Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][O:15][C:14]2=[O:26])=[O:12])=CC=1)([O-])=O.C(OC(=O)[N:33]([CH:40]1[CH2:45][CH2:44][C:43]([C:52]#[N:53])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(C)(C)C.CCCCCC.CCOC(C)=O>C1COCC1>[F:25][C:20]1[CH:19]=[C:18]([CH:17]2[CH2:16][O:15][C:14](=[O:26])[N:13]2[C:11]([N:37]2[CH2:36][CH2:35][CH:34]([NH:33][CH:40]3[CH2:41][CH2:42][C:43]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:52]#[N:53])[CH2:44][CH2:45]3)[CH2:39][CH2:38]2)=[O:12])[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N(C1CCNCC1)C1CCC(C#N)(c2ccccc2)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CC1(c2ccccc2)CCC(NC2CCN(C(=O)N3C(=O)OCC3c3ccc(F)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid 4-nitrophenyl ester (80 mg, 0.21 mmol) in 5 ml of THF was added (4-cyano-4-phenyl-cyclohexyl)-piperidin-4-yl-carbamic acid tert-butyl ester (150 mg, 0.40 mmol) in a portion and the resulting solution was stirred for 12 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow oil, which was subjected to column chromatography (50% Hexane/EtOAc) to provide the tert-butyl ester of the desired product as a colorless oil. The product obtained was dissolved in 5 ml of EtOAc and 1 ml of 1N HCl-Et2O to afford a white solid of the product as the HCl salt: mp 181-192 C; Anal. Calc. For C27H28F2N4O3.1.0HCl requires C, 61.70; H, 5.73; N, 10.28. Found: C, 59.48; H, 5.41; N, 10.34.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[NH:9][C:10]([Br:14])=[C:11]([CH3:13])[N:12]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[S:25](Cl)(=[O:27])=[O:26].O>C(#N)C>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[S:25]([N:12]1[C:11]([CH3:13])=[C:10]([Br:14])[N:9]=[C:8]1[Br:7])(=[O:27])=[O:26]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: Cc1nc(Br)[nH]c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)n1c(Br)nc(Br)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
1.4 g (10 mmol) of potassium carbonate are added to a solution of 1.7 g (7 mmol) of 2,5-dibromo-4-methyl-1H-imidazole in 40 ml of acetonitrile at room temperature. The mixture is stirred for 10 minutes at room temperature, and 1.7 g (7 mmol) of 2-methyl-5-nitro-benzenesulphonyl chloride are then added. Stirring is carried out for a further 20 hours at room temperature and the reaction mixture is then poured onto 100 ml of water. The mixture formed is extracted twice with 50 ml of diethylether in each case. The combined organic~phases are dried over sodium sulphate and then evaporated down under reduced pressure. The remaining residue is chromatographed on silica gel using methylene chloride as mobile phase. 1.6 g (51% of theory) of 1-(2-methyl-5-nitro-benzenesulphonyl)-2,4-dibromo-5-methyl-1H-imidazole are obtained in this manner in the form of a colorless solid substance of melting point 187 to 189° C.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:9]([O:11][C:12](=[O:21])[CH:13](Br)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:10]>CN(C)C=O>[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:10]
Reactant: CCOC(=O)C(Br)c1cccnc1
Reactant: Oc1cccnc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccnc1)c1cccnc1
Yield: 50 %

Procedure:
The product was prepared in a manner similar to preparation 396 using the pre-formed sodium salt of the 3-hydroxypyridine (2.13 g; 18.2 mmol; 1.2 equiv) and an aliquot of bromo-pyridin-3-yl-acetic acid ethyl ester (approx. 3.6 g; 15 mmol) in dimethylformamide (20 mL). Column purification over SiO2 (0.5% then 1.5% methanol/chloroform) produced a yellow/orange oil (2.02; approx. 50% yield). MS(ES) calc'd: [M+H]+=259.2 m/z; [M−H]−=257.2 m/z. Found: 259.1 m/z; 257.1 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([N:18]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][CH:23]=[CH:24]4)=[N:19]3)[N:10]=2)=[CH:4][CH:3]=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][N:12]=[C:11]([N:18]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][CH:23]=[CH:24]4)=[N:19]3)[N:10]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc(-n2cc3ccccc3n2)nc1Nc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(-n2cc3ccccc3n2)nc1Nc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 4.9 %

Procedure:
(4-Chloro-phenyl)-(2-indazol-2-yl-5-nitro-pyrimidin-4-yl)-amine (600 mg, 1.64 mmol) was dissolved in methanol (30 mL), palladium an carbon (10%, 150 mg) was added and the reaction mixture was stirred under a hydrogen atmosphere at room temperature over night. Filtration and evaporation gave the crude product which was purified by preparative HPLC to give N-(4-chloro-phenyl)-2-indazol-2-yl-pyrimidine-4,5-diamine (27 mg, 4.9%) as a brown solid. LC-ESI-HRMS of [M+H]+ shows 337.0955 Da. Calc. 337.096847 Da, dev. −4 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[N+:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)([O-:23])=[O:22].C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CCOC(C)=O.[Cl-].[Na+].O>[N+:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:18](=[O:20])[C@H:16]([CH3:17])[NH:15][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O-:23])=[O:22]
Reactant: O=C(OCCCO[N+](=O)[O-])[C@@H]1CCCN1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a suspension of 1,1-carbonylimidazole (22 g, 136 mmol) in EtOAc (150 mL) a solution of commercial N-[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine (20.2 g, 72.32 mmol) in EtOAc (100 mL) was added dropwise in 10 minutes. The resulting solution was stirred at room temperature for 1 hour then L-proline 3-nitrooxypropyl ester (28.8 g, 113 mmol) was added and the mixture was stirred for 16 hours. Then was treated with saturated NaHCO3 and brine. The organic layer was anhydrified with magnesium sulphate and concentrated. The residue was purified by flash chromatography (nHexane/EtOAc 4:6) affording N-[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl-L-proline 3-nitrooxypropyl ester (14.2 g, 26%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(O[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[N:1]=[CH:11]/[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccnc1
Product: CCOC(=O)C(/C=N/c1cccnc1)C(=O)OCC
Temperature: 110 °C

Procedure:
A 250 ml flask was charged with 3-Aminopyridine (8 g, 85 mmol) and diethyl 2-(ethoxymethylene)malonate (18.5 g, 85.6 mmol). The mixture was heated to 110° C. for 30 min, and then cooled to ambient temperature to give diethyl [(E)-(pyridin-3-ylimino)methyl]malonate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:44])[CH2:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:44])[CH2:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)[CH3:22]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCCO
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCCO)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 4-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamino]-pentan-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]([C:8]1[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20]>>[S:11]1[CH:12]=[C:8]([C:2]([CH2:3][CH2:4][C:5]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:7])=[O:1])[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]1=2
Reactant: O=C(O)CCC(=O)c1csc2ccccc12
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1csc2ccccc12
Yield: 78 %

Procedure:
The γ-oxo-benzo[b]thiophene-3-butyric acid is coupled to L-proline with 1,1'-carbonylidiimidazole to give 1-[3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline (78%) as a glass. As for Example 1, the preceding compound is reacted with bromine in acetic acid to give 1-[3-bromo-3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline as a glass (97%). Reaction with sodium thioacetate in ethanol gives the product (92%) of the Example as a glass.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[C:5]([O:9][C:10]([C:12]1[CH:22]=[C:21]([OH:23])[C:15]2[CH2:16][CH:17]([CH2:19][OH:20])[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:5]([O:9][C:10]([C:12]1[CH:22]=[C:21]([O:23][CH:2]([CH3:4])[CH3:3])[C:15]2[CH2:16][CH:17]([CH2:19][OH:20])[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(CO)O2
Temperature: 60 °C
Yield: 86.4 %

Procedure:
A mixture of 2-iodopropane (0.826 mL, 8.26 mmol), 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (2.00 g, 7.51 mmol), and K2CO3 (1.56 g, 11.3 mmol) in DMF (20 mL) was heated to 60° C. overnight. Additional 2-iodopropane (0.9 mL) and K2CO3 (0.9 g) were added. The resulting mixture was heated to 50° C. for 4 days, then cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The organic layers were washed with 2× H2O, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography with 50-70% EtOAc in hexanes to give a yellow syrup (2.0 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 1 H) 7.03 (d, J=1.01 Hz, 1 H) 4.90-5.05 (m, 1 H) 4.58-4.66 (m, 1 H) 3.81-3.88 (m, 1 H) 3.67-3.77 (m, 1 H) 3.21 (dd, J=16.42, 9.60 Hz, 1 H) 2.94 (dd, J=16.42, 7.07 Hz, 1 H) 1.60 (s, 9 H) 1.32-1.34 (m, 6 H); LCMS for C17H24O5 m/z 253.00 (M-tBu+H+).
Reaction SMILES: Cl[O-].[Na+].ClCl.C([O-])(=O)C.[Na+].[Br:11][C:12]1[C:13]([CH3:25])=[C:14]([C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1)[CH:15]=[N:16][OH:17].[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32]>C(Cl)Cl.O>[Br:11][C:12]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:14]([C:15]2[CH2:32][CH:31]([CH2:30][CH2:29][CH2:28][CH2:27][Cl:26])[O:17][N:16]=2)[C:13]=1[CH3:25]
Reactant: C=CCCCCCl
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C=NO
Agent: CC(=O)[O-]
Agent: ClCl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(Br)ccc(S(C)(=O)=O)c1C1=NOC(CCCCCl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 50 ml of sodium hypochlorite solution (12.5% of active chlorine, admixed with a spatula tip of sodium acetate) were added dropwise with vigorous stirring to a solution of 15 g (51.4 mmol) of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime and 6.7 g (56.5 mmol) of 6-chlorohexene in 200 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then stirred into 300 ml of water. The organic phase was washed three times with water, dried and concentrated to dryness. This gave 19.3 g of a viscous yellow oil (92.4% of theory). The 1H-NMR spectrum corresponds to the given structure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:6]1([CH3:15])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:10]=2[C:9](=[O:13])[CH2:8][CH2:7]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.8 g (47.8 mmol) of 6-ethynyl -1,2,3,4-tetrahydro-4,4-dimethylnaphthalen-1-one (Compound K) flushed for 15 minutes with a stream of argon, and 13.2 g (47.8 mmol) of ethyl 4-iodobenzoate in 200 ml of triethylamine was added 1.1 g (1.6 mmol) of bis (triphenylphosphine) palladium(II) chloride and 0.30 g (1.6 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then stirred at ambient temperature for 18 hours. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>O>[Br:16][CH2:17][CH2:18][CH2:19][C:20]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)CCCBr
Reactant: OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCCBr)OCc1ccccc1
Yield: 36.7 %

Procedure:
Benzyl alcohol (28 mL, 270 mmol) and triethylamine (3.8 mL, 27 mmol) were combined and stirred over an ice bath, under nitrogen (N2). 4-Bromobutyryl chloride (1) (3.1 mL, 27 mmol) was added in a dropwise fashion, then the reaction was stirred an additional 30 minutes. The completed reaction was poured into 250 mL H2O and extracted with Et2O (3×200 mL). The ether extracts were combined, dried over MgSO4, and solvent removed in vacuo. Resulting crude product was purified by column chromatography, eluting with EtOAc/Hex (10/90) to afford 2.55 g (37%) of the desired benzyl 4-bromobutyrate (2a). 1H NMR (200 MHz, CDCl3) d 7.4 (s, 5H), 5.2 (s, 2H), 3.4 (t, 2H), 2.6 (t, 2H), 2.2 (p, 2H); mass spec (DCl, NH3) (M+NH4)+ 275.
Reaction SMILES: O1[C@H]2C[C@@]3(C)C(C4C[C@H](F)C5[C@@](C)([C@]124)C=CC(=O)C=5)C[C@@H](C)[C@]3([O:27][C:28]([C:30]1[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][N:31]=1)=[O:29])C(OC)=O>C1(C)C=CC=CC=1>[CH3:36][C:33]1[N:34]=[CH:35][C:30]([C:28]([OH:29])=[O:27])=[N:31][CH:32]=1
Reactant: COC(=O)[C@@]1(OC(=O)c2cnc(C)cn2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Solvent: Cc1ccccc1
Product: Cc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product of Step 2 (1.92 g) is dissolved in toluene (100 mL). HCl gas is bubbled through the solution for 90 minutes and the reaction mixture is stirred at room temperature for 16 hours. The solvent is evaporated, the crude product triturated with hot ethanol and dried to afford 5-methylpyrazine-2-carboxylic acid 6S,9R,10S,11S,13S,16R,17R)-9-chloro-6-flouro-11-hydroxy-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester.
Reaction SMILES: F[C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([O:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])[CH:8]=1)=[O:5].C(O)(C(F)(F)F)=O.[NH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:38]=1[CH2:39][NH:40][C:41]2=[O:46].Cl.[OH-].[Na+]>C(O)(C)(C)C>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][C:9]1[CH:8]=[C:7]([NH:6][C:4]([C:3]2[C:2]([NH:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[CH2:39][NH:40][C:41]4=[O:46])=[N:28][CH:27]=[CH:26][CH:25]=2)=[O:5])[CH:12]=[CH:11][C:10]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CN1CCCC1COc1cc(NC(=O)c2cccnc2F)ccc1C(F)(F)F
Reactant: Nc1cccc2c1CNC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Product: CN1CCC[C@@H]1COc1cc(NC(=O)c2cccnc2Nc2cccc3c2CNC3=O)ccc1C(F)(F)F
Temperature: 150 °C

Procedure:
2-Fluoro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-nicotinamide (402 mg, 1.0116 mmol) was dissolved in tert-butanol (1 mL). To this mix was added TFA (115 mg, 1.0116 mmol) and 4-amino-2,3-dihydro-isoindol-1-one (450 mg, 3.035 mmol). The mix was heated for 6 h at 150° C., allowing the solvent to boil off. The reaction was cooled to RT, dissolved into 1N aqueous HCl, basified to pH 10 with solid NaOH, extracted twice with EtOAc, and dried over Na2SO4. The product precipitated out of solution along with a minor by-product. The EtOAc was filtered off. The crude product was dissolved in MeOH and filtered. The MeOH solution was concentrated down and eluted on silica gel column to yield the titled compound as a light yellow solid. MS: C27H26F3N5O3—525.528; M+H 526.1
Reaction SMILES: NC1C(OC2C=CC(CC(O)=O)=CC=2Cl)=CC=C2C=1C=C(CCC)N2.NC1C(OC2C=CC(CC(O)=O)=CC=2Cl)=CC=C2C=1C(CC)=C(C)N2.NC1C=C2C(C(CC)=C(C)N2)=CC=1OC1C=CC(CC(O)=O)=CC=1Cl.[Cl:76][C:77]1[CH:78]=[C:79]([CH2:99][C:100]([OH:102])=[O:101])[CH:80]=[CH:81][C:82]=1[O:83][C:84]1[CH:85]=[C:86]2[C:90](=[CH:91][C:92]=1[N+:93]([O-:95])=[O:94])[NH:89]C(C)=C2CC.O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[NH2:89][C:90]1[CH:86]=[CH:85][C:84]([O:83][C:82]2[CH:81]=[CH:80][C:79]([CH2:99][C:100]([OH:102])=[O:101])=[CH:78][C:77]=2[Cl:76])=[C:92]([N+:93]([O-:95])=[O:94])[CH:91]=1
Reactant: CCc1c(C)[nH]c2cc([N+](=O)[O-])c(Oc3ccc(CC(=O)O)cc3Cl)cc12
Agent: CCCc1cc2c(N)c(Oc3ccc(CC(=O)O)cc3Cl)ccc2[nH]1
Agent: CCc1c(C)[nH]c2cc(N)c(Oc3ccc(CC(=O)O)cc3Cl)cc12
Agent: CCc1c(C)[nH]c2ccc(Oc3ccc(CC(=O)O)cc3Cl)c(N)c12
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccc(CC(=O)O)cc2Cl)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
2-(4-(4-Amino-2-propyl-1H-indol-5-yloxy)-3-chlorophenyl)acetic acid, 2-(4-(4-amino-3-ethyl-2-methyl-1H-indol-5-yloxy)-3-chlorophenyl)acetic acid and 2-(4-(6-amino-3-ethyl-2-methyl-1H-indol-5-yloxy)-3-chlorophenyl)acetic acid (7.3). A solution of the mixture of regioisomers 7.2 (1.30 g, 3.34 mmol) and tin chloride dihydrate 3.02 g, 13.4 mmol) dissolved in ethyl acetate (10 mL) was heated to 90° C. (external temperature, oil bath) in a capped vial overnight. The reaction solution was poured into aqueous 1N sodium hydroxide solution and the resulting bi-phase passed through a pad of Celite, rinsing with water and ethyl acetate. The filtrate was acidified to pH<4 with 1N hydrochloric acid solution and the organic layer separated and washed with water and brine then stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator. The regioisomers were isolated by semi-preparative reversed phase HPLC to afford regioisomer A as a brown solid and regioisomer B as a brown solid and regioisomer C as a brown solid. LC-MS ESI (pos.) m/z: 359.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH: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+].CCO>COCCOC.O.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:1][C:2]1[N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Clc1nccc(-c2ccccc2)n1
Temperature: 125 °C
Yield: 83.2 %

Procedure:
To a mixture of 2,4-dichloropyrimidine (1.47 g, 9.8 mmol), benzene boronic acid (1 g, 8.2 mmol), Na2CO3 (2.61 g, 24.6 mmol) in a mixture of DME (15 ml), EtOH (2 ml) and water (3 ml) was added Pd(PPh3)4 (190 mg, 0.16 mmol) and the resulting mixture heated in a microwave at 125° C. for 30 min. The reaction was repeated on same scale. The reaction mixtures were combined and diluted with water and extracted with EtOAc (×2). The EtOAc layers were combined and washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue was purified by MPLC (Biotage Horizon: FLASH 40+M) eluent: 100% Hexanes (180 ml), gradient rising from 100% Hexanes to 10% EtOAc in Hexanes (900 ml), then 10% EtOAc in Hexanes (500 ml) to give 1.3 g of the title compound (41%) as a white solid. 1H NMR (CDCl3): 7.54 (m, 3H), 7.76 (s, 1H), 8.08 (m, 2H), 9.04 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[O-].[Na+]>CO>[CH2:1]([N:8]1[C:24](=[O:25])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:19](=[O:20])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: NC(=O)NCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NC(=O)N(Cc2ccccc2)C(=O)C1c1ccccc1

Procedure:
To a suspension of 100 g (666 mmol) of benzylurea and 156.8 g (666 mmol) of diethyl phenylmalonate in 340 ml of methanol, 164 ml (666 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 163.23 g (83.3%, white crystal) of the desired product.
Reaction SMILES: [C:1]1([P:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](O)[CH3:24].C(N=C=NC(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([P:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH2:23][CH3:24])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1P(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
2-(Diphenylphosphanyl)benzoic acid (0.50 g, 1.63 mmol) and 4-dimethylaminopyridine (DMAP, 20 mg, 0.163 mmol) were dissolved in CH2Cl2 (10 mL). Ethanol (0.29 mL, 4.89 mmol) was added, and the solution was placed under Ar(g) and cooled to 0° C. N,N′-Diisopropylcarbodiimide (DIC, 0.25 mL, 1.63 mmol) was added dropwise, and the resulting solution was allowed to warm to room temperature and stirred overnight. The solution was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with 10% EtOAc(ethylacetate)/hexanes, to give phosphine 1a as a pale yellow solid (0.44 g, 1.32 mmol, 81% yield). 2-(Diphenylphosphanyl)benzoic acid was purchased from Sigma-Aldrich (St. Louis, Mo.).