Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:27][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21](O)=[O:22])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.Cl.[CH3:29][NH:30][CH3:31].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][C:2]1[S:27][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([N:30]([CH3:31])[CH3:29])=[O:22])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1
Reactant: O=C(O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Reactant: CNC
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoic acid (104 mg, 0.26 mmol) was heated in 3 mL of thionylchloride at 80° C. for 3 h. The reaction was cooled to room temperature and the thionylchloride was removed under reduced pressure. The residue obtained was dissolved in 25 mL of DCM followed by addition of dimethylamine hydrochloride (63 mg, 0.77 mmol) and DIEA (200 mg, 1.55 mmol). The reaction was allowed to stir at room temperature for 16 h and extracted with 25 mL of water. The DCM layer was dried over Na2SO4 and evaporated under reduced pressure; the crude product was purified by silica chromatography in 5% MeOH-DCM to obtain 67 mg of product in 60% yield. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.33 (m, 4H), 7.03 (s, 1H), 5.03 (d, 1H), 4.17 (m, 1H), 3.55 (s, 2H), 3.13 (s, 3H), 2.99 (s, 3H), 2.86 (d, 2H), 2.22 (t, 2H), 2.19 (d, 2H), 1.55 (dq, 2H); MS (ESI) m/z: Calculated for C21H25ClN5OS, 430.15; Observed: 430.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](I)[CH:16]=[CH2:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH:16]=[CH2:15]
Reactant: Oc1cccc(Br)c1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Bromophenol (10.0 g, 57.8 mmoles) in anhydrous DMF (60 mL) was treated with K2CO3 (24.0 g, 173 mmoles) and allyl iodide (5.81 mL, 63.6 mmoles). Reaction stirred overnight at 80° C. Reaction allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound with no further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:13]=O)=[O:7])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](Br)(Br)([Br:36])[Br:35]>C(Cl)Cl>[Br:35][C:34]([Br:36])=[CH:13][C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=C(Br)Br

Procedure:
In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:16]([CH3:19])=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCCC1>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])=[CH:14][C:15]=1[CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1
Reactant: Cc1ccc(N)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 77.2 %

Procedure:
Benzyl chloroformate (95%, 4.52 mL, 30.1 mmol) was added dropwise to a stirred mixture of tert-butyl 4-(3-amino-6-methylphenyl)piperidinecarboxylate (6.99 g, 24.1 mmol) and K2CO3 (3.66 g, 26.4 mmol) in tetrahydrofuran (350 mL) and stirred under nitrogen for 18 h. CH2Cl2 was added to the reaction mixture, washed with NaHCO3 solution (saturated), followed by water, then dried over Na2SO4 and concentrated in vacuo to give an oil. Purification by flash column chromatography (eluent: cyclohexane:EtOAc (87:13)) gave tert-butyl 4-{2-methyl-5-[(phenylmethoxy)carbonylamino]phenyl}piperidinecarboxylate (7.90 g, 77.1% yield) as a white foam. ESMS m/e: 425.0 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH2:38])=[O:37])=[CH:31][CH:30]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][C:36]([NH2:38])=[O:37])=[CH:33][CH:34]=3)[C:8]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(OS(=O)(=O)C(F)(F)F)c21
Product: NC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 57.6 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.127 g, 0.29 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.047 g, 0.32 mmol) to afford the title compound (0.074 g, 61%) as a light yellow solid. MW=442.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.79 (s, 1H), 8.24-8.17 (m, 2H), 7.65-7.54 (m, 4H), 7.48 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 6.89 (s, 1H), 3.77-3.71 (m, 2H), 3.41 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 443 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][C@H:12]2[CH2:13][CH2:14][C@@H:15]([OH:18])[CH2:16][CH2:17]2)[CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CC[C@@H](O)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)cc1O[C@H]1CC[C@@H](O)CC1

Procedure:
4-Fluoro-2-(cis-4-hydroxycyclohexyloxy)-nitrobenzene (2.00 g) in methanol (15.0 ml) was hydrogenated under 50 psi hydrogen using palladium on charcoal (5%) as catalyst (300 mg) at RT for 2 h. The catalyst was filtered off; the solvent was removed in vacuo to yield the desired product as 95% pure oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1N=CN(C(N2C=NC=C2)=O)C=1.CO>C1COCC1>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:2]=1[I:1]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1I
Temperature: 70 °C
Yield: 86 %

Procedure:
To 30.7 mmol 2-Iodo-5-methanesulfonyl-benzoic acid in 250 ml THF was added 33.7 mmol CDI and the mixture was heated at 70° C. for 1 h. Methanol (12.4 ml) was then added and the mixture was heated at 70° C. for a further 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed over SiO2 (ethyl acetate/dichloromethane 4:1) to afford the title compound (86%) as a white crystalline solid.
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[C:14]([O:18][C:19]([C:21]1[CH:36]=[CH:35][C:24]([CH2:25][NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[S:28])=[CH:23][CH:22]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1C=CC=CC=1>[F:32][C:31]([F:33])([F:34])[CH2:30][N:29]=[C:27]1[N:26]([CH2:25][C:24]2[CH:35]=[CH:36][C:21]([C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])=[CH:22][CH:23]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH2:2][S:28]1
Reactant: CC(C)(C)OC(=O)c1ccc(CNC(=S)NCC(F)(F)F)cc1
Reactant: Cc1ccc(N(CCl)C(=O)Cl)cc1
Solvent: c1ccccc1
Product: Cc1ccc(N2CSC(=NCC(F)(F)F)N(Cc3ccc(C(=O)OC(C)(C)C)cc3)C2=O)cc1
Yield: 49 %

Procedure:
0.31 g of N-chloromethyl-N-(4-methylphenyl)carbamoyl chloride and 0.49 g of 1-(4-t-butoxycarbonylbenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 30 ml of benzene, and the solution was heated under reflux for 5 hours. After the reaction, benzene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography [silica gel; developing solvent hexane/ethyl acetate (9:1)) to obtain 0.34 g of the captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(c2cc(F)c(F)cc2F)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(F)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.8 %

Procedure:
Methyl 2-(2,4,5-trifluorophenyl)piperidine-4-carboxylate (2.232 g, 8.17 mmol) was dissolved in DCM (50 mL) and DIPEA (1.707 mL, 9.80 mmol), then methyl carbonochloridate (0.965 mL, 12.25 mmol) was added. The solution was stirred at room temperature for 1 h. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3, passed through a phase separator and evaporated to yield crude dimethyl 2-(2,4,5-trifluorophenyl)piperidine-1,4-dicarboxylate (2.971 g, quant.) as a brown oil. MS m/z 332 (M+H)+
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([OH:27])[CH:26]=1.C(O)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([O:27][CH2:1][CH3:2])[CH:26]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (0.461 g, 1.758 mmol) is added to a mixture of 3-bromo-5-hydroxy pyridine (0.3 g, 1.724 mmol) in THF (10 ml). Ethanol (0.103 ml) is added the reaction mixture is cooled to 0° C. (ice-bath). DEAD (0.277 ml, 1.758 mmol) is finally added and the mixture is warmed to room temperature and stirred overnight. The crude material is purified by flash chromatography by wet loading onto a 50 g silica column eluting with 3:1 iso-hexanes:EtOAc to afford the title compound as a yellow oil, [MH+ 201.88].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O.O.NN>C(O)C.[Pd]>[NH2:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][CH:2]=1
Reactant: CC(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a mixture of 4.6 g of 2-(4-chloro-3-nitrophenyl) propionic acid and 250 mg of 10% palladium-on-charcoal in 50 ml of ethanol, was added dropwise 2.5 g of hydrazine hydrate under a stream of nitrogen. After the completion of the addition, the mixture was stirred at room temperature for one hour and then refluxed for 6 hours. The resulting mixture was cooled to room temperature, mixed with 250 mg of 10% palladium-on-charcoal and 2.5 g of hydrazine hydrate, and refluxed for 6 hours. After filtration, the filtrate was evaporated and dissolved in 20 ml of water. The aqueous solution was adjusted to pH 5-6 with 6 N hydrochloric acid and then concentrated to a volume of 20 ml. On standing overnight at room temperature, 3.0 g of 2-(m-aminophenyl)propionic acid was obtained; m.p. 98°-100° C.; Analysis--Calculated for C9H11NO2 : C 65.43%, H 6.71%, N 8.48%, Found C 65.41%, H 6.72%, N 8.48%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.O=C1[N:15]2[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH:14]2[CH2:13]O1.O>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:13][C@@H:14]2[NH:15][CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:19]2)[CH:5]=1
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OCC2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN[C@@H](COc2cccnc2)C1
Temperature: 120 °C
Yield: 41.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 4.50 g, 113 mmol) was added portionwise to a solution of 3-hydroxypyridine (13.2 g, 139 mmol) and tert-butyl tetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (3.37 g, 13.9 mmol) in DMF (100 mL). Upon complete addition, the reaction mixture was heated to 120° C. for 60 h. Upon cooling to rt, water (10 mL) was added and the reaction mixture was concentrated under reduced pressure. The material was dissolved in H2O (150 mL) and EtOAc (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were concentrated under reduced pressure. The material was dissolved in EtOAc (150 mL) and washed with 1 N NaOH (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (0 to 5% MeOH in CH2Cl2 gradient) gave 1.7096 g (42%) of the desired product as a white solid. LC-MS: RT=3.81 min, [M+H]+=294.2.
Reaction SMILES: [OH:1][C:2]1C=C[C:5]([C:6](O)=O)=[CH:4][CH:3]=1.[C:11]1(O)[C:12](=[CH:14][C:15](=[CH:17][CH:18]=1)[OH:16])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:5]1[CH:6]=[C:13]([C:12]2[CH:11]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=2)[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Cc1cc(O)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 178 °C
Reaction time: 0.5 h

Procedure:
A mixture consisting of 276.24 g 4-hydroxybenzoic acid, 124.12 g toluhydroquinone, 20.00 g p-toluenesulfonic acid monohydrate and 1800 ml o-xylene in a chemical reactor equipped with stirrer, thermometer and separator for the azeotropic removal of water under reflux is heated to reflux in an oil bath of 178° C. Refluxing and separation of water starts at a vapour temperature of ca. 137° C. and is continued for a total of 18 hours with ca. 35 ml of water separated. A beige, slightly viscous suspension is formed. It is cooled to 65° C. and 1250 ml of toluene are added. After further cooling to 25° C. the mixture is stirred for 30 minutes at this temperature and then filtered. The crystalline filter residue is washed with toluene to yield a beige solid. The orange filtrates are discarded. The solid is suspended in 1250 ml ethyl acetate and stirred for 1 hour at 45° C. The suspension is cooled to 6° C., filtered, the filter residue washed with ca. 800 ml of ice-cold ethyl acetate and dried in vacuum at 50° C. to constant weight to yield 341.60 g nearly colourless diphenol (XIV). HPLC purity is 99 area %
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:9]([O:20][Si](C)(C)C)([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH:11]([CH3:13])[CH3:12])#[N:8].O.[OH-].[Na+]>C(OCC)C>[CH2:10]([C:9]([OH:20])([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][NH2:8])[CH:11]([CH3:13])[CH3:12]
Reactant: CCCCC#CC(C#N)(CC(C)C)O[Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCC#CC(O)(CN)CC(C)C
Reaction time: 20 h
Yield: 65.1 %

Procedure:
Under a nitrogen atmosphere, 6.3 g of LiAlH4 (0.167 moles) are suspended in 250 mL of anhydrous diethyl ether and the temperature is reduced to 0° C. 43 g of (1b) (0.162 moles) in 75 mL of anhydrous diethyl ether are added dropwise and the mixture is stirred for 20 h. LiAlH4 is hydrolysed with water and 30% NaOH and the phases are separated. The aqueous phase is extracted repeatedly with diethyl ether, the organic phase is extracted with 1N HCl, the aqueous phase is alkalised with 30% NaOH, extracted with diethyl ether, the combined organic phases are washed to neutrality, dried with Na2SO4 and evaporated. 20.8 g of product are obtained, which are used in the subsequent step without further purification. Formula: C12H23NO (m.w. 197.32). Yield 65%.
Reaction SMILES: S(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=O)(=O)C.[CH2:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:20]>C(O)C>[CH2:22]([N:21]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)[CH2:19][CH3:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reactant: CCNCc1ccccc1
Solvent: CCO
Product: CCN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccccc1

Procedure:
4-Methanesulphonamidophenethyl mesylate (10 g, 34 mmole) and N-ethylbenzylamine (10 ml, 67 mmole) were heated at reflux temperature in ethanol (80 ml) for 3 hours. The solvent was evaporated, the residue taken up in 2M hydrochloric acid and washed twice with methylene chloride. The aqueous layer was basified with sodium bicarbonate (to pH~12) and extracted with methylene chloride. The latter organic extract was dried (MgSO4) and evaporated to give an oil which solidified when triturated with diisopropyl ether. The solid was filtered off and discarded and the filtrate was evaporated in vacuo to give the title compound as an oil, yield 4.4 g.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=Cc1cccs1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1csc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.13 g, 0.42 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 2-thiophenecarbaldehyde (0.05 g, 0.45 mmol) was added followed by oxone (0.17 g, 0.28 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.10 g/15 mL) was added to the reaction solution. This was extracted with ethyl acetate, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (60 mg, 36% yield) as light brown crystals.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C(N(C(C)C)CC)(C)C.[N:24]1([CH2:30][CH2:31][N:32]([CH2:44][CH2:45][CH3:46])[CH:33]2[CH2:42][C:41]3[CH:40]=[C:39]([OH:43])[CH:38]=[CH:37][C:36]=3[CH2:35][CH2:34]2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[OH:43][C:39]1[CH:40]=[C:41]2[C:36]([CH2:35][CH2:34][CH:33]([N:32]([CH2:44][CH2:45][CH3:46])[CH2:31][CH2:30][N:24]3[CH2:25][CH2:26][N:27]([CH2:3][C:4]4[CH:13]=[CH:12][C:11]([OH:14])=[C:10]5[C:5]=4[CH:6]=[CH:7][CH:8]=[N:9]5)[CH2:28][CH2:29]3)[CH2:42]2)=[CH:37][CH:38]=1
Reactant: Oc1ccc(CCl)c2cccnc12
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCN(CCN1CCN(Cc2ccc(O)c3ncccc23)CC1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
To a mixture of 5-chloromethyl-8-quinolinol hydrochloride, 11 (0.20 g, 0.86 mmol) and diisopropylethylamine (0.3 mL, 1.73 mmol, 2.2 equiv) in 25 mL CHCl3 at 0° C. was added 9a (0.25 g, 0.78 mmol). The mixture was stirred for 24 h at room temperature. CHCl3 (100 mL) was added and the solution obtained was washed with 10% NaHCO3, brine, and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was made hydrochloride salt and crystallized from ethanol to yield 12a as yellow solid (0.28 g, 57.3%). 1H NMR of HCl salt (400 MHz, DMSO-d6) δ ppm 0.88-0.99 (m, 3H), 1.79-1.81 (bs, 4H), 2.298 (bs, 1H), 2.476-2.48 (m, 2H), 2.74 (s, 2H), 2.96-3.02 (t, 1H, J=12 Hz), 3.122 (bs, 3H), 3.34-3.65 (m, 12H), 6.51-6.56 (m, 2H), 6.86-6.88 (d, 1H, J=8 Hz), 7.50-7.52 (d, 1H, J=8 Hz), 7.997-8.008 (m, 2H); 9.06-9.07 (d, 1H, J=4 Hz); 9.49-9.51 (d, 1H, J=8 Hz). The hydrochloride salt mp 242-242° C. Analysis calculated for (C29H40.6N4O3.3, 4HCl) C, H, N.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6](=O)[CH2:7][CH2:8][C:9](=O)[CH3:10].[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17].C(OCC)(=O)C>C1(C)C=CC=CC=1.O.O.O.C([O-])(=O)C.[Na+]>[Br:13][C:14]1[CH:15]=[C:16]([N:17]2[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]2[CH3:5])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: CC(=O)CCC(C)=O
Reactant: COc1ccc(N)cc1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-n2c(C)ccc2C)cc1Br
Temperature: 25 °C
Yield: 67 %

Procedure:
Using the general procedure described by S. P. Bruekelman, S. E. Leach, G. D. Meakins, and M. D. Tirel (J. Chem. Soc., Perkin Trans. 1, 1984, 2801-2807), acetic acid (0.50 mL, 0.52 g, 8.7 mmol) and sodium acetate trihydrate (70 mg, 0.51 mmol) were added to a solution of 2,5-hexanedione (8.0 mL, 7.8 g, 68 mmol) and 3-bromo-4-methoxyaniline (see Y. -Y. Lui, M. Minich, J. Labelled Compounds and Radiopharmaceuticals, 1981, 18, 791-797) in 40 mL of toluene. The mixture was heated to reflux for 2 h in a flask connected to a Dean-Stark trap. After cooling the mixture to room temperature, ethyl acetate (20 mL) was added and the solution was washed with 25 mL. each of water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried (sodium sulfate), decanted, and evaporated to give brown crystals. Recrystallization from 20 mL of warm hexane cooled to 0° C. yielded 8.17 g of tan crystals (67% yield). 1H NMR (400 MHz, CDCl3): δ 7.42 (d, 1H, J=2 Hz), 7.14 (dd, 1H, J=9, 2 Hz), 6.96 (d, 1H, J=9 Hz), 5.87 (s, 2H), 3.95 (s, 3H), 2.02 (s, 6H). Mass spectrum (NH3CI): m/e=280 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]#[N:18])=[N:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][OH:22].CCN(CC)CC>CCO>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17](=[NH:18])[NH:21][OH:22])=[N:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)OC(=O)Cn1nc(C#N)c2cccnc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1nc(C(=N)NO)c2cccnc21
Temperature: 65 °C

Procedure:
A mixture of (3-cyano-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid tert-butyl ester, hydroxylamine hydrochloride (8.28 g) and Et3N (22.6 mL) in EtOH (120 mL) was heated over night under N2 at 65° C. The resultant mixture was cooled to room temperature, filtered and the collected solid was washed with H2O (100 mL) and Et2O (50 mL×2) to afforded [3-(N-hydroxycarbamimidoyl)-pyrazolo[3,4-b]pyridin-1-yl]-acetic acid tert-butyl ester.