Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[C:8]([CH3:13])=[CH:7][C:6]=1[S:14][C:15]1[C:20](=[O:21])[O:19][C@:18]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33]C(=O)C)=[CH:29][CH:28]=2)([CH:22]([CH3:24])[CH3:23])[CH2:17][C:16]=1[OH:37])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.[C]>C(O)(=O)C.O.C(O)C>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][C@:18]2([CH:22]([CH3:24])[CH3:23])[O:19][C:20](=[O:21])[C:15]([S:14][C:6]3[CH:7]=[C:8]([CH3:13])[C:9]([CH2:11][OH:12])=[CH:10][C:5]=3[C:1]([CH3:2])([CH3:3])[CH3:4])=[C:16]([OH:37])[CH2:17]2)=[CH:28][CH:29]=1
Reactant: CC(=O)Nc1ccc(CC[C@@]2(C(C)C)CC(O)=C(Sc3cc(C)c(CO)cc3C(C)(C)C)C(=O)O2)cc1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: [C]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(SC2=C(O)C[C@@](CCc3ccc(N)cc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 108 °C
Reaction time: 2.5 h
Yield: 81.7 %

Procedure:
(S)-N-(4-{2-[5-(2-tert-Butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}phenyl)acetamide (27b) (8.90 Kg, 16.4 mol correcting for HPLC purity of 96.8%), water (43 L) and cold ethyl alcohol (76 L) were added to a reactor under an inert atmosphere. Sodium hydroxide, 50% aqueous solution (31 Kg) and water (27 L) were added and the vessel sealed. The mixture was stirred and heated to 108° C. Stirring was continued at 108-112° C. for 2.5 hours. The mixture was cooled to 65° C. and the pH adjusted to 6.9 by addition of 23.7 Kg glacial acetic acid over 40 minutes while maintaining the batch temperature between 65 and 69° C. The solution was transferred to a second reactor containing 3 Kg ADP carbon. The first reactor was rinsed with ethyl alcohol (5 L) and the rinse transferred to the second reactor. The resulting mixture was stirred at 65-67° C. for 15 minutes and then filtered with the aid of Supercel Hyflo (5 Kg) into a still. The second reactor and the filter were rinsed with a solution of water (5 L) in ethyl alcohol (25 L) and the rinse combined with the product solution in the still which was then concentrated under vacuum at 40-46° C. to remove 18-20 L solvent. Seed crystals were added to the remaining solution in the still and the mixture stirred and cooled to 0° C. and filtered. The product was washed with water (40 L) and vacuum dried overnight at 61° C. to give (S)-6-[2-(4-aminophenyl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one (27) (7.00 Kg, 13.4 mol, 82% yield correcting for HPLC purity, ethanol and water content): mp: 140° C. (dec); Assay (HPLC): 99.2 area%; Chiral assay (HPLC): 99.7 area % (S) isomer; Ethanol (GC): 6.7 w/w %; Water (KF): 0.32 w/w %. This material is suitable for use in the preparation of pharmaceutically acceptable salts.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:59][O:60][C:61](=[O:65])[C@H:62]([CH3:64])[NH2:63]>CN(C=O)C>[CH3:59][O:60][C:61](=[O:65])[C@@H:62]([NH:63][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])=[CH:7][C:8]=2[N:9]=1)[CH3:64]
Reactant: COC(=O)[C@H](C)N
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
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: COC(=O)[C@H](C)NC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
A 250 mL three neck round bottom flask equipped with a stir bar, thermocouple, cooling bath, addition funnel and nitrogen in/outlet was charged with 10 g (25.3 mmol) of bendamustine hydrochloride, 10.6 g (27.8 mmol) of HATU and 100 mL of DMF. The batch was cooled to 1.9° C. where 8.8 mL (6.54 g, 50.6 mmol) of DIPEA was added over 2 minutes. The reaction exothermed to 9° C. and became orange. A solution of 3.57 g (25.6 mmol) of L-alanine methyl ester hydrochloride and 6.2 mL (4.57 g, 35.4 mmol) of DIPEA in 20 mL of DMF was added drop-wise over 10 minutes at 4.9-5.7° C. The reaction was slowly warmed to RT over one hour and stirred for three hours at which time an in process assay indicated the reaction was complete. The batch was quenched onto 400 mL of 1:1 ethyl acetate/DI water. The layers were separated, the organic was washed with 10% sodium hydrogen phosphate (1×200 mL), 8% sodium bicarbonate 91×200 mL) and brine (1×200 mL), before drying over sodium sulfate, filtering and evaporating to dryness in vacuo. The residue was purified by chromatography using 100 g of silica gel 60, 230-400 mesh, eluting with 1% MeOH/MDC (3 L), 2.5% MeOH/MDC (1 L) and 5% MeOH/MDC (500 mL) collecting ˜100 mL fractions. The product containing fractions were combined and concentrated to dryness in vacuo to yield 7.1 g (16.0 mmol, 63.3%) of the desired product as a white solid with an HPLC purity of 97.4A %. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=6.92 Hz), 1H), 7.40 (d, J=8.84 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 6.86 (dd, J=2.32, 8.88 Hz), 4.25 (q, 1H), 3.72 (s, 8H), 3.71 (s, 3H), 3.62 (s, 3H), 2.87 (t, J=7.48 Hz, 2H), 2.25 (t, J=7.52 Hz, 2H), 1.99 (m, 2H), 1.26 (d, J=7.32 Hz, 3H).
Reaction SMILES: COP([CH2:7][C:8](=[O:17])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)OC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:26]([C@@H:28]1[C@@H:37]2[C@@H:31]([O:32][CH2:33][C@@H:34]([CH2:38][CH2:39][CH2:40][C:41]([O:43][CH:44]([CH3:46])[CH3:45])=[O:42])[CH2:35][CH2:36]2)[CH2:30][C@H:29]1[O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1)=O.[Cl-].[NH4+]>C1COCC1>[O:17]=[C:8]([CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)/[CH:7]=[CH:26]/[C@@H:28]1[C@@H:37]2[C@@H:31]([O:32][CH2:33][C@@H:34]([CH2:38][CH2:39][CH2:40][C:41]([O:43][CH:44]([CH3:45])[CH3:46])=[O:42])[CH2:35][CH2:36]2)[CH2:30][C@H:29]1[O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1
Reactant: COP(=O)(CC(=O)COc1ccccc1)OC
Reactant: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@@H]2OC1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/C(=O)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2OC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
Under the argon atmosphere, dimethyl-(3-phenoxy-2-oxopropyl)-phosphonate (826 mg, 3.20 mmol) and potassium phosphate (679 mg, 3.20 mmol) were added to a THF solution (16 mL) of the compound (634 mg, 1.60 mmol) produced in Example 13, and the mixture was stirred at room temperature for one day. The reaction solution was added to an aqueous saturated ammonium chloride solution, and the aqueous layer was extracted with ethyl acetate two times. The collected organic layers were washed with a saturated saline, and dried with anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and purified with a column apparatus (Hiflash-SI, Size L, hexane→ethyl acetate:hexane=4:6) manufactured by Yamazen Corporation to obtain a titled compound (426 mg) having the following physical property values.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([N+:25]([O-])=O)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([Br:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:9]1[CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Zn]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([Br:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:9]1[CH3:35])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(Br)c2)[N+](=O)[O-])N1C(=O)OC(C)(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(Br)c2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 99.5 %

Procedure:
Add zinc (0.604 g, 9.23 mmol) to a solution of (2R,3S,5R)-5-[(1R,2S)-3-(3-bromo-5-fluoro-phenyl)-1-hydroxy-2-nitro-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (0.520 g, 0.923 mmol) in acetic acid (9.23 mL). Stir the reaction mixture for 22 hours at room temperature. Filter the reaction mixture and wash the filter cake with cold water (100 mL). Add saturated aqueous sodium bicarbonate to the filtrate to neutralize the acid. Extract the neutralized aqueous phase with ethyl acetate (3×250 mL). Dry the combined organic phases with magnesium sulfate and concentrate under reduced pressure to provide the title compound (0.49 g, 99.5%) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[C:23](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Reaction time: 3 h
Yield: 32.3 %

Procedure:
N-(2-Aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 48 mg, 0.16 mmol) was stirred and dissolved in anhydrous DMF (2 ml) at ambient temperature. Potassium carbonate (23 mg, 0.16 mmol) was added followed by iodomethane (0.01 ml, 0.16 mmol) and the mixture stirred for 3 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate. The combined extracts were washed once with brine, dried over magnesium sulfate, filtered and the solvent evaporated to give the title compound as a colourless solid (16 mg, 32%); NMR Spectrum: (DMSO-d6) 1.70 (m, 4H), 1.96 (m, 2H), 2.18 (s, 3H), 2.85 (m, 2H), 3.03 (m, 1H), 4.84 (b, 2H), 6.57 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.16 (d, 1H), 7.36 (d, 2H), 7.99 (d, 2H), 9.54 (b, 1H); Mass Spectrum: M+H+ 310.
Reaction SMILES: [CH:1]1([O:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:11](=[O:27])[N:10]([CH3:28])[C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][C:31]1[S:32][CH:33]=[C:34]([CH3:36])[N:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH:1]1([O:6][C:7]2[N:15]([CH2:30][C:31]3[S:32][CH:33]=[C:34]([CH3:36])[N:35]=3)[C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:11](=[O:27])[N:10]([CH3:28])[C:9]=3[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2[nH]c(OC3CCCC3)nc21
Reactant: Cc1csc(CCl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1csc(Cn2c(OC3CCCC3)nc3c2c(=O)n(CCCOC2CCCCO2)c(=O)n3C)n1
Temperature: 50 °C

Procedure:
To a solution of 8-(cyclopentyloxy)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.12 g, 0.31 mmol) in DMF (5 mL) was added 2-(chloromethyl)-4-methylthiazole (91 mg, 0.62 mmol, intermediate 54), potassium carbonate (85 mg, 0.62 mmol), and TBAI (2 mg, 0.02 mmol). The reaction was heated at 50° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.704 min; LCMS MH+-THP 470.
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:21])[CH2:15][CH:16](OC)OC)[CH:10]=[CH:11][CH:12]=1>O>[F:6][C:7]1[CH:8]=[C:9]2[C:10]([CH:16]=[CH:15][C:14](=[O:21])[NH:13]2)=[CH:11][CH:12]=1
Reactant: COC(CC(=O)Nc1cccc(F)c1)OC
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1ccc2ccc(F)cc2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A solution of 70% H2SO4 was made up by adding chilled H2SO4 (35 ml) to chilled water (15 ml) ensuring the temp remained between 10-20° C. Finely ground N-(3-fluorophenyl)-3,3-bis(methyloxy)propanamide (6.17 g, 27.2 mmol) was then added cautiously to this solution keeping the vessel in ice. This was stirred for 1 hour and then ice water (70 ml) was added. This was then diluted further with water (230 ml). The mixture was stirred for a further 30 mins. The precipitate was filtered off and dried in a vacuum oven overnight to give the desired product (3.67 g, 83%). This material contained approximately 10% of the isomeric 5-fluoro-2(1H)-quinolinone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:14]([CH3:22])=[CH:15][C:16](Br)=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(C)C=CC=C[CH:27]=1>O1CCOCC1.C([Zn]CC)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]>[CH2:1]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:14]([CH3:22])=[CH:15][C:16]([CH2:26][CH3:27])=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: Cc1cc(Br)c(O)c2c1C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[Zn]CC
Solvent: C1COCCO1
Product: CCc1cc(C)c2c(c1O)C[C@@H]1CN(Cc3ccccc3)CCN1C2=O
Temperature: 25 °C

Procedure:
To a degassed mixture of (R)-2-Benzyl-7-methyl-9-bromo-10-hydroxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (45 mg, 0.11 mmol) and Pd(dppf)Cl2 (0.12 g, 0.14 mmol) in dioxane (1.25 mL), 1.1M diethyl zinc in toluene (0.21 mL, 0.22 mmol) was slowly added at 0° C. and heated at reflux for 1 h to give dark brownish reaction mixture. The mixture was then cooled RT and quenched with methanol (10 mL) and filtered off the precipitate and rinsed with more methanol (20 mL). Filtrate was concentrated and purified on prep TLC (SiO2, 95:5, CH2Cl2:MeOH) to give (50 mg, 93%) as a faint yellow oil. MS (ESI) 351 (M+H).
Reaction SMILES: [CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Br:28][C:29]1[CH:30]=[N:31][C:32](Cl)=[N:33][CH:34]=1.CCCCCC>CCO>[CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][N:11]([C:32]2[N:33]=[CH:34][C:29]([Br:28])=[CH:30][N:31]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccccc2)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.2 %

Procedure:
To a solution of ethyl 4-benzylpiperidine-4-carboxylate (0.46 g, 1.86 mmol) in EtOH (10.0 mL) was added DIPEA (0.80 mL, 4.65 mmol) at rt which was stirred at rt for 10 minutes followed by addition of 5-bromo-2-chloropyrimidine (0.30 g, 1.55 mmol). The reaction was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 4% EtOAc:hexane to obtain the desired product as a yellow solid (0.108 g, 45% yield). 1H NMR (DMSO-d6): δ 1.16 (t, J=7.20 Hz, 3H), 1.47 (m, 2H), 2.00 (m, 2H), 2.80 (s, 2H), 2.97 (m, 2H), 4.08 (q, J=7.20 Hz, 2H), 4.40 (m, 2H), 7.02 to 7.27 (m, 5H) and 8.43 (s, 2H).
Reaction SMILES: [CH2:1]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[OH:11])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:12]1[C:17](=[O:18])[N:16]([O:19][C:20](ON2C(=O)CCC2=O)=[O:21])[C:14](=[O:15])[CH2:13]1.CCN(CC)CC>CC#N>[CH2:1]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[O:11][C:20]([O:19][N:16]1[C:17](=[O:18])[CH2:12][CH2:13][C:14]1=[O:15])=[O:21])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: C=CCCC[C@@H]1CCC[C@H]1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCCC[C@@H]1CCC[C@H]1OC(=O)ON1C(=O)CCC1=O
Reaction time: 20 h

Procedure:
To a solution of (1R,2R)-2-pent-4-en-1-ylcyclopentanol (105 mg, 0.68 mmol) in MeCN (1.4 mL) was added N,N′-disuccinimidyl carbonate (174 mg, 0.68 mmol) and Et3N (0.19 mL, 1.36 mmol) and the mixture was stirred at 40 C for 20 hours. The reaction mixture was cooled, concentrated and purified by silica chromatography (gradient elution 0 to 100% EtOAc in hexane). LCMS (M+Na)+=318.1.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[O:17][C:16]([C:18]2[C:23]([C:24]#[N:25])=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:21]=[C:20]3[NH:33][N:34]=[CH:35][C:19]=23)=[CH:15][CH:14]=1.O.NN>C(O)C>[NH2:3][CH2:12][C:13]1[O:17][C:16]([C:18]2[C:23]([C:24]#[N:25])=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:21]=[C:20]3[NH:33][N:34]=[CH:35][C:19]=23)=[CH:15][CH:14]=1
Reactant: N#Cc1c(-c2ccc(O)cc2)nc2[nH]ncc2c1-c1ccc(CN2C(=O)c3ccccc3C2=O)o1
Agent: NN
Solvent: CCO
Solvent: O
Product: N#Cc1c(-c2ccc(O)cc2)nc2[nH]ncc2c1-c1ccc(CN)o1
Yield: 21.5 %

Procedure:
To a suspension of 0.39 g (0.80 mmol) of 4-(5-((1,3-dioxoisoindoline-2-yl)methyl)furan-2-yl)-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile obtained following the sequences of procedures B7 and D1, in 8 ml of ethanol, are added 368 μL (0.38 g, 7.6 mmol) of hydrazine hydrate. The mixture is refluxed for 3 h. The precipitate obtained is filtered and dissolved in water. The mixture is brought to pH=7-8 with 30% sodium hydroxide and extracted with ethyl acetate. The organic phases are dried over magnesium sulfate, filtered, and concentrated. The residue obtained is purified by silica chromatography (eluent 7N NH4OH in methanol in dichloromethane: 10:90) to yield 0.057 g (22%) of 4-(5-(aminomethyl)furan-2-yl)-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:14][CH2:15][CH3:16])([CH3:13])[PH2:11]=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH2:15]([O:14][C:10]([CH3:13])([PH2:11]=[O:12])[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[CH:5][CH:6]=1)[CH3:16]
Reactant: CCOC(C)([PH2]=O)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(C)([PH2]=O)c1ccc(C(=O)O)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-(ethoxy-methyl-phosphinoylmethyl)-benzoic acid methyl ester (660 mg, 2.58 mmol) in THF (5 mL) and MeOH (3 mL) was added 1N NaOH (2.58 mL, 2.58 mmol), and the mixture was stirred for 18 h. The mixture was diluted with H2O and washed with EtOAc. The aqueous layer was acidified with 1 N HCl, saturated with NaCl and extracted with a mixture of CHCl3 and MeOH, dried (MgSO4), and filtered. The solvent was evaporated under reduced pressure and the material was used without further purification. 1H NMR (CDCl3, 600 MHz) δ 7.98 (d, J=7.9 Hz, 2H), 7.34 (dd, J=7.9, 2.0 Hz, 2H), 4.12-4.03 (m, 2H), 3.26 (dd, J=25.2, 14.2 Hz, 1H), 3.23 (dd, J=25.2, 14.2 Hz, 1H), 1.44 (d, J=13.8 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H). MS: cal'd 243 (MH+), exp 243 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.[OH-].[Na+].Cl>O.C(O)C>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])/[CH:10]=[CH:17]/[C:16]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:14]([Cl:13])[CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1cc(C)cc(Br)c1O
Reactant: COc1ccc(C=O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(/C=C/C(=O)c2cc(C)cc(Br)c2O)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
1-(3-Bromo-2-hydroxy-5-methylphenyl)-1-ethanone (10 g, 43.7 mmol) and 3-chloro-4-methoxybenzaldehyde (9.0 g, 1.2 molar eq.) were introduced into 80% aqueous ethanol solution (150 ml), sodium hydroxide (NaOH; 5.2 g, 3.0 molar eq.) was added thereto, and the resulting mixture was stirred for 17 hours at room temperature. After completion of reaction, the reaction solution was neutralized by 2N aqueous hydrochloric acid solution and diluted with water (150 ml). The yellow solid thus precipitated was washed with water and methanol to give 14.2 g (Yield 85%) of the purified title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH2:14])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.Cl[C:16]1[C:17]([N:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24][CH2:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:25]1[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:22]([C:17]2[C:16]([NH:14][CH:7]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:23][CH2:24]1
Reactant: Clc1cccnc1N1CCOc2ccccc21
Reactant: NC(c1cccnc1)c1cccnc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1cncc(C(Nc2cccnc2N2CCOc3ccccc32)c2cccnc2)c1

Procedure:
To a solution of (dipyridin-3-ylmethyl)amine (139 mg, 0.75 mmol) (prepared according to the procedure in German patent DE 2447258 (1976)) and 4-(3-chloropyridin-2-yl)-3,4-dihydro-2H-1,4-benzoxazine (183 mg, 0.75 mmol) in dry dioxane (1.5 mL) was added sodium t-butoxide (91 mg, 0.95 mmol), bis(tri-t-butylphosphine)palladium(0) (30 mg, 0.058 mmol). The vessel was sealed with a septum cap, degassed (3×), and heated at 100 C for 8 hours. The reaction was cooled and diluted with methylene chloride and washed with NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with a 20-90% acetone/hexane gradient to the title compound as a clear glass. 1H-NMR (500 MHz, CDCl3): δ 8.60 (2H, s), 8.56 (2H, d, J=4.4 Hz), 7.91 (1H, d, J=4.6 Hz), 7.54 (1H, d, J=7.8 Hz), 7.26 (1H, t, J=7.5 Hz), 6.97 (1H, dd, J=4.6, 7.8 Hz), 6.87 (1H, d, J=7.8 Hz), 6.77-6.81 (3H, m), 6.37 (1H, d, J=7.6 Hz); 5.57 (1H, d, J=4.4 Hz), 4.77 (1H, d, J=4.1 Hz), 4.40 (2H, t, J=4.4 Hz), 3.76 (2H, br s). m/e (m+1): 396.2
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O:23]C)=[O:22])[CH:14]=[CH:13]1)[CH2:2]2.O.O.[OH-].[Li+:28]>C1COCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O-:23])=[O:22])[CH:14]=[CH:13]1)[CH2:2]2.[Li+:28]
Reactant: COC(=O)c1cccc2ccn(CCN[C@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2ccn(CCN[C@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate (1.6 g, 5.0 mmol) from Step C above in THF (20 ml) and H2O (20 ml) was added lithium hydroxide monohydrate (632 mg, 15.1 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium (R)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate which was used in the next step without further purification: MS (ESI+) m/z 314 (M+H).