Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[C:18]([F:28])=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[C:18]([F:28])[C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc2c(c(Cl)c1F)NCC2
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)c(F)c(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 128–130° C.; 1H NMR (300 MHz, CDCl3) δ 6.96 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 4.08–4.00 (m, 1 H), 3.86 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.94–1.74 (m, 2 H), 1.07–0.97 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.80–0.73 (m, 1 H), 0.55–0.44 (m, 2 H), 0.34–0.27 (m, 1 H); HRMS (ESI) calcd for C19H21N3O2Cl2F (M+H)+: 412.0995; found m/z 412.1019.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:62])[C@H:6]([C:10]([NH:12][C@H:13]([C:17]([N:19]([C@@H:21]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:22]([O:56][CH3:57])[CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[C@H:31]([O:54][CH3:55])[C@@H:32]([CH3:53])[C:33]([NH:35][C@@:36]1([C:45]([N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[O:46])[CH2:38][C@@H:37]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:34])=[O:25])[CH3:20])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH:7]([CH3:9])[CH3:8].C(=O)([O-])O.[Na+].[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])N1C(OC)=O>O1CCOCC1>[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])[N:1]1[CH2:2][CH2:3][CH2:4][N:5]([CH3:62])[C@H:6]([C:10]([NH:12][C@H:13]([C:17]([N:19]([C@@H:21]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:22]([O:56][CH3:57])[CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[C@H:31]([O:54][CH3:55])[C@@H:32]([CH3:53])[C:33]([NH:35][C@@:36]1([C:45]([N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[O:46])[CH2:38][C@@H:37]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:34])=[O:25])[CH3:20])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH:7]([CH3:9])[CH3:8]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCN)C(C)C
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12 mg (14 μmol) of N-(3-aminopropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 66) were taken up in 750 μl of dioxane and admixed with 1.5 ml of saturated sodium hydrogencarbonate solution and then with 3.2 mg (21 μmol) of methyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The remaining residue was purified by means of preparative HPLC. After lyophilization, 4.2 mg (32% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: Cc1cccc([Mg]Br)c1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: Cc1cccc(C(O)(c2cccc(C)c2)C23CCN(CC2)CC3)c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of 3-methylphenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1484 g, 0.810 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.1806 g, 69.4%). E-MS m/z 322 (M+H+) Rt (1.54 min).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][NH2:16])=[O:14])=[CH:9][CH:8]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23](Cl)=O)[CH3:18].O>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[O:14][C:13]([C:10]3[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=3)=[N:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: NNC(=O)c1ccncc1
Reactant: CCOc1ccc(C(=O)Cl)cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1ccc(-c2nnc(-c3ccncc3)o2)cc1OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred suspension of Na2CO3 (1.42 mmol, 150.52 mg) and pyridine-4-carbohydrazide (0.71 mmol, 97 mg) in NMP (0.8 mL) was added a solution of 3,4-diethoxybenzoylchloride (prepare above) in NMP (0.8 mL) The reaction was stirred for 12 h at room temperature, poured to 20 mL of cold H2O and filtered. The precipitated intermediate was dried in vacuo. The solid was added to POCl3 (5 mL) and heated to 70-72° C. for 6 h. The solution was poured in an ice-water container and neutralized with a solution of NaOH (2M). The precipitated product was filtered and purified by C.C. using CH2Cl2:MeOH (9:1) to yield the product in 67% yield (150 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(N(C(C)C)CC)(C)C>>[CH2:27]([O:26][C:24](=[O:25])[NH:22][CH2:21][CH2:20][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCN)cc1OC
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNC(=O)OCc2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethylamine (150 mg in 1.5 mL methylene chloride) at -78° C. was added benzyl chloroformate (0.08 mL) and diisopropylethyl amine (0.093 mL) and the mixture warmed to 0° C. After 40 minutes, the reaction was quenched by the addition of saturated ammonium chloride, extracted with ethyl acetate and the organic portion dried over sodium sulfate. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 2:1) gave the title compound (220 mg).
Reaction SMILES: [Na].C([O:4][C:5](=O)[CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:7](OCC)=[O:8])C.[NH2:20][C:21]([NH2:23])=[S:22].O>C(O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:6]1[C:5](=[O:4])[NH:23][C:21](=[S:22])[NH:20][C:7]1=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1F
Reactant: NC(N)=S
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C1NC(=S)NC(=O)C1c1ccccc1F
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
To absolute ethanol (200 ml), sodium (3.62 g, 157 mmol) was added at room temperature under nitrogen atmosphere. The reaction mixture as stirred until all the sodium had reacted. A solution of diethyl-(2-fluorophenyl)malonate (20 g, 78.7 mmol) in absolute ethanol (50 ml) was then added followed by thiourea (8.38 g, 110 mmol). The reaction mixture was then refluxed under nitrogen atmosphere for 17 hours. The cooled reaction mixture was then poured into water (800 ml), the reswiting mixture stirred for 15 minutes and extracted with diethyl ether (500 ml). The organic phase was extracted with brine (150 ml, ⅓ saturated) and the aqueous layers combined. Now concentrated hydrochloric acid (14 ml) was added to the aqueous phase and the resulting white suspension was stirred gently for 1 hour. The suspension was filtered and the resulting solid washed with water, followed by diethyl ether and dried in vacuo for approximately 12 hours to afford 8.59 g (46% yield) of the title compound as a white solid (melting point: >240° C.).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>C1COCC1>[C:26]([N:16]1[CH2:17][CH2:18][N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a stirred suspension of 1 (2 tert-butylphenyl)piperazine dihydrochloride (29 mg, 0.1 mmol) and triethylamine (0.021 mL, 0.3 mmol) in THF (1.0 mL) was added acetyl chloride (23 mg, 0.3 mmol) at rt. After stirring for 2 h at room temperature, saturated sodium hydrogen carbonate solution (1.5 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (2 mL). The organic layer was separated by phase separation filter kit and the filtrate was evaporated under reduced pressure. The resulting residue was dissolved in DMSO (1 mL) and the solution was purified by preparative HPLC. The eluted fraction was evaporated by air blowing at 60° C. to give a title compound (20.5 mg, 79%). LC/MS (ESI+) m/z 261 [M+H], purity 100%.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:41])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:40])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:29]/[C:30]1[C:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][C:32](=[O:33])[C:31]=1[CH3:39])\[CH3:27])\[CH3:22].Cl([O-])(=O)=[O:43].[Na+]>C(Cl)(Cl)Cl.O.II>[CH3:39][C:31]1[C:32](=[O:33])[CH2:34][CH2:35][C:36]([CH3:38])([CH3:37])[C:30]=1/[CH:29]=[CH:28]/[C:26](/[CH3:27])=[CH:25]/[CH:24]=[CH:23]/[C:21](/[CH3:22])=[CH:20]/[CH:19]=[CH:18]/[CH:17]=[C:16](\[CH3:40])/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:41])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][C:7](=[O:43])[C:2]=1[CH3:1]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: II
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1=O
Temperature: -20 °C
Reaction time: 24 h
Yield: 65.3 %

Procedure:
100 mg of echinenone are dissolved in 10 ml of chloroform under a nitrogen atmosphere and are oxidized with 100 mg of sodium chlorate in 1 ml of water after having added 2 mg of iodine dissolved in 1 ml of chloroform. After stirring for 24 hours at -20° C., 67 mg of canthaxanthin having an all-trans content of 81% are obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[Na+]>O.C(O)(=O)C>[F:1][C:2]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[I:22])([F:12])[F:11]
Reactant: [I-]
Reactant: Nc1ccccc1SC(F)(F)F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)Sc1ccccc1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
2-(trifluoromethylthio)benzenamine (1 g, 5.18 mmol) prepared in accordance with a method described in J. Fluorin. Chem. 1994, 69, 207 to 212, 5 ml of glacial acetic acid, and 3 ml of 50% sulfuric acid were added into a 50-ml eggplant flask equipped with a stirrer, and were dissolved. Then the mixture was cooled to 0° C. on an ice bath. To the mixture, 1 ml of an aqueous solution of sodium nitrite (0.43 g, 6.22 mmol) was added and the mixture was stirred for 1.5 hours. 1 ml of an aqueous solution of sodium iodide (0.95 g, 6.3 mmol) was added dropwise at 0° C. and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction solution was gradually heated to room temperature and added to water, and the solution was extracted three times with ether. The obtained organic layer was washed three times with water, two times with a saturated sodium bisulfite aqueous solution, and three times with water, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (Hexane 100) to give target (trifluoromethyl)-(2-iodophenyl)sulfide (1.5 g, 95%) as a yellow oil.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([C:5]1[N:6]([CH3:22])[C:7]2[C:12]([C:13]=1[C:14](=[O:19])C(F)(F)F)=[CH:11][CH:10]=[C:9]([O:20][CH3:21])[CH:8]=2)[CH3:4]>O.CCO>[CH2:3]([C:5]1[N:6]([CH3:22])[C:7]2[C:12]([C:13]=1[C:14]([OH:19])=[O:1])=[CH:11][CH:10]=[C:9]([O:20][CH3:21])[CH:8]=2)[CH3:4]
Reactant: CCc1c(C(=O)C(F)(F)F)c2ccc(OC)cc2n1C
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1c(C(=O)O)c2ccc(OC)cc2n1C
Yield: 65.8 %

Procedure:
KOH (1.9 g, 33.49 mmole) in 20 ml H2O was added to a solution of 1-(2-ethyl-6-methoxy-1-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone 73d (2.42 g, 8.47 mmole) in 20 ml EtOH. The reaction mixture was heated to reflux for 8 h and concentrated. The residue was dissolved in H2O, acidified with 1N HCl to pH˜1 and filtrated. The solid was purified by flash column chromatography (2–5% CH3OH in CH2Cl2) to give yellow color solid (1.3 g, 72%). 1H NMR (CDCl3) δ 11.88 (1H, bs), 7.82 (1H, d, J=8.7 Hz), 7.04 (1H, s), 6.77 (1H, d, J=8.7 Hz), 3.80 (3H, s), 3.70 (3H, s), 3.51 (2H, q, J=7.4 Hz), 1.15 (3H, t, J=7.4 Hz). ESIMS (MH+): 234.05.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]2[C:12]([O:39]CC3C=CC(OC)=CC=3)=[N:13][C:14]([CH:17]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH:36]4[CH2:38][CH2:37]4)(=[O:35])=[O:34])=[CH:29][CH:28]=3)[O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:16]=2)[CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[CH:8]1([C:11]2[C:12](=[O:39])[NH:13][C:14]([CH:17]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH:36]4[CH2:38][CH2:37]4)(=[O:35])=[O:34])=[CH:31][CH:32]=3)[O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COc1ccc(COc2nc(C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)ccc2C2CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(C(Oc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)ccc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
Trifluoroacetic acid (50 mg) was added to a solution of 3-cyclopropyl-6-{[4-(cyclopropylsulfonyl)phenyl](2,4-difluorophenoxy)methyl}-2-[(4-methoxybenzyl)oxy]pyridine (90 mg) in chloroform (5 mL), and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=88:12→0:100) to give the title compound as a yellow powder (53 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=2[C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]2[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]=1[C:18](=[O:20])[CH3:19]
Reactant: COc1ccc(COc2cccc([N+](=O)[O-])c2C(C)=O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2cccc(N)c2C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 175.5 %

Procedure:
To a stirred suspension of 1-{2-[(4-methoxybenzyl)oxy]-6-nitrophenyl}ethanone (0.50 g, 1.659 mmol) in ethanol was added a solution of ammonium chloride (0.10 g, 1.825 mmol) in water (5 mL) followed by iron powder (0.75 g). The mixture was stirred at 100° C. for 1 hr. The reaction mixture was filtrated on Celite®. The filtrate was diluted with ethyl acetate and washed with water. The separated organic phase was washed with brine and dried over Na2SO4, filtrated and concentrated under reduced pressure to give 1-{2-amino-6-[(4-methoxybenzyl)oxy]phenyl}ethanone as a yellow solid (0.790 g, yield; 108%). The residue was used for the next step without further purification. [Starting Compound 1I]
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39]COC)[CH2:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.CO>O1CCCC1.Cl>[Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([OH:39])[CH2:36][CH2:37][CH2:38]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(C(=O)O)cc3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc(C(=O)O)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 80 °C

Procedure:
A solution of 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid (Example 16A) (700 mg, 1.122 mmol) in tetrahydrofuran (9.3 mL) and 10% aqueous HCl solution (1.9 mL) was heated to 65° C. for 24 hours. An additional 3 mL 10% aqueous HCl solution and 3 mL methanol were added, and the reaction was heated to 80° C. for 3 hours. The reaction was removed from the heat bath and allowed to slowly cool to room temperature. The reaction was diluted with 5 mL water, and the solid was filtered and air-dried to yield the title compound. MS ESI(+) m/z 580.1 [M+H]+;
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[CH3:4].[C:14](O)(=O)C(C)(C)C>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[C:7]([CH3:14])([CH3:8])[CH3:9])[CH3:4]
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Reactant: CC(C)(C)C(=O)O
Product: CSC(=O)OC(C)OC(=O)C(C)(C)C

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing isobutyric acid with pivalic acid in Step B affords O-(1-pivaloyloxyethyl) S-methyl thiocarbonate (5) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Cl:9][C:4]1[N:3]=[C:2]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)[N:7]=[C:6]([NH2:8])[CH:5]=1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2nc(N)cc(Cl)n2)cn1
Temperature: 50 °C
Yield: 25.1 %

Procedure:
A flask was charged with 2,6-dichloropyrimidin-4-amine (10.0 g, 61.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation E; 29.7 g, 91.5 mmol), and K2CO3 (25.3 g, 183 mmol) in dioxane (40 mL) before 300 mL of dioxane and 11 mL of water were added to the reaction mixture. The reaction mixture was then purged with argon for 30 minutes before tetrakis(triphenylphosphine)palladium (0) (3.52 g, 3.05 mmol) was added in one portion to the reaction which was then purged with argon for another 30 minutes. The reaction mixture was then sealed and heated at 50° C. overnight. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (300 mL) and aqueous saturated sodium bicarbonate (300 mL). The aqueous layer was then extracted with ethyl acetate twice more and separated. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexanes to afford 6-chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (5.00 g, 15.3 mmol, 25.2% yield). MS (apci) m/z=326.1 (M+H). Structure and regioisomer confirmed by observed nOe.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O.[Cl-].CO.CO>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Agent: [Cl-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(Nc2ncnc3cnc(NCC4CCNCC4)nc23)cc1Cl

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[(1-tert-butyloxycarbonyl-4-piperidinyl)methylamino]pyrimido[5,4-d]pyrimidine by reaction with trifluoroacetic acid. Melting point: 204°-206° C.; Rf : 0.42 (alumina; methanol chloride/methanol=10:1)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[C:13]([O:25][CH3:26])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5]([I:27])=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([I:27])[C:6]=3[O:10][CH:9]=2)=[CH:12][C:13]=1[O:25][CH3:26]
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1N
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Tert-butyl 4-(4-amino-7-iodofuro[32-c]pyridin-3-yl)-2-methoxyphenylcarbamate (3.98 g 8.28 mmol) was added to a 20% solution of trifluoroacetic acid in dichloro-methane (150 mL). The mixture was stirred for two hours and then the solvent was removed in vacuo. To the residue was added water (15 mL) and dichloromethane (25 mL). The mixture was adjusted to pH 12 with 1 N aqueous sodium hydroxide and the layers were separated. The aqueous layer was extracted with dichloromethane (2×10 mL) and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound (2.534 g, 80%). 1H NMR (DMSO-d6, 400 MHz) □ 8.03 (s, 1H) 7.94 (s, 1H) 6.91 (d, 1H) 6.82 (dd, 1H) 6.75 (d, 1H) 5.69-5.77 (bs, 2H) 4.96-5.05 (bs, 2H) 3.81 (s, 3H); RP-HPLC (Conditions f) Rt 11.22 min.; MS: MH+ 382.