Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]CN)[CH:26]=1.F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:41][C:22]([C:18]2[S:17][C:16]([C:12]3[CH:13]=[C:14]([CH3:15])[N:10]([CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:11]=3)=[N:20][C:19]=2[CH3:21])=[O:24])[CH:26]=1
Reactant: NCCc1cccnc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1nc(-c2cc(C)n(CCc3ccc(F)cc3)n2)sc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(-c2cc(C)n(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
To a solution of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (0.15 g, 0.43 mmol) in methylene chloride (10 mL) was added 2-pyridin-3-yl-ethylamine (0.05 g, 0.48 mmol), benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (0.21 g, 0.48 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.87 mmol). The reaction mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (50 mL), washed with water (50 mL) and brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (methylene chloride:methanol, 98:2) to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl-amide as a white solid (0.052 g, 29% yield). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.57 (d, J=4 Hz, 1H), 7.73 (d, J=4 Hz, 1H), 7.27-7.32 (m, 1H), 6.90-6.99 (m, 4H), 6.49 (s, 1H), 6.05-6.11 (bm, 1H), 4.64 (d, J=4 Hz, 2H), 4.23 (t, J=7 Hz, 2H), 3.13 (t, J=7 Hz, 2H), 2.76 (s, 3H), 1.56 (s, 3H); MS (M+H)+=435.9; Rt=1.31 min; HRMS (M+H)+=436.16.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5](C(OC)=O)([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]1C(OC)=O.[Cl-].[Na+].O>CN(C=O)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1CC(C(=O)OC)(C(=O)OC)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCC(=O)CC1

Procedure:
A 55 g (0.2 mole) portion of trimethyl 4-oxocyclohexane-1,1,3-tricarboxylate is dissolved in 240 ml DMF and to this is added 26 g (0.445 mole) of sodium chloride and 16 ml (0.89 mole) of water, under nitrogen. This mixture is heated to reflux and maintained for 48 hours, under nitrogen. The reaction is then stripped to dryness under reduced pressure, the residue added to water and the crude product extracted into dichloromethane (3×100 ml). The combined extracts are dried over MgSO4 and stripped to dryness, giving a yellow oil. This crude product is vacuum-distilled to obtain methyl 4-oxocyclohexane-1-carboxylate (b.p. 82°-108° C. at 1.0 mm Hg) which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].IC.[C:15](OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15]
Reactant: CCOC(C)=O
Reactant: Clc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 0.794 mL (6.60 mmol) of 4-chloroindole in 10 mL of dry dimethylformamide is reacted with 0.260 g (6.60 mmol) of 60% sodium hydride dispersed in mineral oil at room temperature for 4 h. 0.411 mL (6.60 mmol) of iodomethane is added and the reaction is allowed to stir at room temperature 15 h. TLC (2:1 hexanes:ethyl acetate) indicates the starting material is gone and new less polar spot. The reaction is quenched with 50 mL of water, extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated. The crude product is purified by chromatography using hexanes:ethyl acetate as a solvent system to obtain 0.785 g of the title compound, 72% yield. MS, ES=166.1 (M+1); 1H NMR (DMSO-d6) δ 7.431-7.413 (m, 2H); 7.145-7.064 (m, 2H); 6.442-6.432 (m, 1H); 3.795 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:29])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:16][CH2:17][C:18]4([CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]4=[O:29])[CH2:19][CH2:20]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: O=C1c2ccccc2CC12CCNCC2
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)Cc3ccccc3C4=O)nn2)n1

Procedure:
The object product (173 mg, 76%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (124 mg) obtained in Example 43(2), spiro[indene-2,4′-piperidin]-1(3H)-one hydrochloride (150 mg) and potassium carbonate (174 mg).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[C:21]([O:30][CH2:31][CH2:32][OH:33])[N:20]=[C:19]([CH2:34][CH2:35][CH3:36])[N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:38]1[N:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1>O1CCCC1.CC(N(C)C)=O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[C:21]([O:30][CH2:31][CH2:32][O:33][C:38]3[N:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=3)[N:20]=[C:19]([CH2:34][CH2:35][CH3:36])[N:18]=2)(=[O:14])=[O:15])=[CH:11][CH:12]=1)([CH3:5])([CH3:6])[CH3:4]
Reactant: CCCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccc(C)cc2)c(OCCO)n1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccc(C)cc2)c(OCCOc2ncc(Br)cn2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.4 %

Procedure:
To a suspension of sodium hydride (0.25 g) in tetrahydrofuran (5 ml) is added dropwise a solution of 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl]benzenesulfonamide (1.00 g) in dimethylacetamide (3 ml) and tetrahydrofuran (10 ml) at room temperature, and thereto is added 2-chloro-5-bromopyrimidine (0.56 g), and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is acidified with ice-cold diluted hydrochloric acid, and extracted with ethyl acetate. The extract is washed, dried, and evaporated to remove the solvent. The resulting oily product is purified by silica gel column chromatography (solvent; chloroform), and crystallized from n-hexane to give 4-tert-butyl-N-[6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl]benzenesulfonamide (1.21 g) as crystals.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([CH2:8][OH:9])[CH2:6][OH:7].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25](S(C)(=O)=O)[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:40]>C1COCC1>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25]([O:3][CH2:4][CH:5]([CH2:8][OH:9])[CH2:6][OH:7])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:40]
Reactant: OCC(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(OCC(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.17 h

Procedure:
NaH (15 mg, 0.6 mmol) was added to 2-(hydroxymethyl)-1,3-propanediol in THF (5 mL). The mixture was allowed to stir at 23° under Ar for 10 min and was then cooled to −78°. The product of Example 48 (224 mg, 0.5 mmol) in THF (5 mL) was added at −78° and the mixture allowed to warm to 23° and stir for 2 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 70% EtOAc/CH2Cl2 the title compound as a white-amorphous solid. mp 77-81°, LC MS m/z=472 (MH+) Retention time=1.79 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].Br[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>>[CH2:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=CCCCCCOCc1ccccc1
Product: O=[N+]([O-])c1ccc(CCCCCCCOCc2ccccc2)cc1
Yield: 68.3 %

Procedure:
General procedure M was used to convert 5.90 mmol of 11a and 6.49 mmol of 1-bromo-4-nitrobenzene to 4.03 mmol (68%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]([N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COCCN(C)c1ncc(C(=O)O)cc1Br
Product: COCCN(C)c1ncc(C(=O)O)cc1-c1ccc(Cl)cc1

Procedure:
In analogy to example 32c, 5-bromo-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinic acid was reacted with 4-chlorophenylboronic acid to give 5-(4-chloro-phenyl)-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinic acid as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[C:10]([Cl:18])=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1.O>CN(C=O)C>[Br:8][C:9]1[C:10]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1.[Br:8][C:9]1[C:10]([Cl:18])=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1
Reactant: OCC1CC1
Agent: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of sodium hydride (2.21 g, 55.34 mmol) in anhydrous DMF (20 ml) was added cyclopropylmethanol (CAS Registry No. 2516-33-8) (12.45 ml, 153.2 mmol) under nitrogen at 0° C. and the reaction mixture was stirred at 25° C. for 30 minutes. Then 3-bromo-2-chloro-5-nitropyridine (CAS Registry No. 5470-17-7) (7.3 g, 30.74 mmol) was added drop wise at 0° C. and stirred for two hours at 25° C. Water (60m1) was added to the reaction mixture and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to get the crude residue (12 g). The crude was purified by column chromatography (2% ethyl acetate/hexane) to get the desired product (2.06 g, 32%) as light yellow solid and 1.7 g of unreacted 3-bromo-2-chloro-5-nitropyridine was recovered. MS (LC/MS): not responding, NMR is in agreement with the structure: 1H-NMR (400 MHz, CDCl3): δ 0.41 (m, 2H), 0.65 (m, 2H), 1.32 (m, 1H), 4.34 (d, 2H), 8.60 (d, 1H), 8.96 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([CH3:21])(=[O:20])=[O:19])[C:8]([CH2:22][NH2:23])=[CH:7]2.Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([CH3:21])(=[O:19])=[O:20])[C:8]([CH2:22][NH:23][C:25]1[N:33]=[CH:32][N:31]=[C:30]3[C:26]=1[N:27]=[CH:28][NH:29]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CS(=O)(=O)c1ccccc1-c1nc2c(Cl)cccc2cc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CS(=O)(=O)c1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-(methylsulfonyl)phenyl) quinolin-3-yl)methanamine (0.060 g, 0.173 mmol), 6-chloropurine (0.032 g, 0.21 mmol, 1.2 eq) and DIEA (0.34 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=222 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.29 (s, 1H), 8.13 (s, 1H), 8.01-8.09 (m, 2H), 7.78-7.81 (m, 1H), 7.66-7.76 (m, 1H), 7.57-7.65 (m, 1H), 7.46 (d, J=7.83 Hz, 2H), 4.87-4.98 (m, 2 H), 3.28 (s, 3H), Mass Spectrum (ESI) m/e=465 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][N:11]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([C:19]([F:20])([F:21])[F:22])=[CH:12][N:11]=1
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.1 %

Procedure:
In a 10 ml flask, hydroxy-acetic acid methyl ester (0.4 ml, 0.53 mmol) was dissolved in tetrahydrofuran (1.5 ml), and then sodium hydride (23 mg, 0.57 mmol) was added thereto. After 40 minutes, 2-chloro-3-nitro-5-trifluoromethyl-pyridine (100 mg, 0.44 mmol) was added and then stirred for 2 hours at room temperature. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain white solid (84 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:22]3=[C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29][CH2:28]4)[CH:24]=[CH:25][N:21]3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.NC1CCN(CC2C=CN3C=2C(NC2C=CC(OCC4C=CC=CN=4)=C(Cl)C=2)=NC=N3)CC1.FC(F)(F)C(O)=O>CO>[NH2:33][CH:30]1[CH2:31][CH2:32][N:27]([CH2:26][C:23]2[CH:24]=[CH:25][N:21]3[C:22]=2[C:17]([NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=4)=[C:2]([Cl:1])[CH:3]=2)=[N:18][CH:19]=[N:20]3)[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5ccncc5)c(Cl)c4)c23)CC1
Agent: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5ccncc5)c(Cl)c4)c23)CC1

Procedure:
Compound 21C (31 mg) was prepared from 21B by a route analogous to that used for the preparation of 1G as a white solid. Analytical HPLC retention time=1.480 min. (Chromolith Speed ROD column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% trifluoroacetic acid, 4 mL/min, monitoring at 254 nm) and a LC/MS M++1=464+.
Reaction SMILES: [OH:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20]>C1COCC1.FC(F)(F)C(O)=O>[CH2:19]([O:21][CH:22]([O:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH3:23])[CH3:20]
Reactant: C=COCC
Reactant: CC1CC(=O)C2CCCCCCCCCC2(O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(C)OC12CCCCCCCCCC1C(=O)CC(C)C2
Yield: 81.9 %

Procedure:
A mixture of 2 g (7.9 mmol) of (16) and 0.84 ml (8.7 mmol) ethyl vinyl ether in 2 ml THF was stirred at room temperature in the presence of 20 μl (0.32 mmol) trifluoroacetic acid for 2 days. After a short column filtration (SiO2) using diethyl ether as eluent and evaporation of the solvent 2.6 g of the crude product (18) was obtained. Flash chromatography, using SiO2 and cyclohexanelEtOAc=95:5 as eluent, afforded 2.10 g (82%) of (18) as a ˜1:1 mixture of diastereomers.
Reaction SMILES: [CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:32])[F:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:41])C(=O)C1>>[Br:41][C:15]1[C:14]2[CH:13]=[C:12]([O:11][CH2:10][C:9]3[CH:28]=[CH:29][C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:7]([C:30]([F:33])([F:31])[F:32])[CH:8]=3)[CH:20]=[CH:19][C:18]=2[N:17]2[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]=12
Reactant: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: O=C1CCC(=O)N1Br
Product: O=C(O)CC1CCn2c1c(Br)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12

Procedure:
From 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid and NBS, in a similar manner to the one described in Example 1.4, the title compound was obtained as a light yellow solid. LCMS m/z=536.6 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.71 (m, 4H), 1.80-1.89 (m, 2H), 1.95-2.04 (m, 2H), 2.25-2.36 (m, 1H), 2.51-2.57 (m, 1H), 2.78-2.88 (m, 1H), 2.98 (dd, J=16.42, 3.66 Hz, 1H), 3.22-3.28 (m, 1H), 3.58-3.67 (m, 1H), 3.98-4.06 (m, 1H), 4.13-4.20 (m, 1H), 5.18 (s, 2H), 6.88 (dd, J=8.84, 2.40 Hz, 1H), 6.91 (d, J=2.15 Hz, 1H), 7.29 (d, J=8.72 Hz, 1H), 7.63 (d, J=8.21 Hz, 1H), 7.70-7.76 (m, 2H), 12.33 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C=O)C>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=c1c2ccccc2oc2c(Cl)c(O)ccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(=O)c3ccccc3oc2c1Cl
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of 1.2 g of 4-chloro-3-hydroxy-9-oxo-9H-xanthene, 1.7 g of potassium carbonate, 2.1 g of ethyl bromoacetate and 30 ml of DMF was stirred at 60°-70° C. for 3 hours. After cooling the mixture, water was added and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.1 g of ethyl 4-chloro-9-oxo-9H-xanthene-3-yloxyacetate. m.p. 183°-185° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:13][NH:12][CH2:11]2)[S:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:45]=[C:46]1[NH:55][C:54]2[N:53]=[CH:52][C:51](/[CH:56]=[CH:57]/[C:58](O)=[O:59])=[CH:50][C:49]=2[CH2:48][CH2:47]1>CN(C)C=O>[CH3:2][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:11][N:12]([C:58](=[O:59])[CH:57]=[CH:56][C:51]3[CH:50]=[C:49]4[C:54](=[N:53][CH:52]=3)[NH:55][C:46](=[O:45])[CH2:47][CH2:48]4)[CH2:13]2)[S:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: Cc1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(COC2CN(C(=O)C=Cc3cnc4c(c3)CCC(=O)N4)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
3-(4-methyl-thiophen-2-ylmethoxy)-azetidine hydrochloride (128.0 mg, 0.6 mmol), EDCI (113.0 mg, 0.6 mmol), HOBt (80.0 mg, 0.6 mmol) and diisopropylethylamine (170 μL, 1.0 mmol) were successively added to a solution of (E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (100.0 mg, 0.4 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at room temperature overnight and then partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with a saturated solution of sodium chloride (3×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (99:1 to 95:5) as eluent. The residue was triturated with acetone to give a white solid (40 mg, 27%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:10][O:11][CH3:12])=[CH:17][CH:16]=1
Reactant: COCCl
Reactant: Oc1ccc(I)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.33 ml of N,N-diisopropylethylamine and 900 μl of methoxymethyl chloride were added to a chloroform (20 ml) solution of 2 g of 4-iodophenol, and stirred overnight at room temperature. With cooling with ice, aqueous saturated ammonium chloride solution was added to it, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain 1.08 g of the entitled compound as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:2]=1.[Mg+].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19]C([O-])=O>O1CCCC1>[O:14]=[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:16][CH:15]=1)[CH2:19][C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc(Oc2cccnc2)cc1
Agent: [Mg+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(Oc2cccnc2)cc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4-(pyridin-3-yloxy)benzoic acid (11.2 g, 52.0 mmol) in tetrahydrofuran (160 ml) was added N,N′-carbonyldiimidazole (9.28 g, 57.3 mmol), and the mixture was heated under reflux for 3 hrs. After cooling the reaction solution to room temperature, monobenzyl malonate magnesium salt (11.7 g, 28.6 mmol) was added, and the mixture was heated under reflux for 2 hrs. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective substance (14.1 g, 78%).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]1)(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.C(OCC)(=O)C>O1CCCC1>[C:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]1)(=[S:26])[NH2:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=S)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.9 %

Procedure:
A solution of Example 120A (0.5 g, 2.2 mmol) in tetrahydrofuran (10 mL) was added Lawesson's reagent (0.53 g, 1.3 mmol). After stirring at room temperature for 5 hours, the reaction mixture was poured into ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Analogix® Intelliflash280™, SiO2, 0-100% of ethyl acetate in hexanes) to obtain 0.33 g of the title compound. MS (ESI+) M/Z 245 [M+H]+.