Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(C)(=O)=[O:2].OC[CH2:8][C:9]1[C:18]2[CH2:17][S:16][N:15]=[C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]3=[N:27][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=[C:11]([C:12]=23)[CH:10]=1.ClCCl.[CH2:44]([N:46]([CH2:49][CH3:50])[CH2:47]C)[CH3:45]>>[CH3:39][O:38][C:35]1[C:34]([CH3:40])=[CH:33][N:32]=[C:31]([CH2:30][N:28]2[N:29]=[C:11]3[CH:10]=[C:9]([CH2:8][CH2:47][N:46]4[CH2:49][CH2:50][O:2][CH2:45][CH2:44]4)[C:18]4[CH2:17][S:16][N:15]=[C:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:13]([C:12]=43)=[N:27]2)[C:36]=1[CH3:37]
Reactant: CCN(CC)CC
Reactant: COc1c(C)cnc(Cn2nc3cc(CCO)c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2nc3cc(CCN4CCOCC4)c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
Mesyl chloride (5 μl) was added dropwise to a mixture composed of tert-butyl {8-(2-hydroxyethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}carbamate of Example 134 (25 mg), dehydrated dichloromethane (0.5 ml) and triethylamine (15 μl) under ice-cooling, and the mixture was stirred at 0° C. for 10 minutes. After confirming that the raw material disappeared, the solvent in the reaction mixture was evaporated by spraying. Dioxane (0.2 ml) and morpholine (44 μl) as an amine were added to the residue, and the mixture was stirred at 60° C. for six hours. The reaction mixture was concentrated under reduced pressure, and a 0.5 N sodium hydroxide solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was concentrated, and the resulting residue was purified by NH silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (17 mg, 60%) as an oil.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O.[NH2:30][C@H:31]1[CH2:36][C:35]2[C:37]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)=[CH:38][CH:39]=[CH:40][C:34]=2[O:33][CH2:32]1>CN(C)C=O>[CH3:47][N:44]1[CH2:45][CH2:46][N:41]([C:37]2[C:35]3[CH2:36][C@H:31]([NH:30][C:17](=[O:19])[C:16]4[CH:20]=[CH:21][C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:23][C:15]=4[O:14][CH3:13])[CH2:32][O:33][C:34]=3[CH:40]=[CH:39][CH:38]=2)[CH2:42][CH2:43]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: COc1cc(N2CCOCC2)ccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cc(N2CCOCC2)ccc1C(=O)N[C@@H]1COc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 120 h
Yield: 32.7 %

Procedure:
A stirred solution of 1,1′-carbonyldiimidazole (222 mg, 1.37 mmol) and 2-methoxy-4-morpholinobenzoic acid (176 mg, 0.740 mmol) in anhydrous N,N-dimethylformamide (5 mL) was heated at 75° C. for 2 h, and was then allowed to cool. A solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (183 mg, 0.740 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added. The reaction mixture was stirred at room temperature for 5 days. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and a 2 M NH3 solution (15 mL). The organic layer was dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol, 93:7+0.5% conc. NH3) affording 113 mg (30% yield) of the title compound as an uncolored foam: [α]21D−141° (c 0.5, chloroform); EIMS (70 eV)) m/z (relative intensity) 466 (20, M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:14][CH2:13][CH2:12][Cl:11])[CH:3]=1
Reactant: ClCCCI
Reactant: Oc1cncc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1cncc(Br)c1
Temperature: 25 °C
Yield: 148.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-bromo-3-hydroxypyridine (1.90 g, 10.92 mmol) in DMF (10 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.52 g of an 80% dispersion in mineral oil, 17.47 mmol) in DMF (14 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1H. To this slurry was added dropwise over 5 min 1-choro-3-iodopropane (2.68 g, 13.10 mmol), and the resulting dark-brown mixture was stirred at ambient temperature for 48 h. Cold water (30 mL) was carefully added, followed by saturated NaCl solution (20 mL). The resulting mixture was extracted with ether (5×25 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing a dark-brown oil (4.07 g). The product was used in the next step without further purification. EI-MS: m/z (relative intensity) 251 (M+, 31.89%), 249 (M+, 23.99%), 175 (65.68%), 173 (67.42%), 94 (37.06%), 41 (100.00%).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1.[CH2:11]([Br:20])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>>[Br-:20].[Cl:1][C:2]1[S:10][C:9]2[CH:8]=[CH:7][N+:6]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:13])=[CH:5][C:4]=2[CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Clc1cc2cnccc2s1
Product: O=C(C[n+]1ccc2sc(Cl)cc2c1)c1ccccc1
Product: [Br-]
Yield: 80.1 %

Procedure:
Reaction of 2-chloro-thieno[3,2-c]pyridine (17 g) with phenacyl bromide (20 g) according to the procedure of Example 1 gives white crystals (29.60 g) having a melting point (Koefler block of 239° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][NH:15][C:14](=[O:23])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(C)C=CC=CC=1.IC.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][N:15]([CH3:28])[C:14](=[O:23])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CNC(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C1CN(C)C(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl 3-benzyloxy-7-ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (4.0 g, 10.71 mmol) was azeotroped from toluene and dissolved in anhydrous DMF (20 mL), and iodomethane (700 μL, 11.25 mmol) was passed through a plug of activated basic alumina and added to the solution. After being cooled to 0° C., the solution was treated with sodium hydride (270 mg, 11.25 mmol, 95% dispersion in oil) and stirred for 1 hour. The reaction was quenched with acetic acid, and the solvent removed in vacuo. The resulting residue was triturated with diethyl ether to afford a solid which was partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous layer was extracted into EtOAc three times more, and the combined organic extracts were dried over Na2SO4 and concentrated to afford the title product as a yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 7.49-7.44 (m, 2H), 7.39-7.32 (m, 3H), 5.29-5.15 (m, 2H), 4.23-4.13 (m, 3H), 4.00-3.80 (m, 1H), 3.79 (s, 3H), 3.41-3.36 (m, 1H), 3.00 (s, 3H), 1.20-1.11 (m, 3H); ES MS (M+H)=388.
Reaction SMILES: Br[C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[S:7][C:8]2[C:14]3[CH:15]=[N:16][NH:17][C:13]=3[CH:12]=[C:11]([C:18]([F:21])([F:20])[F:19])[C:9]=2[N:10]=1)=[O:4].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:41])=[C:29]([CH:40]=1)[C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31].O>C(O)CO>[Cl:41][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:2]([CH3:23])([C:3](=[O:4])[NH:5][C:6]2[S:7][C:8]3[C:14]4[CH:15]=[N:16][NH:17][C:13]=4[CH:12]=[C:11]([C:18]([F:21])([F:20])[F:19])[C:9]=3[N:10]=2)[CH3:22])=[CH:40][C:29]=1[C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31]
Reactant: CC(C)(Br)C(=O)Nc1nc2c(C(F)(F)F)cc3[nH]ncc3c2s1
Reactant: CCOC(=O)CCNC(=O)c1cc(N)ccc1Cl
Solvent: OCCO
Solvent: O
Product: CCOC(=O)CCNC(=O)c1cc(NC(C)(C)C(=O)Nc2nc3c(C(F)(F)F)cc4[nH]ncc4c3s2)ccc1Cl
Temperature: 25 °C
Yield: 13.4 %

Procedure:
0.1 g (0.25 mmol) of 2-bromo-2-methyl-N-(4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-yl)-propionamide and 0.23 g (0.85 mmol) of ethyl 3-(5-amino-2-chlorobenzoylamino)-propionate were heated at 100° C. in 4 ml of ethylene glycol. After the completion of the reaction was confirmed by HPLC, the mixture was cooled to room temperature, and 4 ml of water was added to the mixture. The mixture was extracted with 4 ml of ethyl acetate twice, dried over 3 g of anhydrous magnesium sulfate, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 20 mg of ethyl 3-{2-chloro-5-[1-methyl-1-(4-trifluoromethyl-6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylcarbamoyl)-ethylamino]-benzoylamino}-propionate.
Reaction SMILES: [CH2:1]([N:3]([CH2:65][CH3:66])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:19](=[O:45])[N:20]([CH3:44])[CH2:21][CH2:22][N:23]([CH3:43])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:46]2[CH:51]=[C:50]([C:52](=[O:64])[NH:53][C@@H:54]3[C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH2:57][CH2:56][CH2:55]3)[CH:49]=[CH:48][N:47]=2)[CH:5]=1)[CH3:2].[ClH:67]>O1CCOCC1>[ClH:67].[ClH:67].[ClH:67].[ClH:67].[NH2:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][N:23]([CH3:43])[CH2:22][CH2:21][N:20]([CH3:44])[C:19](=[O:45])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:65][CH3:66])=[CH:5][C:6]=2[C:46]2[CH:51]=[C:50]([C:52](=[O:64])[NH:53][C@@H:54]3[C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH2:57][CH2:56][CH2:55]3)[CH:49]=[CH:48][N:47]=2)=[O:12])[CH:14]=1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN(C)CCOCCOCCOCCNC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN(C)CCOCCOCCOCCN)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
(S)-tert-Butyl 1-(3-(4-(diethylamino)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-2,5-dimethyl-1-oxo-8,11,14-trioxa-2,5-diazahexadecan-16-ylcarbamate Example 339 (1.08 g, 1.23 mmol) and hydrochloric acid in dioxane (4N, 20 mL) were stirred for 4 hours at room temperature and then evaporated to dryness to give the intermediate (S)—N1-(14-amino-3-methyl-6,9,12-trioxa-3-azatetradecyl)-N3-(4-(diethylamino)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)-N1-methylisophthalamide tetrahydrochloride 340a as a foam (1.2 g, quantitative); MS (ES, m/z): 808 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C1C=C([O:15]O)C(C(O)=O)=C(C(O)=O)C=1>>[C:1]([C:3]1[CH:4]=[N+:5]([O-:15])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: N#Cc1cccnc1
Product: N#Cc1ccc[n+]([O-])c1

Procedure:
Other methods known to one skilled in the art are also useful in the preparation of certain compounds within the scope of the present invention. For example, in a method to prepare 2,4-diamino-5-chloro-6-substituted-5-deazapteridine derivatives, 3-cyanopyridine is oxidized with monoperoxyphthalic acid, magnesium salt, hexahydrate, affording 3-cyanopyridine N-oxide. The oxide is in turn nitrated with potassium nitrate and fuming sulfuric acid, yielding 4-nitro-3-cyanopyridine N-oxide. The nitro compound is then chlorinated with phosphorous oxychloride, giving the corresponding 2,4-dichloro-3-cyanopyridine. The dichloro compound is then cyclized with guanidine carbonate in N,N-dimethylformamide, yielding the corresponding 2,4-diamino-5-chloro-5-deazapteridine. The so-prepared 5-deazapteridine is in turn brominated using N-bromosuccinimide in N,N-dimethylformamide, affording 2,4-diamino-6-bromo-5-chloro-5-deazapteridine. This compound is then reacted with an appropriate boronic acid, for example, 3,5-di(trifluoromethyl)phenylboronic acid, yielding the targeted 2,4-diamino-5-chloro-6-substituted-5-deazapteridine, for example, 2,4-diamino-5-chloro-6-[3,5-di(trifluoromethyl)phenyl]-5-deazapteridine. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C:13]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[CH:2]1.Br[C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.CCN(C(C)C)C(C)C>C(O)C.CN(C1C=CN=CC=1)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C:13]3([CH2:21][CH2:20][N:19]([C:24]4[S:25][C:26]5[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=5[N:28]=4)[CH2:18][CH2:17]3)[C:12]2=[O:22])=[CH:2]1
Reactant: O=C1N(Cc2c[nH]c3ccccc23)CCCC12CCNCC2
Reactant: Brc1nc2ccccc2s1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N(Cc2c[nH]c3ccccc23)CCCC12CCN(c1nc3ccccc3s1)CC2
Temperature: 160 °C
Yield: 59.2 %

Procedure:
To the solution of 2-((1H-indol-3-yl)methyl)-2,9-diazaspiro[5.5]undecan-1-one (60 mg, 0.20 mmol) and 2-bromobenzo[d]thiazole [2516-40-7] (56 mg, 0.26 mmol) in ethanol (0.7 ml) was added DIPEA (176 μl, 1.0 mmol) and DMAP (1.2 mg, 0.01 mmol). The mixture was heated at 160° C. for 1.25 h under microwave conditions. The solvent was evaporated and the residue was purified by flash chromatography (EtOAc/hexane 2:3) to yield 51 mg (56%) of the title compound as a pale yellow solid. [1H NMR (600 MHz, DMSO-d6) ♀ ppm 10.96 (br. s., 1H), 7.76 (d, J=7.9 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.22-7.32 (m, 2H), 7.01-7.11 (m, 2H), 6.96 (t, J=7.3 Hz, 1H), 4.63 (s, 2H), 3.82-3.96 (m, 2H), 3.38-3.49 (m, 2H), 3.17 (t, J=5.9 Hz, 2H), 2.06-2.18 (m, 2H), 1.74-1.84 (m, 2H), 1.61-1.74 (m, 2H), 1.53 (d, J=13.7 Hz, 2H); LCMS RtC=2.37 min, [M+H]+=431.2].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:20][CH3:21]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([CH2:20][CH3:21])[C:7]#[N:8])=[CH:2]1
Reactant: N#CCc1ccsc1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C#N)c1ccsc1
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
A cooled solution of 2-(3-thienyl)acetonitrile (3.144 g, 25.52 mmol) in THF (30 mL) under nitrogen was treated with LHMDS in THF (22.70 g, 25.51 mL of 1 M, 25.50 mmol) dropwise over a period of 20 minutes. The mixture was allowed to stir for 30 minutes and then treated with iodoethane (4.180 g, 2.144 mL, 26.80 mmol) dropwise. The reaction was stirred at RT for a further hour and then quenched by the addition of MeOH and concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (2×). The combined organics were dried (MgSO4), filtered, concentrated and purified by column chromatography (6:1 Petroleum ether/EtOAc) to give the product as an oil (708 mg, 18% Yield). 1H NMR (CDCl3, 400 MHz) δ 1.08 (3H, t), 1.93-2.00 (2H, q), 3.86 (1H, m), 7.03 (1H, m), 7.25 (1H, m), 7.37 (1H, m)
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]2[CH:16]=[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[S:14][C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)(=O)=O.[CH:23]1(CN)[CH2:27][CH2:26][CH2:25][CH2:24]1.C[CH2:31][N:32](C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CC#N>[CH:17]1([C:15]2[S:14][C:9]3[N:10]=[C:11]([CH3:13])[N:12]=[C:7]([CH2:6][N:32]([CH3:31])[CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[C:8]=3[CH:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCC1CCCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCCCC3)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc(CN(C)C2CCCC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (150 mg), cyclopentylmethylamine (100 mg), and CH3CN (3 mL) was added DIPEA (200 μL), followed by stirring at room temperature overnight. To the reaction mixture was added saturated aqueous sodium bicarbonate, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure, and the residue was purified by silica gel column (hexane/EtOAc) to obtain N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]-N-methylcyclopentaneamine (131 mg).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:11][CH2:12]C)(=[O:10])[CH3:9]>>[C:1]1([CH3:7])[CH:6]=[CH:5][C:4]([CH2:9][C:8]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccccc1
Product: COC(=O)Cc1ccc(C)cc1

Procedure:
Rf=0.81 (toluene:ethyl acetate=2:1)
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Cl:7][C:8]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([Cl:35])[Cl:34])[CH:27]=[C:26]([Cl:36])[C:9]=1[O:10][CH2:11][C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]=[C:33]([Cl:34])[Cl:35])[CH:27]=[C:26]([Cl:36])[C:9]=1[O:10][CH2:11][C:12]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(COc1ccc(C(F)(F)F)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(COc1ccc(C(F)(F)F)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
189 mg of potassium tert-butylate and 532 mg of methyltriphenylphosphonium bromide are heated in 8 ml of toluene for 3 hours at 80° C. The reaction mixture is cooled to 50° C. and a solution of 500 mg of 1-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-3-(4-tri-fluoromethyl-phenoxy)-propan-2-one in 5 ml of toluene is added in the course of 5 minutes. After 2 hours at 80° C., the reaction mixture is filtered, diluted with ethyl acetate and washed with water. After concentration of the organic phase and purification over silica gel, the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH2:11][OH:12])([CH3:10])[C:6]1=[O:13])=[O:4].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:9][CH2:8][C:7]([CH2:11][O:12][S:30]([CH3:29])(=[O:32])=[O:31])([CH3:10])[C:6]1=[O:13])=[O:4]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(COS(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 20 ml of methylene chloride, 1.00 g of Compound 2-1 obtained in Production Example 1 was dissolved. To the solution thus obtained, 0.68 ml of triethylamine and 0.324 ml of methanesulfonyl chloride were added. Thereafter, the resulting mixture was stirred at room temperature for 1.5 hours. After the reaction, water was added to the reaction solution thus obtained, and extraction with ethyl acetate was then carried out. The organic layer thus extracted was washed with an aqueous solution of sodium hydrogen carbonate and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 1.141 g of Compound 3-1-1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>[Pd](Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[CH:11]=[C:10]([C:33]3[CH:32]=[N:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@H](O)CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2cc3c(C)nc(N)nc3n([C@H]3CC[C@H](O)CC3)c2=O)cn1
Temperature: 100 °C

Procedure:
A flask containing 2-amino-6-bromo-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (105 mg, 0.297 mmol), potassium carbonate (123 mg, 0.892 mmol), and 2-methoxy-5-pyridine boronic acid (52 mg, 0.34 mmol) was evacuated and back-filled with nitrogen (2×). A solution of 5:1 dimethylformade:water (1.8 mL) was bubbled with argon for 15 min then added to the flask followed by bis(tripehnylphosphine) palladium (II) chloride (10 mg, 0.015 mmol). The flask was fitted with a cold finger, evacuated and back filled with nitrogen (2×) then heated to 100° C. for 4 hr. The mixture was cooled overnight, diluted with methanol and chloroform then filtered through a glass fiber filter to filter out palladium. The filtrate was concentrated and the residue was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0.5-6%) to afford the title compound (80, 71%).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([C:27](=[O:39])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:38][C:35]([F:36])([F:37])[C:31]1[CH:30]=[C:29]([NH:28][C:27]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][C:14]4[C:15]5[CH2:16][NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)=[O:39])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CNC4)ccc21
Reaction time: 1 h

Procedure:
To a solution of 4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester in DCM (20 mL), TFA (20 mL, 260 mmol) is added at 0° C. The reaction is allowed to reach room temperature and stirred for an additional 1 h. TFA/DCM are evaporated and then the product is taken up in EtOAc (100 mL) and washed with dilute NH4OH in H2O (20 mL). The organic layer is separated and the water layer is extracted further with EtOAc (2×). The combined organics are dried and evaporated. The crude residue is separated via FCC (eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1)) to give 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl phenyl)-amide. MS (ESI) m/z 440.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.55 (s, 1H) 8.33 (d, J=8.84 Hz, 1H) 8.06 (br. S., 1H) 7.89 (d, J=8.34 Hz, 1H) 7.94 (d, J=3.54 Hz, 1H) 7.57 (t, J=7.96 Hz, 1H) 7.41-7.46 (m, 2H) 7.13 (dd, J=9.09, 2.27 Hz, 1H) 6.74 (d, J=3.03 Hz, 1H) 4.26 (d, J=12.13 Hz, 4H).