Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:37]1[CH2:42][CH2:41][CH:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:37]4[CH2:42][CH2:41][CH:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCN(CCc2cccc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]acetaldehyde (D78) (160 mg), acetic acid (0.036 mL) and sodium acetate (51.0 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added ethyl 4-piperidinecarboxylate (189 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (165 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D89) (216 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C30H37ClN2O3S requires 540. found 541.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Si](C)(C)C.N1C=CC=CC=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])[CH3:12]
Reactant: CCc1ccc(N)c(C(=O)O)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(NS(=O)(=O)c2ccccc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Example 1C (0.033 g, 0.200 mmol) in dichloromethane (1 mL) was treated with 1M chlorotrimethylsilane in dichloromethane (440 μL, 0.044 mmol) and pyridine (56.6 μL, 0.70 mmol), shaken for 4 hours at ambient temperature, treated with a solution of benzenesulfonyl chloride (0.042 g, 0.24 mmol) in dichloromethane (1 mL), and shaken for 16 hours at ambient temperature. The mixture was concentrated, the residue was acidified to pH 1.0 with 5% aqueous HCl, and the solution was extracted with dichloromethane. The extracts were washed sequentially with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by C18 reverse-phase HPLC with acetonitrile/water/0.5 mM ammonium acetate to provide the desired product. MS (ESI(+)) m/e 306 (M+H)+, 323 (M+NH4)+, 328 (M+Na)+; (ESI(−)) m/e 304 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.96 (br s, 1H), 7.78 (d, 2H), 7.73 (d, 1H), 7.64 (m, 1H), 7.55 (m, 2H), 7.42 (m, 2H), 2.54 (q, 2H), 1.10 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40](Cl)(=[O:42])=[O:41])=[CH:39][C:34]=2[O:33][CH2:32]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40]([NH:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:11]=3[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6])(=[O:41])=[O:42])=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3c(c2)OCO3)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.04 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 1.1 g of benzo[1,3]-dioxol-5-sulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained the desired methyl 3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a resin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH2:17][C:18]([OH:20])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:6]=1[C:18](=[O:20])[CH2:17][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]12
Reactant: COc1cc(OC)cc(N2CCCCC2CC(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(c1)N1CCCCC1CC2=O

Procedure:
Under a nitrogen atmosphere, a mixture of 12.1 g. (0.043 mole) dl-2-[1-(3,5-dimethoxyphenyl)piperidin-2-yl]acetic acid, 100 ml. glacial acetic acid, 6.0 g. sodium acetate and 100 ml. acetic anhydride was stirred at room temperature overnight. The acetic acid and acetic anhydride were removed by evaporation in vacuo, the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution, and the organic phase washed with sodium bicarbonate, water, brine and dried (MgSO4). The extracts were evaporated to dryness to give 13 g. of a green oil. The oil was purified by chromatography on a column containing 300 g. of silica gel (230-400 mesh), eluting with ethyl acetate. Fractions of 300 ml. each were taken. Fractions 7-12 were combined and evaporated to afford 5.5 g. of the desired dl product, M.P. 91°-94° C. 1H-NMR (CDCl3) ppm (delta): 2.50 (m, 2H, CH2CO), 3.79 (s, 3H), 3.81 (s, 3H), 5.90 (m, 2H). After recrystallization from isopropyl ether, 2.6 g. of crystals were obtained, M.P. 92°-93° C.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)=O>>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH3:14])[CH:1]=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)OC
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 100 °C
Yield: 59.5 %

Procedure:
In an apparatus as in Example 1, 10.0 g (0.054 mol) of syringaldehyde and 5.00 g (0.036 mol) of potassium carbonate were heated to 100° C. and 8 ml (0.094 mol) of dimethyl sulfite was added over a 5 minute period. The pasty mixture was heated to 100° C. for 3 hours then cooled to 25° C. and quenched with 50 ml water. The mixture was extracted with 100 ml of methylene chloride. The extracts were washed with water and concentrated in vacuo to get 4.2 g (54% based on recovered syringaldehyde) of 3,4,5-trimethoxybenzaldehyde.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][CH:9]=[CH:8][C:7]=1[C:17]1[C:18]([CH3:23])=[N:19][NH:20][C:21]=1[NH2:22].[OH:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>C(O)(C(F)(F)F)=O>[CH3:23][C:18]1[C:17]2[C:7]3[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=3[C:29]([C:28]3[CH:31]=[CH:32][C:25]([OH:24])=[CH:26][CH:27]=3)=[N:22][C:21]=2[NH:20][N:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCOc1cccc(-c2c(C)n[nH]c2N)c1OCCOC
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1ccc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2c1OCCOC
Yield: 37.6 %

Procedure:
A solution of 4-(2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-methyl-1H-pyrazol-5-amine (70 mg, 0.22 mmol), and 4-hydroxybenzaldehyde (40 mg, 0.33 mmol) in TFA (2 mL) was stirred in a sealed pressure vessel at 90° C. for 14 h. The reaction mixture was concentrated and purified by HPLC to give 4-(1-methyl-8,9-bis{[2-(methyloxy)ethyl]-oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol (35 mg, 38% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ9.90 (br. s, 1H), 7.79 (d, 1H), 7.46 (m, 2H), 7.38 (d, 1H), 6.93 (m, 2H), 4.32 (m, 2H), 4.27 (m, 2H), 3.76 (m, 2H), 3.69 (m, 2H), 3.34 (s, 3H), 3.23 (s, 3H), 2.82 (s, 3H); MS (EI) for C23H25N3O5: 424 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1>O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(OC)cc1OCCCNC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
Methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoate (18.61 g, 54.8 mmol) was suspended in 3:1 tetrahydrofuran:water (100 mL), then solid LiOH monohydrate (5.06 g, 121 mmol) was added and the mixture was stirred at 50° C. for 24 hours. The mixture was diluted with water (350 mL) and washed with diethyl ether (2×250 mL). The aqueous layer was acidified to pH 1-2 with 1 N sodium bisulfate and the resulting slurry was extracted with EtOAc (2×300 mL). The combined EtOAc layers were washed with brine, dried, then concentrated in vacuo to give a solid white mass. Recrystallization from EtOAc provided 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoic acid as white needles (15.52 g, 87%).
Reaction SMILES: C(O)C.[ClH:4].Cl.[N:6]1([C:11]2[CH:24]=[CH:23][C:14]([C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=O)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1>[Pd].O>[ClH:4].[ClH:4].[N:6]1([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:23][CH:24]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(c1ccc(N2CCCC2)cc1)C1CCNCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: c1cc(N2CCCC2)ccc1CC1CCNCC1
Reaction time: 2 h
Yield: 25.1 %

Procedure:
In a solvent mixture of 20 ml of ethanol and 20 ml of water was added 3.33 g of the 4-(4-pyrrolidinobenzoyl)piperidine dihydrochloride (Compound No. 1) prepared in Example 11, followed by addition of 10% palladium-on-carbon, and the catalytic reduction was carried out at atmospheric temperature and pressure for 2 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in a saturated aqueous solution of sodium chloride. The solution was made basic by addition of solid sodium hydrogen carbonate and extracted with acetonitrile. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. After addition of 2N-methanolic hydrochloric acid to the oily residue, the solvent was distilled off and the residue was recrystallized from ethyl ether-methanol to give 0.4 g of colorless crystals melting at 152°-154° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CO>[C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])(=[O:18])[CH3:17]
Reactant: NCCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-amino-1-hexanol (0.650 g, 6.31 mmol) in methanol (15 mL) is cooled to 0° C. and treated with triethylamine (1.62 mL, 11.6 mmol) followed by acetic anhydride (0.891 mL, 9.45 mmol). The reaction mixture is stirred at room temperature overnight. Additional triethylamine (1.6 mL, 11.6 mmol) and acetic anhydride (0.9 mL, 9.5 mmol) is added at room temperature and the solution is stirred 16 h further. Concentration in vacuo and flash chromatography affords 6-acetamido-1-hexanol. To a solution of 6-acetamido-1-hexanol (22.2 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 6-acetamido-1-hexyltriflate (25) which is used without further purification.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][C:6]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:8])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: COc1ccc(C(OC(C)=O)C(=O)O)cc1
Product: CCCCNC(=O)C(OC(C)=O)c1ccc(OC)cc1

Procedure:
was prepared from intermediate 79a and butylamine following Method A. 1H NMR (300 MHz, CDCl3) δ 7.34 (d, 2H, J=8.85 Hz), 6.87 (d, 2H, J=8.67 Hz), 6.01 (s, 1H), 3.79 (s, 3H), 3.31–3.23 (m, 2H), 2.15 (s, 3H), 1.54–1.43 (m, 2H), 1.37–1.22 (m, 2H), 0.94–0.87 (m, 3H). LCMS (ESI+) [2M+Na]/z Calc'd 581, found 581.
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7])(=O)C.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>>[S:11]([O:4][CH:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OC1CCOC1=O
Product: Cc1ccc(S(=O)(=O)OC2CCOC2=O)cc1

Procedure:
reacting enantiopure (S) or (R) α-hydroxy-γ-butyrolactone with tosyl chloride to give enantiopure (S) or (R) α-tosyloxy-γ-butyrolactone (Step 5);
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.F[C:38]1[N:53]=[CH:52][CH:51]=[CH:50][C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH3:49])=[O:41].CN1C(=O)CCC1.Cl>O1CCOCC1>[ClH:1].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:53]=[CH:52][CH:51]=[CH:50][C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[CH3:49])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Cc1ccccc1NC(=O)c1cccnc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ccccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 140 °C
Yield: 55.9 %

Procedure:
To a homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.042 g, 0.17 mmol, Compound C of Example 1) and 2-fluoro-N-o-tolylnicotinamide (0.040 g, 0.17 mmol), in anhydrous 1,4-dioxane (0.22 mL) and anhydrous NMP (0.40 mL), was added HCl (4N in 1,4-dioxane, 0.18 mL, 0.72 mmol). The reaction mixture was heated in a sealed tube at 140° C. for 65 hours before being partitioned between chloroform and 10% LiCl (aq). The aqueous layer was extracted with chloroform and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and concentrated in vacuo to a tan solid that was dissolved in anhydrous THF (1 mL), cooled to 0° C. and treated with HCl (4N in 1,4-dioxane, 0.5 mL, 2.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.025 g, 29%) as a tan solid. 1H NMR (DMSO-d6) δ 12.74 (s, 1H), 10.89 (s, 1H), 10.26 (s, 1H), 8.10-8.50 (m, 4H), 7.10-7.70 (m, 7H), 6.95-7.05 (m, 1H), 6.65-6.75 (m, 1H), 6.45-6.53 (m, 1H), 2.19 (s, 3H);
Reaction SMILES: [N:1]1C=CC=NC=1.[N:7]1[CH:15]=[C:14]2[C:10]([N:11]=C[NH:13]2)=[N:9][CH:8]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:13][C:14]1[C:10]([NH2:11])=[N:9][C:8]([NH2:1])=[N:7][CH:15]=1
Reactant: c1cncnc1
Reactant: c1ncc2[nH]cnc2n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1ncc(N)c(N)n1

Procedure:
The amine of the formula 69 is subsequently reacted with a substituted chloropyrimidine. The amine can be condensed, for example, with 2-amino-6-chloro-5-nitro-4-(3H)-pyrimidinone in the presence of a tertiary amine base, preferably triethylamine, in refluxing n-butanol to give a pyrimidine compound of formula 70. The pyrimidine compound of formula 70 can then be converted to a purine derivative by a two step procedure. In the first step, the nitro moiety of the pyrimidine is reduced with, for example, sodium dithionite, to give a triaminopyrimidine intermediate. Alternative reducing agents and conditions that can also successfully reduce the nitro group include NaBH4/THF, NaBH4—BiCl3, Sn/HCl, SnCl2, Mg/(NH4)2SO4/MeOH, CuBr.SMe2, TiCl2(Cp)2/Sm, iron and nickel catalyzed procedures. In the second step, treatment of the triaminopyrimidine intermediate with formic acid, hydrochloric acid, and an orthoformate derivative, e.g., triethylorthoformate, effects cyclization and provides the methylene compound of formula 71. The methylene compound of formula 71 can be converted to the compound of formula 21 by the oxidation procedure described in the final steps of Processes B and C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21]O)[CH2:16][CH2:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.C1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][N:46]4[C:42](=[O:52])[C:43]5[C:44](=[CH:48][CH:49]=[CH:50][CH:51]=5)[C:45]4=[O:47])[CH2:18][CH2:19]3)[CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCC1CCN(c2cccc(-c3ccc(F)cc3)n2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C1c2ccccc2C(=O)N1CCC1CCN(c2cccc(-c3ccc(F)cc3)n2)CC1
Yield: 48.9 %

Procedure:
The procedure described in Example 1 (step 1.2.) is followed, Starting from g (6.66 mmol) of 2-[6′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethanol, prepared in step 4.1., 2.096 g (7.99 mmol) of triphenylphosphine, 1.077 g (7.32 mmol) of phthalimide and 1.61 g (7.99 mmol) of diisopropyl azodicarboxylate (DIAD), and after chromatography on silica gel, eluting with a 15/85 mixture of ethyl acetate and cyclohexane, gives 1.4 g of pure product in the form of a white powder.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:23][CH2:24][CH:25]=O)[CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20]>>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:23][CH2:24][CH:25]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)[CH:16]=[CH:17][C:18]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=CCCc1ccc(C(F)(F)F)c(Cl)c1
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)c(Cl)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (4.497 mmol) and 3-(3-chloro-4-trifluoromethyl-phenyl)-propionaldehyde (1.064 g; 4.497 mmol) afforded 8-[2-(3-chloro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.81 min.; [M+H]+=483.73 g/mol.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([CH2:20][O:21][CH3:22])[NH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=[O:13])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([C:4]2[N:5]=[C:6]([CH2:20][O:21][CH3:22])[NH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([OH:14])=[O:13])[CH2:2][CH2:3]1
Reactant: COCc1nc(C2CC2)c(-c2cc(C(=O)OC)ccc2C)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1nc(C2CC2)c(-c2cc(C(=O)O)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Into a round-bottom flask, was placed a solution of methyl 3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 4.8, 35 mg, 0.12 mmol) in methanol (5 mL), a solution of sodium hydroxide (9.6 mg, 0.24 mmol) in water (0.3 mL) was added to the reaction mixture. The resulting solution was stirred for 2 h at room temperature, then diluted with water (5 mL). Aqueous HCl (6 M) was carefully added to adjust the pH to 1-2 and the mixture was extracted with dichloromethane (4×10 mL). The combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound as a yellow oil (30 mg, crude), which was used in the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[F:15][C:16]1[C:17](I)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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>[F:15][C:16]1[C:17]([C:14]#[C:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H]3CCCN3)c21
Reaction time: 2 h

Procedure:
Using Method C above, (R)-N-Boc-2-ethynyl-pyrrolidine (100 mg, 0.52 mmol) (Example 89B) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and a catalytic amount of Cul (2 mg) in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 40-70% EtOAc in hexanes gradient. The intermediate that was obtained from this operation was directly dissolved at 0° C., in 5 mL of a solution of 50% trifluoroacetic acid in CH2Cl2 that contained 0.3 mL of H2O and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after reverse phase column chromatography with 0-90% MeOH in H2O gradient, a silica gel column chromatography with neat THF and a precipitatiion out of THF with excess of hexanes. (Yield 14 mg, 31%).