Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=O)C(F)(F)F.CI.[H-].[Na+]>C1COCC1>[CH3:19][NH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2]
Reactant: COC(=O)CCOCCOCCOCCOCCNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CNCCOCCOCCOCCOCCC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under an inert atmosphere of argon, in a round bottom flask, with magnetic stirring, 120.1 mg of 3-[2-(2-{2-[2-(2,2,2-trifluoro-acetylamino)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-propionic acid methyl ester, 1 ml of anhydrous THF and 59.8 μl of CH3I and successively introduced. The reaction medium is cooled with a ice/water bath at about 0° C., and 16.1 mg of NaH (50% pure in oil) is slowly added by small portions. After 15 min at 0° C., and 1 hr at RT, the crude reaction medium is concentrated to dryness under RP, and diluted with 0.5 ml of THF and 0.8 ml of water. At RT, 30.6 mg of LiOH is then added to the reaction medium. The crude reaction medium is kept 2 hrs at RT, 16 hrs at −20° C., and then purified by flash-chromatography on 30 g of C18-grafted silica gel (gradient of elution water:acetonitrile from 95:5 to 5:95 by volume). After concentration of fractions containing the desired product under RP, 115.3 mg of 3-(2-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid are obtained in the form of a yellow oil.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(OCC)=O)C.[H-].[Na+].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1>C1COCC1>[CH3:16][O:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][CH:19]=[C:10](/[CH:9]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH:11]=1
Reactant: COc1cccc(C=O)c1
Reactant: CCOP(=O)(Cc1cccc(C(=O)OC)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/c2cccc(OC)c2)c1
Temperature: 0 °C
Yield: 78.2 %

Procedure:
To a solution of methyl 3-[(diethoxyphosphoryl)methyl]benzoate (1.02 g, 3.56 mmol; see step (i) above) in THF (5 mL, dry) under a nitrogen atmosphere was added sodium hydride (0.212 g, 60%, 18.8 mmol). After cooling the reaction mixture to 0° C., m-anisaldehyde (0.485 g, 3.56 mmol) in THF 10 mL, dry) was carefully added dropwise with stirring. The reaction mixture was stirred for 1 h at room temperature and then quenched with water. After neutralisation with dilute HCl, the two layers were separated. The water layer was extracted with ethyl acetate and the organic layers were combined, dried (MgSO4), filtered and the solvent removed under reduced pressure. The product was purified using silica gel column chromatography (RF=0.80 20% ethyl acetate/n-hexane) to give the sub-title compound as a white solid (0.747 g, 78%), m.p.=92-94° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17](=[O:19])[NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH2:27])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 212.9 %

Procedure:
A mixture of 3.5 g of piperidine-1,4-dicarboxylic acid monobenzyl ester, 1.5 g of phenylendiamine, 2.3 mL of DIPEA and 6.9 g of PyBOP in 40 mL of DCM was stirred overnight at rt. The reaction was quenched with H2O, extracted with DCM, dried over MgSO4 and concentrated in vacuo to obtain 10 g of the desired compound as crude brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:28](=O)[O:27][CH2:26]2>C(COC)OC.CN(C=O)C>[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:28](=[C:5]1[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]1=[O:11])[O:27][CH2:26]2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Nc1ccc2c(c1)COC2=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.13 h
Yield: 31.3 %

Procedure:
To a solution of 5-chlorooxindole (0.629 g, 3.78 mmol) in 10.0 mL monoglyme was added 7.51 mL sodium hexamethyldisilazane (1.0 M in THF) over 3 min. After stirring a troom temperature for 8 min, a solution of 5-aminophthalide (0.561 g, 3.78 mmol) in 3.0 mL of DMF was added over 1 min. The mixture was stirred for 40 min and then quenched into 4% aqueous HCl solution. The aqueous solution was neutralized to pH 7 with 1 M NaOH and then made basic with saturated NaHCO3. The solid was filtered and washed with H2O and then partitioned between EtOAc and saturated NaHCO3 (heated to dissolve the solid). The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the residue triturated with MeOH to give the title compound (353 mg, 31%) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][C@@:3]1([OH:8])[CH2:7][O:6][NH:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:18]1([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34]([N:5]4[CH2:4][C@:3]([CH3:2])([OH:8])[CH2:7][O:6]4)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: C[C@]1(O)CNOC1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)c1nc2cc(C(=O)N3C[C@](C)(O)CO3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
Following the same procedure in Example 3, Step A, using (4S)-4-methylisoxazolidin-4-ol hydrochoride (36.8 mg, 0.264 mmol), diisopropylethylamine (144 μL, 106.6 mg, 0.83 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (83.2 mg, 0.253 mmol) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU (114.0 mg, 0.30 mmol). The mixture was stirred for 4 h at room temperature,and quenched by adding H2O (5 mL). Upon evapoartion, the desired title compound was purified by reversed-phase HPLC (C-18 column) using 20-50% CH3CN/H2O to give 74.9mg (56%) of a white solid. [a]D: −14.1° (c 0.17,EtOH). 1H NMR (400 MHz, CD3OD): δ 0.85 (t, J=7.52 Hz, 3H), 1.27 (m, 5H), 1.50 (s, 3H), 1.66 (m, 3H), 1.69 (s, 6H), 1.79 (m, 2H), 2.04 (q, J=7.42 Hz, 2H), 2.13 (m, 1H), 3.82 (d, J=11.33 Hz, 1H), 3.89 (d, J=8.40 Hz, 1H), 3.97 (m, 2H), 4.50 (d, J=7.62 Hz, 2H), 7.99.(m, 2H), 8.18 (s, 1H). MS (ESI) (M+H)+=414.2. Anal. Calcd for C24H35N3O3+1.30 TFA+2.00 H2O (597.83): C, 53.44; H, 6.79; N, 7.03. Found: C, 53.39; H, 6.64; N, 7.22.
Reaction SMILES: [Si:1]([O:18][C@H:19]([C@H:22]1[O:26][C:25](=[O:27])[CH2:24][CH2:23]1)[CH2:20][CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Si:1]([O:18][C@H:19]([C@H:22]1[O:26][C:25](=[O:27])[C@H:24]([CH3:28])[CH2:23]1)[CH2:20][CH3:21])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1CCC(=O)O1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1C[C@@H](C)C(=O)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (5S)-5-[(1S)-1-[tert-butyl(diphenyl)silyl]oxypropyl]tetrahydrofuran-2-one (Compound 28e-S, 3.0 g, 7.8 mmol) in THF (60 mL) at −78° C. was added lithium diisopropylamide (2M in THF, 5.9 mL, 11.8 mmol) dropwise. After addition, the reaction was stirred at −78° C. for 1 hour. To the mixture was added iodomethane (5.5 g, 39 mmol) and the mixture was stirred at −78° C. for another 1 hour. The mixture was quenched with saturated NH4Cl solution (40 mL), extracted with EtOAc (100 mL) twice. The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:10 EtOAc in petroleum ether) to afford 2.7 g of (3R,5S)-5-[(1S)-1-[tert-butyl(diphenyl)silyl]oxypropyl]-3-methyl-tetrahydrofuran-2-one (compound 28f) as a colourless oil. (Refer to Tetrahedron. 1997, 53, 6281-6294).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=3)[O:8][C:7](=[O:16])[C:6]=2[CH:17]=1.II>CC(C)=O.CN1CCCC1=O>[OH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]1[C:6](=[C:17]3[C:2](=[CH:3][CH:4]=1)[NH:1][C:5]([CH3:14])([CH3:6])[CH:4]=[C:3]3[CH3:2])[C:7](=[O:16])[O:8]2
Reactant: Nc1ccc2c(c1)c(=O)oc1cc(O)ccc12
Agent: II
Solvent: CC(C)=O
Solvent: CN1CCCC1=O
Product: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1cc(O)ccc13
Temperature: 110 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
In a pressure tube, 8-amino-3-hydroxybenzo[c]chromen-6-one (Reference Compound No. 1-(3), 40.0 g, 176 mmol) was dissolved in acetone (440 mL)-N-methylpyrrolidone (240 mL), iodine (17.9 g, 70.5 mmol) was added thereto, the pressure tube was sealed, and then the reaction mixture was stirred at 110° C. for 3 days. After cooling down, acetone was removed under reduced pressure. To the obtained residue, ethyl acetate (700 mL), hexane (150 mL) and 1% aqueous sodium thiosulfate solution (700 mL) were added thereto and the mixture was separated into a water phase and an organic layer. The water layer was extracted with a mixed solvent of ethyl acetate (250 mL)-hexane (50 mL) (3 times). The combined organic layer was washed with water (500 mL, 3 times) and saturated brine (500 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. To the obtained residue, chloroform (150 mL) was added and the unsoluble materials were filtered out. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (26.0 g) as a yellow solid. (Yield 48%)
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:29]([Cu])#[N:30]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3c(C)cccc3C)cc2c1O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3C)cc2c1O

Procedure:
The title compound was synthesized from 1-Bromo-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to example 3a; MS-(+)-ion: M+1=390.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:2]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:14]3[C:13]4[C:17](=[CH:18][CH:19]=[C:11]([S:8](=[O:10])(=[O:9])[NH:7][C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH:12]=4)[NH:16][C:15]3=[O:20])[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccnc3)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)Nc4cccnc4)cc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 73.9 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid pyridin-3-ylamide (110 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (100 mg) to give 150 mg (74%) of the title compound as an orange solid.
Reaction SMILES: [F:1][C:2]([F:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]>CO.[Pd]>[F:1][C:2]([F:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/C(F)(F)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC(F)(F)c1ccccc1

Procedure:
A solution of Intermediate 20 (1 g, 4.42 mmol) in methanol (20 ml) was hydrogenated in the presence of palladium on charcoal (10 mg, 10%) for 3 hours. The mixture was then filtered over Celite and the solvent removed under reduced pressure. The residue (0.91 g) was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=2)[N:5]=[C:4]2[CH2:18][N:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH:26]=3)[C:20](=[O:21])[C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[CH2:38](OB(OCC)OCC)[CH3:39].C1COCC1>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:18][N:19]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH:26]=4)[C:20](=[O:21])[C:3]3=[C:2]([CH2:38][CH3:39])[CH:7]=2)[CH:9]=[N:10][C:11]=1[O:16][CH3:17]
Reactant: COc1cc(-c2cc(Cl)c3c(n2)CN(c2cnn(CC(F)(F)F)c2)C3=O)cnc1OC
Reactant: CCOB(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(-c2cnc(OC)c(OC)c2)nc2c1C(=O)N(c1cnn(CC(F)(F)F)c1)C2
Temperature: 80 °C

Procedure:
As shown in step 10-iii Scheme 10, 4-Chloro-2-(5,6-dimethoxypyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 82, 75 mg, 0.165 mmol and a degassed solution of 2M aqueous sodium carbonate (826 uL, 1.65 mmol] were suspended in 10 mL of toluene. The reaction mixture was purged with nitrogen for 5 minutes and tetrakistriphenylphosphine palladium(0) (38 mg, 0.033 mmol] was added, followed by the addition of 2 M triethylborate solution in THF (992 μL, 1.0 mmol). The reaction vessel was sealed and heated for 14 hours at 80° C. The reaction mixture was cooled and the volatiles removed under reduced pressure. The residue was dissolved in EtOAc/DCM 1:1 and filtered. The filtrate was concentrated under reduced pressure. The product was purified by preparative thin layer chromatography produced 2-(5,6-dimethoxypyridin-3-yl)-4-ethyl-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 182, 1.1 mg): ESMS (M+1) 448.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:20])([CH3:19])[CH2:11][C:10]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[O:13][C:12]([CH3:20])([CH3:19])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: COc1cc2c(cc1Br)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 6.1 mL, 21.3 mmol) was added to a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 700 mg, 2.46 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.OS(O)(=O)=O.[CH3:16]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][N:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)nc1

Procedure:
In 70 ml of MeOH was suspended 12.0 g (0.086 mole) of 6-hydroxynicotinic acid followed by addition of 4 ml of concentrated H2SO4. The mixtrue was refluxed for 10 hours. After cooling, MeOH was distilled off and the residue was adjusted to pH about 8 with a saturated aqueous solution of sodium hydrogen carbonate. The precipitate was collected by filtration, rinsed (twice) with water and dried to give 10.5 g of methyl 6-hydroxynicotinate as pale yellow crystals. This product was in the pyridone structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:12][CH2:11]3)[CH2:9][N:8]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][CH2:36][C:32]=4[N:33]=[CH:34][N:35]=3)[C:5]2=[CH:6][CH:7]=1.CN>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:14][CH2:15]3)[CH2:9][N:8]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][CH2:36][C:32]=4[N:33]=[CH:34][N:35]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(CCCN5C(=O)c6ccccc6C5=O)CC4)c4cc(Cl)ccc43)c21
Agent: CN
Solvent: CO
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(CCCN)CC4)c4cc(Cl)ccc43)c21
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(3-(5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-yl)propyl)isoindoline-1,3-dione (9 mg, 0.02 mmol) and 2M MeNH2 in MeOH (0.5 mL) was stirred at about room temperature overnight. The solvent was evaporated. The residue was purified by column chromatography (DCM:7N ammonia in MeOH, 8:1) to give (R)-3-(5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-yl)propan-1-amine as a free base, which was taken up in DCM and acidified with 2N HCl in ether. Removal of the solvents under reduced pressure afforded (R)-3-(5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-yl)propan-1-amine trihydrochloride (5 mg, 74%) as a solid. LCMS (APCI+) m/z 412, 414 [M+H]+; Rt=2.47 min.
Reaction SMILES: [CH3:1][C:2]12[CH2:27][CH:5]([C:6]3([CH3:26])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([CH:16]([OH:25])[C:17]4[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCCCCC.C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]12[CH2:27][CH:5]([C:6]3([CH3:26])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([C:17]4[CH:18]=[CH:19][C:20]([CH:23]=[O:24])=[CH:21][CH:22]=4)=[O:25])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: CC12CCC(C1)C1(C)Oc3ccc(C(O)c4ccc(CO)cc4)cc3C21C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC12CCC(C1)C1(C)Oc3ccc(C(=O)c4ccc(C=O)cc4)cc3C21C
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
3.1 g (8.5 mmol) of the diol obtained in Example 10, in solution in 60 ml of CH2Cl2, were treated with 5.5 g of pyridinium chlorochromate. The reaction mixture was maintained under stirring at room temperature for 3 hours. The reaction mixture was then filtered through Celite. The organic phase was washed with a saturated ammonium chloride solution, rinsed with water, dried and evaporated to yield, after chromatography on silica in a CH2Cl2 /hexane (9/1) eluent mixture, 2 g (66%) of the expected compound, melting at 138°-142° C.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].[C:10](OC(=O)C)(=[O:12])C.C(O)=O.[OH-].[Mg+2].[OH-]>O>[CH:10]([N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[OH:1])=[O:12]
Reactant: O=P(O)(O)CCCNO
Reactant: CC(=O)OC(C)=O
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: O=CN(O)CCCP(=O)(O)O
Yield: 65.8 %

Procedure:
An oily 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (12.05 g.), which was prepared by the reaction of 3-(N-hydroxyamino)propylphosphonic acid (15.5 g.), acetic anhydride (12.3 g.) and formic acid (9.8 ml.) conducted in substantially the same manner as that of Example (31), was dissolved in water (80 ml.) and treated with magnesium hydroxide (5.83 g.) for 15 minutes under ice-cooling with stirring.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].N1C=CC=CC=1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 175.6 %

Procedure:
To a stirred solution of (4-nitro-phenyl)-acetyl chloride (2.20 g, 11.05 mmol) in anhydrous dichloromethane (50 mL) was added 2-aminobenzoic acid (0.76 g, 5.50 mmol) followed by the addition of pyridine (3 mL). After stirring for 5 hours at rt, the cloudy solution was diluted with dichloromethane and thoroughly washed with 3 M HCl solution, then with brine and dried over Na2SO4. The solvent was removed and the solid crystallized from ethyl acetate to provide the title compound (2.9 g, 88% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](Cl)=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=[N:11]1.[OH-:19].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([OH:19])=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=[N:11]1
Reactant: O=[N+]([O-])c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1O
Yield: 49 %

Procedure:
3.3 g of 1-(2,4,6-trichlorophenyl)-4-nitro-5-chloropyrazole are suspended in 10 ml of methanol, and 20 ml of 1N methanolic potassium hydroxide solution are added. The mixture is refluxed for 12 hours. In order to achieve complete reaction, a further 10 ml of 1N methanolic potassium hydroxide solution are added to the reaction mixture, which is refluxed for a further 12 hours. For work-up, the mixture is filtered, the solvent is stripped off in vacuo, the residue is taken up in hot water, and the product is precipitated by acidification with 2N hydrochloric acid. After filtering off and drying, 1.5 g (49% of theory) of 1-(2,4,6-trichlorophenyl)-4-nitro-5-hydroxypyrazole of melting point 106°-115° C. are obtained.
Reaction SMILES: N1C=C([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:8][CH:7]=2)C=N1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[C:45](=[O:49])[NH:44][CH2:43]3)O1>>[O:49]=[C:45]1[C:46]2[C:42](=[CH:41][C:40]([C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:24][CH2:23]5)=[CH:20][CH:21]=4)=[N:8][CH:7]=3)=[CH:48][CH:47]=2)[CH2:43][NH:44]1
Reactant: NC(=O)CN1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)CC1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Product: NC(=O)CN1CCC(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ccnc34)cc2)CC1

Procedure:
This compound may be prepared using the methods as described for Compound 224, using 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydroisoindol-1-one in Step 4. LCMS: Rt=0.79 min (100%), m/z (ESI) 483 (M+H)+.