Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:8]1=[O:25])[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCC(CCCc2ccc3cccnc3n2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCC(CCCc2ccc3c(n2)NCCC3)C1=O

Procedure:
A mixture of 2-8 (340 mg, 0.7991 mmol) and 10% Pd/carbon (170 mg) in EtOH (10 mL) was stirred under a balloon of hydrogen for 4 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) to give 2-9 as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][O:22][CH3:23].O>CN(C=O)C>[CH3:23][O:22][CH2:21][CH2:20][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitroindole (3.5 g; 21.6 mmol) in DMF (100ml) was added Cs2CO3 (13.9 g; 42.6 mmol). The mixture thus obtained was stirred 1 h hour at room temperature then 1-bromo-2-methoxyethane (5.9 g; 42.6 mmol) was added dropwise. The resulting mixture was heated to 120° C. under stirring for 4 hours. After cooling, the mixture was poured into water (500 ml) and the crude product was filtered, dried under vacuum to give 1-(2-methoxyethyl)-5-nitro-1H-indole which was used in the following reaction without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1B(O)O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(COC)OC.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>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:33]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=2[O:31][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
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: COCCOC
Product: CCOC(=O)c1cccc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)c1
Yield: 39.3 %

Procedure:
3-(2-Bromocyclopent-1-enyl)-benzoic acid ethyl ester (148 mg, 0.5 mmol), tetrakis(triphenylphosphine)palladium (0) (30 mg), potassium carbonate (0.20 g) and (2-benzyloxy-5-chlorophenyl) boronic acid (150 mg, 0.5 mmol) in dimethoxyethane (5 mL) were refluxed for 17 h under nitrogen. The reaction mixture was then filtered through Kieselguhr and evaporated down to an oil. Purification was carried out on a Water's separation pack (10 g) with dichloromethane/iso-hexane to give the product (85 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N+:13]([C:5]1[CH:4]=[CH:3][C:2]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][C:6]=1[CH:8]1[O:12][CH2:11][CH2:10][O:9]1)([O-:15])=[O:14]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C1OCCO1
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1C1OCCO1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A mixture of 2-(5-chloro-2-nitrophenyl)-1,3-dioxolane (21.3 g, 0.09 mole) and piperidine (39.6 g, 0.46 mole) was heated at reflux in an oil bath. After 3 hours, excess piperidine was evaporated and the residue partitioned between water and dichloromethane. The organic phase was separated and the aqueous layer extracted with dichloromethane. Combined extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to afford 2-(2-nitro-5-piperdinylphenyl)-1,3-dioxolane (21.6 g, 100%) as a dark colored oil which was used without further purification. An analytical sample was purified by flash chromatography using dichloromethane as eluant to give a light yellow oil.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)=[CH:26][CH:25]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NCc1ccc(F)cc1
Product: Cc1nc(NCc2ccccn2)nc(NCc2ccc(F)cc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (4-fluorobenzyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.92 (s, 3H), 2.27 (s, 3H), 4.56 (d, J=3.8 Hz, 2H), 4.72 (d, J=2.8 Hz, 2H), 4.78 (bs, 1H), 5.70 (bs, 1H), 6.94 (t, J=8.6 Hz, 2H), 7.13 (d, J=7.8 Hz, 1H), 7.20 (t, J=7.5 Hz, 2H), 7.29 (bs, 1H), 7.57 (t, J=7.5 Hz, 1H), 8.57 (d, J=3.2 Hz, 1H); MS (ESI) m/z 338.8 (M+1)+.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12.[I-].[Li+]>>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: [I-]
Agent: [Li+]
Product: O=C1CCCCCCCCCCC1
Yield: 91.2 %

Procedure:
Further, Zh. Org. Khim (1990), 26(7), 1497-1500, discloses that when an isomerization reaction of an epoxycyclododecane was carried out in the presence of 2.3 molar % of a catalyst consisting of LiBr (lithium bromide) at a reaction temperature of 150° C. for a reaction time of 10 hours, the target cyclododecanone was obtained at a yield of 96.6%, and when the reaction of the epoxycyclododecane was effected in the presence of 1.5 molar % of LiI (lithium iodide) at 150° C. for 5 hours, the target cyclododecanone was obtained at a yield of 91.2%. In the case of this report, however, it is assumed that to make the conversion of the epoxycyclododecane close to 100%, a very long reaction time is necessary. Also, the reaction of the report was effected in a batch-type reaction system, and thus no continuous method for the reaction is disclosed in the report.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].C(O)(=O)C.[CH:15]([OH:18])([CH3:17])[CH3:16]>>[N:6]1[CH:7]=[CH:8][C:3]([C:1](=[NH:2])[O:18][CH:15]([CH3:17])[CH3:16])=[CH:4][CH:5]=1
Reactant: CC(C)O
Reactant: N#Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)OC(=N)c1ccncc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in isopropanol (50 ml), and sodium hydride (0.23 g, 9.6 mmol) from which oily matters had been removed by washing with ether was added. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was neutralized by adding acetic acid (0.64 g, 10.7 mmol) and concentrated under reduced pressure. To the residual concentrate was added diethyl ether (50 ml). Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. To this concentrate was added hexane (80 ml), and deposited unreacted 4-cyanopyridine was removed by filtration. The filtrate was concentrated under reduced pressure to give crude isopropyl 4-pyridinecarboximidate (11.0 g) as a pale yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+].Cl>CO>[C:18]1([CH2:17][NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][OH:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@H](N)CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CO)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to literature (ref. JOC, 1990, 55(1), 111-122) starting from (D)-serine methyl ester hydrochloride (98%, from Aldrich) (D)-serine methyl ester hydrochloride (10 g, 0.065 moles) was suspended in 50 ml of anhydrous methanol and cooled to 0° C. under nitrogen. Triethylamine (9 ml, 0.065 moles) was added dropwise, followed by benzaldehyde (6.6 ml, 0.065 moles). The reaction mixture was then warmed up and stirred at room temperature for 2 hours. Sodium borohydride (4.85 g, 0.13 moles) were added in small portions over 2 hours. The resulting mixture was stirred at room temperature overnight. The mixture was then slowly added to 50 ml of HCl (20% solution) at 0° C. and the resulting solution was washed with diethyl ether (50 ml). The aqueous layer was then brought to basic pH by adding solid potassium carbonate and extracted with diethyl ether (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated under vacuum to afford the title compound as colourless oil (10.95 g).
Reaction SMILES: [C:1]([N:5]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:31][C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH:34]=[CH:35][CH:36]=[N:37]2.O>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([N:5]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:31][C:32]2[CH:41]=[CH:40][C:39]([OH:42])=[C:38]3[C:33]=2[CH:34]=[CH:35][CH:36]=[N:37]3)=[O:19])=[CH:21][CH:22]=1)[O:6][Si:7]([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:8])[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc(O)c2ncccc12
Reactant: CC(C)(C)N(O[Si](C)(C)C(C)(C)C)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)N(O[Si](C)(C)C(C)(C)C)c1ccc(C(=O)Nc2ccc(O)c3ncccc23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
To a solution of 0.15 g (0.464 mmol) of compound 2 in CH2Cl2 (2 mL) were added 0.11 g (0.561 mmol) of 1-(3-dimethylamino)propyl-3-ethylcarbodiimide hydrochloride, 0.03 g (0.232 mmol) of 4-dimethylaminopyridine, 2 mL of triethylamine, and 0.16 g (0.695 mmol) of 5-amino-8-hydroxyquinoline HCl salt. After stirring for 24 hours at room temperature, H2O and ethyl acetate were added. The organic layer was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, Hex:EtOAc=1:1) to give 0.076 g of compound 9 in 35% yield.
Reaction SMILES: OC(C)(CO)C[C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C)[CH2:6][CH2:5]1.IC1C=CN(C)C(=O)C=1>C([O-])([O-])=O.[Cs+].[Cs+].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>[C:28]1([CH:4]2[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(O)CO)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cn1ccc(I)cc1=O
Agent: O=C([O-])[O-]
Product: O=C1NCCC(c2ccccc2)O1

Procedure:
A mixture of (S)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (105 mg, 211.9 mmol), 4-iodo-1-methylpyridin-2(1H)-one (65 mg, 275.5 mmol), Pd(PPh3)2Cl2 (20 mg) in aq. Cs2CO3 solution (3 mL) was stirred at reflux for 2 h. After the reaction was finished, the mixture was washed with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to afford two isomers of (6S)-6-(2,3-dihydroxy-2-methylpropyl)-3-(S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
Reaction SMILES: [OH-:1].[Na+].BrBr.Br[O-].[Na+].[OH:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])C)[CH2:10]1.Cl>O.O1CCOCC1>[OH:8][C@@H:9]1[CH2:10][CH2:11][C@@:26]2([CH3:29])[C@@H:27]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19]([OH:21])=[O:1])[CH2:28]1
Reactant: [OH-]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)O)CC[C@@H]12
Reaction time: 1 h

Procedure:
A solution of sodium hydroxide (1.1 g) in water (18 mL) was stirred at -5° C. and bromine (0.4 mL) was added very slowly. Cold dioxane (12 mL) was added and the resulting sodium hypobromite solution was added to a solution of 3α-hydroxy-5α-pregnane-20-one (0.6 g) in dioxane (30 mL) at 0° C. The resulting mixture was kept at this temperature for 1 hr., neutralized with concentrated hydrochloric acid and poured into water. Excess 2N hydrochloric acid was then added and the precipitated solid was collected by filtration and dried in vacuo which gave the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][OH:8])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][O:8][S:38]([CH3:37])(=[O:40])=[O:39])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
A solution of the compound of Example 47 (900 mg, 2.28 mmol) and triethylamine (322 mg, 3.18 mmol) in DCM (20 mL) is cooled to 0° C. before methanesulfonyl chloride (313 mg, 2.73 mmol) is added. The mixture is stirred at rt for 90 min. The mixture is diluted with DCM and washed with water. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give methanesulfonic acid 2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-ethyl ester (1.10 g) as a white solid; LC-MS: tR=1.16 min, [M+H]+=474.02.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12.Cl.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1.[OH-].[Na+]>CCO.CC#N>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][N:31]=[C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=4)[N:30]=3)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12
Reactant: N=C(N)Nc1ccc(O)cc1
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2ccnc(Cl)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: CCn1cc(-c2ccnc(Nc3ccc(O)cc3)n2)c2ccnc(Cl)c21
Temperature: 150 °C

Procedure:
A mixture of (E)-1-(7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one (0.5 mmol), 1-(4-hydroxyphenyl)guanidine hydrochloride (0.5 mmol) and NaOH (2 mmol) in a mixture of EtOH-MeCN (1:2, v/v, 3 mL) was heated in a microwave at 150° C. for 25 minutes. The residue was purified by column chromatography using EtOAc/PE (1:3, v/v) to yield 4-(4-(7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-ylamino)phenol as white solid. 1H-NMR (DMSO-d6) δ: 1.43 (m, 3H, CH3), 4.49 (m, 2H, CH2), 6.74 (m, 2H, Ph-H), 7.11 (d, 1T-F=5.6 Hz, Pyrimidin-H), 7.52 (m, 2H, Ph-H), 7.74 (d, 1H, J=5.6 Hz, Ar—H), 8.10 (d, 1H, J=5.2 Hz, Ar—H), 8.29 (d, 1H J=5.6 Hz, Pyrimidin-H), 8.37 (s, 1H, Ar—H), 9.04 (s, 1H, OH), 9.09 (s, 1H, NH). MS (ESI+) m/z 362.1609 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([NH:18]C(=O)OC(C)(C)C)[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:5]1[CH2:6][CH2:7][CH2:8][C:2]([NH2:18])([CH3:1])[CH2:3][CH2:4]1)=[O:47]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(C)(NC(=O)OC(C)(C)C)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1N1CCCC(C)(N)CC1
Yield: 74 %

Procedure:
Following the procedure for Example 101 starting from tert-butyl 4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonyl-amino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave 412 as a pale brown solid (87 mg, 74% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.13 (t, J=7.7 Hz, 1H), 7.85 (s, 1H), 7.39-7.30 (m, 1H), 7.26-7.11 (m, 2H), 6.11 (s, 2H), 3.75 (s, 3H), 3.40-3.18 (m, 3H), 3.17-3.09 (m, 1H), 1.98-1.89 (m, 1H), 1.90-1.71 (m, 5H), 1.23 (s, 3H). Exchangeable NH2 not observed. LCMS (ES+) m/z 444 (M+1)
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[NH:6][CH2:5][C@@H:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]1[CH2:18][C:19]([O:21]CC)=[O:20].[Li+].[OH-].[ClH:26]>C1COCC1.O>[ClH:26].[O:1]=[C:2]1[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[NH:6][CH2:5][C@@H:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)CN1C(=O)C2(CCCC2)NC[C@H]1c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)C2(CCCC2)NC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl [(8R)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate from Step B (407 mg, 1.29 mmol) in THF (8 mL) and H2O (2 mL) was added 1 N aqueous LiOH (1.54 mL, 1.54 mmol) and the resulting mixture was stirred at ambient temperature for 4 h. The mixture was adjusted to pH 4 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=289 (M+1).
Reaction SMILES: CN1CCCC1=O.F[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.O>C(OCC)(=O)C>[N:19]1([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C1COCCN1
Reactant: O=C1CCc2cc(F)ccc21
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCc2cc(N3CCOCC3)ccc21
Yield: 77.2 %

Procedure:
A 1-methyl-2-pyrrolidone (10 mL) solution of 5-fluoroindanone (1.97 g) and morpholine (1.71 g) was agitated at 100° C. for 26 hours and 30 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system), and 2.20 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([OH:36])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[CH:28][CH:29]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3O)cc2)OC1(C)C
Reactant: COC(=O)c1c[nH]c2cc(Br)c(I)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cc(Br)c(-c3ccc(-c4ccccc4O)cc3)cc12
Temperature: 110 °C

Procedure:
To a solution of methyl 6-bromo-5-iodo-1H-indole-3-carboxylate (100 mg, 0.26 mmol) in toluene (1 ml) and ethanol (1 ml) was added 4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-2-ol (70 mg, 0.24 mmol) followed by aqueous potassium carbonate (2 M, 1 ml, 2.0 mmol). The solvent was degassed by passing nitrogen through the system for 5 min. Pd(dppf)Cl2 (10 mg, 0.0053 mmol) was added then sealed and reaction heated to 110° C. The reaction was cooled then partitioned between water and ethyl acetate, then washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo to afford the title compound mixed with unidentified byproducts as a dark tan solid (120 mg). TLC (50% EtOAc/Heptane) indicates no separation between product and byproducts. Crude was taken on to the next step without purification.
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:68])[CH:10]([NH:25][C:26]([NH:28][CH:29]([C:56]([O:58]CC2C=CC(OC)=CC=2)=[O:57])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([Sn](CCCC)(CCCC)CCCC)[CH:42]=2)=[O:36])=[O:27])[CH2:11][CH2:12][C:13]([O:15]CC2C=CC(OC)=CC=2)=[O:14])=CC=1.C(O)(=O)C.[I-:75].[Na+].ClN1C(=O)CCC1=O>CO>[C:56]([CH:29]([NH:28][C:26](=[O:27])[NH:25][CH:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:8])=[O:68])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([C:37]1[CH:38]=[N:39][CH:40]=[C:41]([I:75])[CH:42]=1)=[O:36])([OH:58])=[O:57]
Reactant: [I-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(C(=O)NCCCCC(NC(=O)NC(CCC(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)c1
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)c1cncc(I)c1)C(=O)O)C(=O)O
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
To a solution of 7 (0.025 g, 0.023 mmol) in 2 mL methanol was added 0.020 mL acetic acid and sodium iodide (0.017 g, 0.113 mmol), followed by N-chlorosuccinimide (0.025 g, 0.187 mmol). After 20 min at room temperature, the solvent was removed under a stream of nitrogen. A solution of TFA in CH2Cl2 (1:1, 2 mL) was then added to the residue. After 1 h at room temperature, 8 (0.008 g, 62%) was isolated by HPLC (Econosphere C18 10μ., 250×10 mm, H2O/CH3CN/TFA (85/15/0.1), 4 mL/min, product peak eluting at 10 min). 1H NMR (400 MHz, D2O) δ 9.00-9.15 (m, 3H), 4.18-4.24 (m, 2H), 3.40-3.41 (m, 2H), 2.45-2.49 (m, 2H), 2.12-2.13 (m, 1H), 1.85-1.97 (m, 2H), 1.64-1.73 (m, 3H), 1.44 (m, 2H). ESI-Mass calcd for C18H24IN4O8 [M+H]+ 551.1. found 551.0. FAB-HRMS calcd for C18H24IN4O8 [M+H]+ 551.0639. found 551.0607.