Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].CCOC(C)=O.O>CO.O1CCOCC1.[Fe]>[NH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(N)cccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 68.1 %

Procedure:
Concentrated HCl (39 mL) was added to a solution of 2,6-dinitrobenzonitrile (11.3 g, 58.5 mmol) in MeOH (235 mL) and 1,4-dioxane (145 mL) at 70° C. External heating was removed, and iron powder (11.44 g, 205 mmol) was added slowly in portions at a rate which maintained a temperature of 70° C. After the addition of iron was complete, the reaction was heated at reflux for a further 30 min, then cooled to room temperature and poured into EtOAc (400 mL) and water (400 mL). The solids were filtered out and extracted twice with boiling EtOAc (300 mL). The combined organic extract was dried with MgSO4, filtered and evaporated to give 2-amino-6-nitrobenzonitrile (6.5 g, 68%) as a red solid, which was used without further purification. 1H-NMR (400 MHz, DMSO-d6) δ 7.48-7.54 (m, 1H), 7.41-7.45 (m, 1H), 7.18-7.22 (m, 1H), 6.74 (broad s, 2H).
Reaction SMILES: O[C:2]1([C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[N:22][CH:23]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][O:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.C(N(S(F)(F)[F:32])CC)C>ClCCl>[F:32][C:2]1([C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[N:22][CH:23]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][O:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: COc1ncncc1C1(O)c2ccccc2OCOc2ccccc21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ncncc1C1(F)c2ccccc2OCOc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.8 g of 5-(12-hydroxydibenzo[d,g][1,3]dioxocin-12-yl)-4-methoxypyrimidine, 1 mL of DAST (diethylaminosulfur trifluoride) and 30 mL of dichloromethane was prepared and allowed to stir at ambient temperature overnight. The mixture was then washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was recrystallized from a mixture of dichloromethane and hexane to obtain 0.25 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O.Cl[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>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.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:28]2[C:29]([C:30]#[N:31])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:9]=1)[CH3:2]
Reactant: N#Cc1ccccc1Cl
Reactant: CCOc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)c(-c2ccccc2C#N)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
Under argon, 5-ethoxy-2-fluorophenylboronic acid (300 mg, 1.63 mmol), potassium phosphate (433 mg, 2.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol) were dissolved in abs. N,N-dimethylformamide (8 ml), and the mixture was stirred at room temperature for 5 minutes. 2-Chlorobenzonitrile (112 mg, 0.82 mmol) was then added, and the reaction mixture was stirred at 160° C. for 4 h. After cooling to room temperature, water (>100 ml) was added and the aqueous phase was repeatedly extracted thoroughly with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered off and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 5′-ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 76% of theory) in the form of a colourless solid. 5′-Ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 0.62 mmol) was then dissolved in methanol (5 ml), finely powdered potassium hydroxide (174 mg, 3.10 mmol) was added and the mixture was stirred under reflux conditions for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, water was added and the resulting precipitated solid was filtered off and dried. This gave 2-ethoxyphenanthridin-6(5H)-one (72 mg, 46% of theory) as a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.58 (br. s, 1H, NH), 8.56 (d, 1H), 8.32 (d, 1H), 7.86 (d, 1H), 7.82 (dd, 1H), 7.64 (dd, 1H), 7.29 (d, 1H), 7.13 (dd, 1H), 4.17 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[C:20]1([CH3:33])[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[C:29]([CH:31]=O)[N:30]=2)=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:31][C:29]3[N:30]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([CH3:33])=[CH:21][CH:22]=4)[S:27][CH:28]=3)[C:5](=[O:7])[CH:4]([CH3:9])[CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1ccc(-c2nc(C=O)cs2)cc1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1csc(-c2ccc(C)cc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with commercially available 2-(p-tolyl)thiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 423.98 g/mol.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([NH2:15])=[O:14])=[CH:12][C:7]=2[CH2:6][O:5]1.CS([O-])(=O)=O.CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O.[CH2:41]1[C:51]2=[C:52]3[C:47](=[CH:48][CH:49]=[CH:50]2)[C:46]([N:53]2[CH2:58][CH2:57][NH:56][C@H:55]([CH3:59])[CH2:54]2)=[CH:45][CH:44]=[C:43]3[CH2:42]1>>[CH2:41]1[C:51]2=[C:52]3[C:47](=[CH:48][CH:49]=[CH:50]2)[C:46]([N:53]2[CH2:58][CH2:57][N:56]([CH2:2][CH2:3][C@H:4]4[C:8]5[CH:9]=[CH:10][C:11]([C:13]([NH2:15])=[O:14])=[CH:12][C:7]=5[CH2:6][O:5]4)[C@H:55]([CH3:59])[CH2:54]2)=[CH:45][CH:44]=[C:43]3[CH2:42]1
Reactant: NC(=O)c1ccc2c(c1)COC2CCO
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Agent: CS(=O)(=O)[O-]
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1CC[C@@H]1OCc2cc(C(N)=O)ccc21

Procedure:
The title compound was prepared from 1-(2-hydroxyethyl)-1,3-dihydro-2-benzofuran-5-carboxamide by initial formation of the methanesulfonate as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate, and condensation of this sulfonate with (3R)-1-(1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazine, as described for Example 1b). The mixture of diastereomers was separated by chiral HPLC using a Chiracel OJ column, eluting with hexane/ethanol (1:1) with 0.2% dimethylethylamine. M+H=442.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.[CH3:54][N:55]1[C:59]([CH:60]=O)=[N:58][C:57]([CH3:62])=[N:56]1.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:60][C:59]3[N:55]([CH3:54])[N:56]=[C:57]([CH3:62])[N:58]=3)[C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25]
Reactant: Cc1nc(C=O)n(C)n1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: Cc1nc(CC2=C(O)CC(CCc3ccc(C(C)(C)C#N)c(Cl)c3)(C3CCCC3)OC2=O)n(C)n1

Procedure:
The title compound was prepared analogously to example A(1): where 2-{2-chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile from step 5 below, was substituted in place of 6-[2-(3-chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2,5-dimethyl-2H-[1,2,4]triazole-3-carbaldehyde was substituted instead of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (300 MHz, DMSO-d6): δ 1.47-1.74 (m, 8H), 1.79 (s, 6H), 2.01-2.11 (m, 8H), 2.36-2.42 (m, 1H), 2.56 (d, J=16 Hz, 1H), 2.60-2.66 (m, 2H), 2.77 (d, J=16 Hz, 1H), 3.53 (d, J=16 Hz, 1H), 3.62 (d, J=16 Hz, 1H), 7.25 (dd, J=8.2, 1.8 Hz, 1H), 7.4 (d, J=1.8 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H). Anal. Calcd. For C27H33ClN4O3.0.25H2O: C, 64.66; H, 6.73; N, 11.17. Found: C, 64.88; H, 6.74; N, 10.86. ESIMS (MH+): 498.
Reaction SMILES: [NH4+].[OH-].[NH2:3][C:4]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[N:16][NH:17]3)=[CH:13][C:12]=2[CH3:20])=[O:9])=[C:6](Cl)[CH:5]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>O1CCOCC1>[NH2:3][C:4]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[N:16][NH:17]3)=[CH:13][C:12]=2[CH3:20])=[O:9])=[C:6]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:5]=1
Reactant: C1CNCCN1
Reactant: Cc1cc2cn[nH]c2cc1NC(=O)c1cc([N+](=O)[O-])c(N)cc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc2cn[nH]c2cc1NC(=O)c1cc([N+](=O)[O-])c(N)cc1N1CCNCC1
Temperature: 25 °C

Procedure:
A solution of the amide from above (1 mmol) in dioxane (2 mL) was reacted with aqueous NH4OH using the conditions described in Example 115. After the formation of 4-amino-2-chloro-N-(5-methyl-1H-indazol-6-yl)-5-nitrobenzamide was complete, charged with piperazine (5 mmol). The contents were heated at reflux for 10 h and the reaction mixture was cooled to RT. The contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-(5-methyl-1H-indazol-6-yl)-5-nitro-2-piperazin-1-yl-benzamide as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[C:16]1(C)C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: Cc1ccccc1
Reactant: O=C(O)Cc1c(Br)cccc1C(F)(F)F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(Br)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-(2-bromo-6-(trifluoromethyl)phenyl)acetic acid (0.306 g, 1.08 mmol) in 4:1 toluene/MeOH (8 mL) was added trimethylsilyldiazomethane (2.0 M in Et2O; 0.80 mL, 1.6 mmol). The resulting mixture was stirred at room temperature for 20 hours before diluting with EtOAc (40 mL) and washing with saturated aqueous NaHCO3 (3×40 mL). The organics were passed through a phase separation cartridge then concentrated under reduced pressure to give the title compound A91 (0.293 g, 91%); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.29 (m, 1H), 4.04 (m, 2H), 3.72 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O-:10])=[O:9])[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[CH:15][CH:14]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[CH:17][CH:18]=2)=[N:3]1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(COc2nn(C)cc2CC(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(COc2nn(C)cc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of methyl [1-methyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]-1H-pyrazol-4-ylacetate (379 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]-1H-pyrazol-4-yl]acetic acid (333 mg, yield 91%), which was then recrystallized from ethanol-hexane. melting point: 148–149° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[C:9]1([C:2]2[CH:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)ncn2)cc1
Yield: 38 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 5.02 g of 4,6-dichloropyrimidine, 8.29 g of phenylboronic acid, 7.19 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium (II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 2.08 g of phenylboronic acid, 1.79 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained solution of the extract was washed with water and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane as a developing solvent, so that a pyrimidine derivative Hdppm was obtained (yellow white powder, yield of 38%). Note that for the irradiation with microwaves, a microwave synthesis system (Discover, manufactured by CEM Corporation) was used. A synthesis scheme (a-1) of Step 1 is shown below.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[C:20]([O:24][CH3:25])[NH:21]2)=[C:17]([NH2:26])[N:16]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:38][CH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:10][CH:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[C:20]([O:24][CH3:25])[N:21]2[CH2:38][CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[C:17]([NH2:26])[N:16]=1)[CH3:8]
Reactant: COc1nc2c(N)nc(OCCOC(C)C)nc2[nH]1
Reactant: CS(=O)(=O)OCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc2c(N)nc(OCCOC(C)C)nc2n1CC1CCOCC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 112.7 %

Procedure:
To a solution of 2-({2-[(1-methylethyl)oxy]ethyl}oxy)-8-(methoxy)-9H-purin-6-amine trifluoroacetate salt (400 mg) in dry N,N-dimethylformamide (6.4 ml) was added potassium carbonate (579 mg). The reaction was stirred at 60° C. for 1.5 hours. The reaction was cooled and tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (224 mg) was added. The reaction was stirred at 90° C. for 4 hours. The reaction was cooled and taken up in ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo to yield a yellow oil (432 mg). The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-50%) to afford the title compound as a clear viscous oil (166 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5]2.[Mg]>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]([O:13][CH3:14])=[O:12])[CH2:5]2
Reactant: COC(=O)c1cc2cc(C)ccc2[nH]1
Agent: [Mg]
Solvent: CO
Product: COC(=O)C1Cc2cc(C)ccc2N1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
Methyl 5-methylindole-2-carboxylate (0.95 g, 5 mmol) and magnesium shavings (0.62 g, 25 mmol) were suspended in methanol (25 ml) and the mixture was stirred at 15° C. for 2 h. The mixture was filtered, diluted with methylene chloride (100 ml) and washed with NH4Cl solution. The organic phase was dried (Na2SO4) and the solvent removed to give the crude product, which was purified by chromatography on a column of silica gel, using a 7/3 petroleum/ethyl acetate mixture as eluent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[CH3:13][C:14]1([CH3:21])[CH2:19][O:18][PH:17](=[O:20])[O:16][CH2:15]1.CN(C)C(N(C)C)=N>C1(C)C=CC=CC=1.Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:17]2(=[O:20])[O:18][CH2:19][C:14]([CH3:21])([CH3:13])[CH2:15][O:16]2)=[CH:6][CH:5]=1
Reactant: CC1(C)CO[PH](=O)OC1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CP2(=O)OCC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Bromomethyl-benzoic acid methyl ester (0.50 g, 2.18 mmol) was made 2.0 M in anhydrous toluene and to this mixture was added 5,5-dimethyl-[1,3,2]dioxaphosphinane 2-oxide (0.66 g, 4.37 mmol) followed by N,N,N′,N′-tetramethyl-guanidine (0.25 g, 2.18 mmol). The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with 1N aq HCl and extracted with EtOAc. The organic layer was again washed with 1 N aqueous HCl, brine, dried (MgSO4) then concentrated in vacuo. The residue was purified by MPLC (0-70% EtOAc in CH2Cl2) to afford the title compound: MS: cal'd 299 (MH+), exp 299 (MH+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([O:10][CH3:11])[CH:9]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[CH3:11][O:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH2:1]
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1-c1ccccc1
Yield: 99 %

Procedure:
2.6 g of 10% by weight of palladium on charcoal is added to a solution of 11.2 g of the product obtained in Stage A in 150 ml of ethyl acetate. The suspension obtained is agitated under 1.3 atmospheres of hydrogen. After the absorption of hydrogen has stopped, the reaction medium is returned to normal atmospheric pressure, followed by filtration and evaporation under reduced pressure in order to obtain 9.64 g of sought product melting at 56° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][C@H:28]1[CH2:32][CH2:31][O:30][CH2:29]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][C@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC[C@H]1CCOC1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC[C@H]3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 215 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (3R)-3-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: Nc1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Nc2ccccc2Cl)cc1
Temperature: 100 °C
Yield: 36 %

Procedure:
To a solution of 4-bromobenzonitrile (3.0 g, 16.4 mmol) in toluene (40 mL) is added 2-chloroaniline (2.09 mL, 19.7 mmol), cesium carbonate (7.5 g, 23.0 mmol), palladium (II) acetate (110 mg, 0.50 mmol) and S-BINAP (460 mg, 0.74 mmol). The reaction mixture is then heated to 100° C. for 12 hours under an argon atmosphere. Once complete, the reaction is cooled to room temperature, diluted with diethyl ether and filtered. The filtrate is then concentrated and purified by column chromatography (6% ethyl acetate in hexanes) to afford 1.35 g of 4-[(2-chlorophenyl)amino]benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:9])([CH3:8])[C:5]([NH2:7])=[O:6])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:21]([O:23][C:24]([CH3:26])=[CH2:25])=[O:22]>C1COCC1>[CH2:1]([O:3][C:4]([CH3:9])([CH3:8])[C:5]([NH:7][C:21](=[O:22])[O:23][C:24]([CH3:26])=[CH2:25])=[O:6])[CH3:2]
Reactant: CCOC(C)(C)C(N)=O
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C(C)(C)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
A −78° C. solution of 2-ethoxy-2-methylpropanamide (1.1 g, 8.39 mmol) in THF (37 mL), under Ar, was treated with LiHMDS (1 M in THF, 11 mL, 11 mmol) stirred for 0.5 h, treated with a solution of isopropenyl chloroformate (1.46 g, 12.10 mmol) in THF (2 mL), stirred for 15 minutes at −78° C. then slowly warmed to RT as the cooling bath expired. The mixture was treated with satd. NH4Cl, extracted with DCM (4×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford prop-1-en-2-yl (2-ethoxy-2-methylpropanoyl)carbamate (2.0 g, 84%) as an orange oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[C:21]([O:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]2[CH3:30])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CCO>[CH3:29][O:28][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[N:19]=[C:18]([CH3:30])[N:17]([CH2:16][CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:26]2=[O:27]
Reactant: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C)nc12
Agent: Cl
Solvent: CCO
Product: COc1cccc2c(=O)n(CCCC3CCNCC3)c(C)nc12
Reaction time: 1 h

Procedure:
The product from Step A above was dissolved in conc HCl/EtOH (1:2 mixture, 18 mL) and was stirred for 1 h. The reaction mixture was concentrated under vacuum and azeoptroped with EtOH (2×) to provide the desired product as a white solid. API-MS: 316 (M+1)
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:20]
Reactant: CCOC(=O)C(C)Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)C(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of anhydrous ethanol (500 mL) was added sodium (9 g, 0.39 mol) in pieces. After all the sodium dissolved, diethyl malonate (50 g, 0.31 mol) was added dropwise at 0° C., and the mixture was stirred at 0° C. for another 30 minutes, followed by the addition of (±)-ethyl 2-bromopropanoate (56.5 g, 0.31 mol) dropwise. The mixture was warmed to room temperature for 1 hour and then heated at reflux for 12 hours. After cooling to room temperature, most of solvents were removed, and the residue was diluted with ethyl acetate. The organic phase was washed by brine, dried over anhydrous sodium sulfate and evaporated to afford the product (±)-triethyl propane-1,1,2-tricarboxylate (67.8 g, yield 83.4%), which was used for the next step without purification.