixture was stirred at 70° C. for 1.5 hours, at -40° C. for 2 hours and at -20° C. for 1.5 hours, and then brought to -10° C. over 1 hour and stirred at the same temperature for 2 hours. After it was cooled again to -20° C., 150 ml of an aqueous solution of 38.5 g of iron sulfate hexahydrate and 15.4 g of citric acid monohydrate was added dropwise over 0.5 hour below 5° C. The mixture was stirred vigorously at 0° C. for 0.5 hour and filtered through celite. The filtrate was allowed to separate, and the aqueous layer was extracted again with methylene chloride. The organic layers were combined and washed with a saturated sodium hydrogen carbonate aqueous solution, water and a saturated saline solution. After the solvent was distilled off, the residue was dissolved in diethyl ether, and sodium sulfate and activated carbon were added, and the mixture was allowed to stand for 0.5 hour. The mixture was filtered through celite, and the ether solution thus obtained was cooled with ice. 172 ml of 1N sodium hydroxide aqueous solution was added, and then, the resulting mixture was stirred vigorously for 1 hour. After it was allowed to separate, the organic layer was washed with water (twice) and with a saturated saline solution, treated with activated carbon and filtered through celite. After the solvent was distilled off, the residue was purified by silica gel chromatography (eluent; methanol/chloroform=1/99) and crystallized from cyclohexane to obtain 6.35 g of the title compound as white crystals of [α]D25 +39.42° (chloroform, c 1.042).
Reaction SMILES: C(O)C.[CH:4]([C:7]1[CH:8]=[CH:9][C:10]([CH3:45])=[C:11]([N:13]2[CH2:44][CH2:43][C:16]3[N:17]=[C:18]([C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[C:25]([CH3:42])=[CH:26][N:27]5[S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[N:19]=[C:20](OC)[C:15]=3[CH2:14]2)[CH:12]=1)([CH3:6])[CH3:5].Cl.[Cl-].[Cl:48]C=[N+](C)C>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:48][C:20]1[C:15]2[CH2:14][N:13]([C:11]3[CH:12]=[C:7]([CH:4]([CH3:6])[CH3:5])[CH:8]=[CH:9][C:10]=3[CH3:45])[CH2:44][CH2:43][C:16]=2[N:17]=[C:18]([C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[C:25]([CH3:42])=[CH:26][N:27]3[S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:33])=[O:34])[N:19]=1
Reactant: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C(C)C)ccc1C)CC2
Reactant: C[N+](C)=CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4cc(C(C)C)ccc4C)C5)cccc32)cc1
Temperature: 68 °C
Reaction time: 0.42 h

Procedure:
Ethanol (4 mL) was added to 6-(5-isopropyl-2-methylphenyl)-4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.92 g, 1.58 mmol) and then 12 N aqueous HCl (2 mL, 24 mmol) was added and the mixture was heated to 68° C. for ca. 15 hours. The reaction was then cooled to room temperature, diluted with dichloromethane, and neutralized via the slow addition of saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The resulting residue was then dissolved in dichloromethane (20 mL) and cooled to 0° C. and N-chloromethylene-N,N-dimethyl ammonium chloride (Vilsmeier reagent) (0.41 g, 3.21 mmol) was added. The reaction was then placed at room temperature for 25 minutes. The reaction was then diluted with dichloromethane and saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layer was extracted one additional time with dichloromethane. The organic layers were combined, dried over Na2SO4 filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (0-45% ethyl acetate/heptanes) to provide 4-chloro-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 585.2 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][CH:9]([NH2:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:15][C@@H:16]1[C@H:20]([O:21]C(=O)C)[C@@H:19]([CH2:25][O:26]C(=O)C)[O:18][C@H:17]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([Cl:40])=[N:34][C:35]=2Cl)(=O)C.C(N(CC)CC)C.[Na].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.CO.O.C(OCC)(=O)C>[Cl:40][C:33]1[N:34]=[C:35]([NH:11][CH:9]([CH3:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:36]2[N:37]=[CH:38][N:30]([C:31]=2[N:32]=1)[C@@H:17]1[O:18][C@H:19]([CH2:25][OH:26])[C@@H:20]([OH:21])[C@H:16]1[OH:15]
Reactant: CC(N)COc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(COc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 75.9 %

Procedure:
The title compound was prepared by reacting 1-phenoxy-2-propylamine (16.62 g, 0.11 mol) with 9-(2,3,5-tri- O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (24.6 g, 55 mmol) in dioxan (250 ml) in the presence of triethylamine (7.23 g, 71.5 mmol) followed by deprotection of the product using a solution of sodium (0.15 g, 6.5 mmol) in methanol (250 ml). The reaction mixture was neutralized with citric acid, and treated with a mixture of ethyl acetate (300 ml) and water (200 ml). The ethyl acetate phase was separated, dried (MgSO4) and evaporated before being purified by flash chromatography on silica gel, eluting initially with dichloromethane, and later with a mixture of dichloromethane and ethanol (9:1). This provided the title 2-chloro- N-(1-phenoxy-2-propyl)adenosine (18.2 g, 76%)(a mixture of diastereoisomers) as an amorphous foam, 1H NMR (DMSO-d6)δ 1.31 (3H, d, --CH3), 3.53-3.59 (1H, m, H-5'a), 3.64-3.71 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.06-4.20 (3H, 2 m, H-3' and --CH2 --), 4.54 (1H, m, H-2'), 4.65 (1H, m, --C HCH3), 5.07 (1H, t, 5'-0H), 5.21, 5.50 (2H, 2d, 2'- and 3'--OH), 5.84 (1H, d, H-1'), 6.87-7.00 (3H, m, Ar--H), 7.23-7.32 (2H, t, Ar--H), 8.31-8.45 (2H, m, H-8 and N--H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10]=1[C:20]([OH:22])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN>C1COCC1>[CH3:23][NH:24][C:20]([C:10]1[N:11]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2)nc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CNC(=O)c1nc(-c2ccccc2)sc1NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 6 h

Procedure:
A solution of 5-tert-butoxycarbonylamino-2-phenyl-thiazole-4-carboxylic acid (138 mg, 0.43 mmol) in THF (2.5 ml) was treated with HATU (187 mg, 0.49 mmol), N-methylmorpholin (0.25 ml, 2.24 mmol) and methylamine (0.29 ml, 2M THF solution) and stirred at 75° C. for 6 h. The reaction mixture was partitioned between potassium hydrogen sulfate (10% aqueous solution) and ethyl acetate and extracted. The organic layer was washed with water, sodium bicarbonate and brine. The combined organic phases were dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (98 mg, 65%).