Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([NH:19][C@H:20]([C:22]4[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH2:29](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4=[N:11][C:12]([NH:19][C@H:20]([C:22]5[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=5)[CH3:21])=[CH:13][CH:14]=[C:15]4[N:16]=[CH:29]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1ccc2ncn(-c3cc(C4CC4)[nH]n3)c2n1)c1ncc(F)cn1
Temperature: 25 °C

Procedure:
N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N6-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 16, 0.45 g) was dissolved into ethanol (20 mL) with Pd—C (60 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 95° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.08 g of the title compound. MS (electrospray): 365 (M+1) for C18H17FN8. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.30 (s, 1H) 7.70 (d, 1H) 6.70 (d, 1H) 6.50 (s, 1H) 5.30 (dd, 1H) 2.00 (m, 1H) 1.60 (d, 3H) 1.10 (m, 2H) 0.90 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.[CH3:27][S-:28].[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:27][S:28][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CSc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (100 mg, 0.26 mmol) was dissolved in NMP (2.6 mL), and sodium methanethiolate (18.2 mg, 0.26 mmol) was added. The reaction was stirred at r.t. for 30 min. The reaction crude was diluted with ethyl acetate (10 mL) and was washed with water (10 mL, ×1) and brine (10 mL, ×1), dried over magnesium sulfate, filtered and concentrated by rotavapor. The crude mixture was purified by preparative TLC with 30% ethylacetate:hexane to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]=[C:11]([NH:23][NH2:24])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]#[N:28].CCOC(C)=O>CCO>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:27]([NH2:28])=[N:24][N:23]=[C:11]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)NCc1cc(NN)ncc1-c1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cc2nnc(N)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 65 °C
Yield: 51.3 %

Procedure:
A mixture of the crude [5-(2,4-dichloro-phenyl)-2-hydrazino-pyridin-4-ylmethyl]-carbamic acid tert-butyl ester (1.66 g) and BrCN (638 mg, 6.0 mmol) in EtOH (40 mL) was heated at 65° C. and stirred for 2 h30. The reaction mixture was cooled to RT, poured into AcOEt (100 mL) and washed with a 2.0 M aqueous Na2CO3 solution (2×50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/MeOH 95:5→4:6) to yield the title compound (908 mg, 2.22 mmol, 74% over 2 steps) as a brownish solid. MS: 408 [M+1]+; HPLC: AtRet=1.62; TLC: RF 0.16 (DCM/MeOH 95:5).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:31])=[C:21]([CH:30]=1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:30]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(Cl)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 5 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (57.5 mg), 5-chloro-2-hydroxybenzophenone (309 mg), and 4-dimethylaminopyridine (173 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 5 hr. The mixture was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure, and chloroform was added to the residue. The mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to quantitatively give 114 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[C:6]([O:34][CH3:35])=[CH:5][CH:4]=1.CCN(CC)CC.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[CH3:35][O:34][C:6]1[C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(OC)c2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c2[nH]c(CCCN(C)CC[C@]3(OC(=O)C(C)C)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12
Reaction time: 8 h

Procedure:
To a solution of 199 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol in 4 mL DCM were added 0.2 mL of NEt3 and 0.1 mL of isobutyrylchloride at 0° C. The reaction mixture was stirred overnight allowing the temperature to reach slowly rt. The reaction was quenched with sat. aq. NaHCO3, the phases were separated and the water phase was re-extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was redissolved in 3 mL EtOAc, silica gel and 1.5 mL MeOH were added and the mixture was stirred vigorously for 7 d. The mixture was filtered, thouroughly washed with EtOAc-MeOH (2:1) and evaporated. Purification by CC using EtOAc-MeOH (5:1 to 3:1+0.1% NEt3) yielded 186 mg of rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as beige foam.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:19][O:20]C)[NH:5][C:6]=1[C:7]1[C:8]([CH3:18])=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>Br>[Cl:1][C:2]1[N:3]=[C:4]([CH2:19][OH:20])[NH:5][C:6]=1[C:7]1[C:8]([CH3:18])=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COCc1nc(Cl)c(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Agent: Br
Product: Cc1cc(C)c(-c2[nH]c(CO)nc2Cl)cc1C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 5-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 230.5, 20 mg, 0.06 mmol) in HBr (5 mL, 40% in AcOH). The reaction mixture was stirred overnight at 90° C. The resulting mixture was concentrated under reduced pressure. This resulted in 10 mg (55%) of the title compound as a yellow crude solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][NH2:12])=[CH:4][CH:3]=1.[C:14](O)(=O)C.C(N)=N>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH:10]2[CH2:11][NH:12][CH:14]=[N:13]2)=[CH:6][CH:7]=1
Reactant: NCC(N)CCc1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Product: Clc1ccc(CCC2CNC=N2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 4-(4-chlorophenyl)-1,2-butanediamine (0.084 mg, 0.42 mmol) in ethanol (8 ml) was added formamidine acetate (0.15 g, 1.45 mmol) and the mixture was stirred overnight at room temperature. The solvent was evaporated, water (5 ml) was added and the mixture was extracted 3 times with dichloromethane (10 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent:ethyl acetate/methanol=90:10) to yield an off-white amorphous solid (0.041 g, 47%); MS (ISP): 209.3 ((M+H)+).
Reaction SMILES: CS[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].C(OCC)C>C(O)(=O)C.S([O-])([O-])(=O)=O.[Cu+2].[Zn]>[O:17]([C:13]1[CH:12]=[C:11]([CH:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH:16]=[CH:15][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(SC)(c1cccc(Oc2ccccc2)c1)C(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C(c1cccc(Oc2ccccc2)c1)C(C)C
Yield: 87.9 %

Procedure:
Methyl α-methylthio-α-(m-phenoxyphenyl)isovalerate (702 mg) was dissolved in 5 ml of acetic acid, and 50 mg of anhydrous copper sulfate and 500 mg of zinc powder was added. The mixture was heated under reflux for 23 hours. Diethyl ether (80 ml) was added, and the insoluble matter was separated by filtration. The filtrate was washed twice with 25 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using benzene as an eluent to afford 531 mg of methyl α-(m-phenoxyphenyl)isovalerate in a yield of 88%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:11]2[C:12]([CH3:14])([CH3:13])[CH:9]([CH2:10]2)[CH2:8][CH:7]=1.CC1(C)C2CC1CCC2=C.C=CC1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:5][C:6]1[CH2:11][CH2:10][C@@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:8][CH:7]=1
Reactant: CC1=CCC2CC1C2(C)C
Agent: C=C1CCC2CC1C2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: C=Cc1ccccc1
Product: C=C(C)[C@H]1CC=C(C)CC1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a 1.0 Liter flask is charged 140 g of xylene and 5.7 g of anhydrous aluminum chloride and the suspension is stirred under a nitrogen atmosphere at ambient temperature. The suspension is then warmed to 45° C. Using an addition funnel, 175 grams of a blend of alpha pinene, beta pinene and styrene (30:40:30 weight ratio) is introduced into the flask over a period of 60 minutes, while maintaining the polymerization temperature at 45-47° C. (cooling externally, as needed, using a water-ice mixture). After the blend has been fed, the reaction contents are quenched (catalyst is neutralized) with 100 g cold water. The contents are stirred and heated to 75-80° C. After stirring at 75-80° C. for 10 minutes, the aqueous layer is removed and the organic solution is washed with 100 g of water. The contents are heated again to 75-80° C. and the aqueous and organic layers separated. The organic layer constitutes the resin solution. This resin solution is then heated under a nitrogen atmosphere to 240° C. Most solvent and low boiling by-products are distilled between 140-200° C. Once the temperature reaches 240° C., a sample of the molten resin is collected and its softening point measured. The resin is stripped further using a nitrogen sparge (to remove low molecular weight by-products) till the desired s.p. is achieved. The maximum softening achieved was 91.1° C. At this point, the molten resin is poured into a container for storage. Resin had a neat color=2+Gardner, and overall yield was 84%. If required, the resin can be bleached, to lighten its color, at 240° C. during the stripping process, by introducing of a solution of iodine in xylene and stirring for 15 minutes. The iodine is 300 ppm by weight of total molten resin in the flask. Bleaching results in a resin neat color of about 1+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2)[N:7]=1.Br[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(C#Cc2ccc(CC(=O)OC)cc2)ccc1O
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Product: COC(=O)CCc1nc(C#Cc2ccc(CC(=O)OC)cc2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 54.8 %

Procedure:
Under the conditions of example 1 D, 600 mg of 3-{3-hydroxy-6-[2-(4-methoxycarbonylmethylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is reacted with 460 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 504 mg of 3-{3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-[2-(4-methoxycarbonylmethylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]>CO.[Rh].[Pd]>[CH2:6]1[CH2:5][CH2:4][C:3]([CH2:1][NH2:2])([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7]1
Reactant: N#CC1(CC(=O)O)CCCCC1
Agent: [Pd]
Agent: [Rh]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1
Reaction time: 24 h

Procedure:
In U.S. Pat. Nos. 5,132,451, 5,319,135 & 6,294,690, 1-cyanocyclohexane acetic acid was hydrogenated in methanol at room temperature for 2 hours, using 15% Rhodium on carbon catalyst containing 1% palladium. The mixture was filtered and the filtrate concentrated. Addition of isopropanol and stirring at 0-5 deg for 24 hrs gave gabapentin. In EP Patent no 414262B1,1-cyano cyclohexene acetic acid was hydrogenated on Raney nickel to produce Gabapentin.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([O:25][CH2:26][CH3:27])[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:28]>CC(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([O:25][CH2:26][CH3:27])[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:28])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Reactant: N
Solvent: CC(C)O
Product: CCOc1nc(-c2cccc(OCc3ccccc3)c2)c2c(N)nccn12
Temperature: 110 °C

Procedure:
A solution of 1-(3-benzyloxy-phenyl)-8-chloro-3-ethoxy-imidazo[1,5-a]pyrazine (20.0 mg, 0.05 mmol) in i-PrOH (5 mL) was saturated with NH3 at −20° C. and heated in a Parr pressure vessel to 110° C. for 72 h. The reaction was concentrated in vacuo, partitioned between DCM and H2O and separated. The aqueous layer was washed with DCM (3×) and the combined organic layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo and purified by chromatography on silica gel [eluting with 2% EtOAc in DCM] to yield the desired product as an off-white solid; 1H NMR (CDCl3, 400 MHz) δ 1.45 (t, J=7.2 Hz, 3H), 4.58 (q, J=7.2 Hz, 2H), 4.91 (brs, 2H), 5.10 (s, 2H), 6.86 (d, J=4.8 Hz, 1H), 6.95-6.99 (m, 1H), 7.04 (d, J=5.2 Hz, 1H), 7.17-7.21 (m, 2H), 7.26-7.43 (m, 7H); MS (ES+): m/z=361.19 (100) [MH+], HPLC: tR=2.36 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH3:14])=[CH:8][CH:7]=1.P(=O)(O)(O)O.N1C=CC=CC=1>CO>[CH2:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH:4]=[CH:3][O:2][CH3:1])=[CH:11][CH:10]=1)[CH2:13][CH3:14]
Reactant: CCCc1ccc(CCC(OC)OC)cc1
Agent: O=P(O)(O)O
Solvent: CO
Solvent: c1ccncc1
Product: CCCc1ccc(CC=COC)cc1

Procedure:
A reaction flask was charged with 3-(4-propyl-phenyl)-propionaldehyde (147 g, prepared as above), methanol (500 mL), and TMOF (90 g). The reaction mass was cooled to 0° C. and hydrochloric acid (37%, 1 g) was added in one portion. The reaction was exothermic and the temperature rose to 23° C. The reaction mass was quenched with sodium methoxide in methanol (25%, 10 g) and the solvent was removed by evaporation. The crude intermediate product 3-(4-propyl-phenyl)-propionaldehyde dimethylacetal was provided and confirmed by the NMR analysis. 3-(4-Propyl-phenyl)-propionaldehyde dimethylacetal was further treated with phosphoric acid (10 g) and pyridine (8 g) at 200° C. The reaction mass was aged for 4 hours, during which methanol was recovered in a Dean Stark trap. The reaction mass was then cooled and washed with aqueous sodium carbonate solution. Fractional distillation of the organic layer afforded the product 4-propyl 1-(3-methoxy-2-propen-1-yl)benzene (80 g), which had a boiling point of 101° C. at a pressure of 3 mmHg.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20](OCC)=[O:21])[CH:12]=[N:11][C:10]1=2>C(#N)C>[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[O:21])[CH:12]=[N:11][C:10]1=2
Reactant: NCCOCCO
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCOCCO
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
0.500 g (4.76 mmol) of 2-(2-aminoethoxy)ethanol was heated with 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) in a 10 ml round bottom flask at 120° C. for one hour. The solution was treated with 8 ml of acetonitrile and stirred vigorously for 20 minutes. The white precipitate was obtained by filtration and was washed with acetonitrile and then with ether. Upon drying, 265 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(2-hydroxyethoxy)ethyl]propanamide (AIT-047) as a white solid was obtained. Yield: 85%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1.O>[C:11]([C:13](=[C:8]([CH3:9])[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1
Yield: 69.9 %

Procedure:
A mixture of p-fluoroacetophenone (100 g, 0.72 mole), ethyl cyanoacetate (81.8 g, 0.72 mole), ammonium acetate (13 g, 0.17 mole) and acetic acid (34.7 g, 0.57 mole) is refluxed for 24 hours in benzene (200 mL) with a continuous removal of water by a Dean Stark trap. The cooled mixture is diluted with benzene (150 mL) and extracted with water (2×300 mL). The organic phase is separated, dried (Na2SO4), filtered and concentrated in vacuo to a brown oil. Kugelrohr distillation (125°-127°/0.03 Torr.) affords 108.4 g (64.3%) of product as a yellow green oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].[CH:20]1([CH2:25]Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([CH2:25][N:4]2[C:5]3=[N:6][C:7]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([CH3:1])=[N:3]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrCC1CCCC1
Reactant: Cc1n[nH]c2nc(-c3ccncc3)nc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(CC2CCCC2)c2nc(-c3ccncc3)nc(N)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To a solution of 3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine (6.0 g, 0.027 mol) in DMF (50 ml) at 0° C. was added 60% NaH/mineral oil dispersion (1.06 g, 0.027 mol) in one portion. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0° C. and cyclopentylmethyl bromide (4.3 g, 0.027 mol) was added dropwise over 5 minutes. The reaction mixture was warmed to room temperature and stirred for 50 hours. The solvent was removed in vacuo, the yellow slurry was added to water (100 ml) and acidified with acetic acid. The resulting paste was stripped to dryness and the residue was slurried with ethanol. A tan solid was collected by filtration and purified by column chromatography on silica eluting with ether/ethanol/water (97.5/2/0.5) followed by recrystallization from cyclohexane to afford 2.2 g (26%) of 1-cyclopentylmethyl-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d] -pyrimidin-4-amine, m.p. 177°-178° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](C1C=CN=CC=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:36]1[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc2nc(-c3ccncc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: OB(O)c1cccnc1
Product: Cc1cc2nc(-c3cccnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-3-yl)quinolin-6-yl)acetic acid (74) was prepared following the procedure for (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-4-yl)quinolin-6-yl)acetic acid of Example 73 except that pyridin-3-ylboronic acid was used instead of pyridin-4-ylboronic acid. 1H-NMR: 400 MHz, (CD3CN) δ: 9.49 (s, 1 H), 8.94 (d, J=8.4 Hz, 1 H), 8.79 (s, 1 H), 7.91 (m, 2H), 7.80 (Abq, J=26.2, 8.8 Hz, 2 H), 7.58 (m, 3 H), 7.34 (m, 1 H), 5.25 (s, 1 H), 2.61 (s, 3H), 0.97 (s, 9 H). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H26ClN2O3: 461.16. found: 461.00.