Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.CO[C:4]1[O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1.[OH-:15].[K+].Cl>O.C(O)(=O)C>[OH:15][C:12]1[CH:13]=[CH:14][C:6]2[O:5][CH2:4][CH2:9][C:8](=[O:10])[C:7]=2[CH:11]=1
Reactant: COc1cc(=O)c2ccccc2o1
Reactant: [OH-]
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCOc2ccc(O)cc21
Yield: 81.2 %

Procedure:
Glacial acetic acid and HBr (>40%) each 20 ml are successively added to methoxy benzopyran-4-one 2.9 g (0.0163 mol), stirred and refluxed for 1 h, and then the reactant liquor is modulated pH for 10-11 by KOH, the water layer is modulated pH for 2-3 by concentrated hydrochloric acid, and then extracted by ethyl acetate; the organic layers are combined and dried over anhydrous Na2SO4, cooled to precipitate black solid, and recrystallized by ethyl acetate, to obtain bright yellow crystal 2.17 g, m.p.: 142-144° C., yield: 81.2%.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[NH:16][CH2:15]2.BrC1C=CC=C2C=1CNC2=[O:32]>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[CH2:17][NH:16][C:15]2=[O:32]
Reactant: COc1ccc(-c2ccc3c(c2)CNC3=O)c(O)c1OC
Reactant: O=C1NCc2c(Br)cccc21
Product: COc1ccc(-c2cccc3c2CNC3=O)c(O)c1OC

Procedure:
4-(2-Hydroxy-3,4-dimethoxy-phenyl)isoindolin-1-one is synthesized following the same procedure as the one described for the synthesis of Compound 307 using 4-bromo-2,3-dihydro-1H-isoindol-1-one as starting material.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26]Cl)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1.C(O)C.[OH-].[Na+]>O>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][SH:3])[CH2:20][CH2:19]2)=[CH:10][CH:9]=1
Reactant: ClCCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: SCCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Yield: 30.2 %

Procedure:
The procedure described in Example 1(b) was followed, using 1.0 g of thiourea, 4.0 g of 1-[4-(4-chlorophenyl)butyl]-4-(3-chloropropyl)piperazine dihydrochloride and 50 ml of reagent ethanol. The hydrolysis was effected with 4.0 g of sodium hydroxide in 50 ml of water. Work-up of the free base, as described above followed by purification on a silica gel column (methylene chloride:methanol, 97:3), precipitation as the hydrochloride salt and recrystallization from reagent ethanol, gave 0.6 g (16% of theory) of 3-{4-[4-(4-chlorophenyl)butyl]piperazin-1-yl}propanethiol dihydrochloride as a white crystalline solid, M.p. 254°-259° C.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]1[C:13]([Cl:14])=[N:12][C:11]([C:15]#[N:16])=[C:10]([C:17]#[N:18])[N:9]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([SH:26])[CH:21]=1>ClCCCl>[Cl:14][C:13]1[N:12]=[C:11]([C:15]#[N:16])[C:10]([C:17]#[N:18])=[N:9][C:8]=1[S:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=1
Reactant: Cc1cccc(S)c1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1cccc(Sc2nc(C#N)c(C#N)nc2Cl)c1
Reaction time: 0.25 h

Procedure:
Pyridine (2.37 g) was mixed rapidly with a solution of 6.00 g of 2,3-dichloro-5,6-dicyanopyrazine in 240 ml of 1,2-dichloroethane. After 15 minutes the well stirred mixture, protected from moisture, was cooled to -30° and 3.72 g of m-thiocresol was added in one portion. The temperature was maintained at -30° for 0.5 hour and then was allowed to return to ambient over the course of 2 hours. The mixture was then washed with water to remove pyridine hydrochloride, dried over MgSO4, and concentrated on a rotary evaporator to a solid residue. The residue was purified by the technique of dry column chromatography using silica gel adsorbent and 1-chlorobutane as solvent and eluent. The yield of pure product was 6.9 g, mp 117°-119°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[O:24]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]([C:35](O)=[O:36])[C:25]1=[O:26].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:24]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]([C:35]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:36])[C:25]1=[O:26]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)c1cc2ccccc2oc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)c1cc2ccccc2oc1=O
Yield: 72.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), coumarin-3-carboxylic acid (2.3 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (2.8 g, 71%) as crystals.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>O1CCCC1O>[C:1]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NCCc1ccc(O)cc1
Reactant: CCCCCCCCC(=O)Cl
Agent: Cl
Agent: OC1CCCO1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-nonanoyl tyramine was prepared by adding dropwise about 2.74 moles of nonanoyl chloride to a cooled solution comprising about 1.0 g tyramine and about 2.03 ml of triethylamine in 35 ml of tetrahydrofuranol (THF). The reaction mixture was stirred at room temperature for 48 hours. It was then poured into about 70 ml of 10% HCl solution and the mixture extracted with ethyl acetate (3×50 ml). The ethyl acetate layer was separated, dried (MgSO4) and concentrated under reduced pressure to give a crude N-nonanoyl tyramine product. The product was purified by chromatography on a silica gel column eluted with methylene chloride/ethyl acetate (30:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[NH4+].[OH-:28]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:28])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: [OH-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole (0.80 g, 2.2 mmol) [See Ex 17 above] in glacial acetic acid (15 mL) was added a solution of K2S2O8 (0.72 g, 2.6 mmol) in H2O (20 mL). Additional glacial acetic acid (15 mL) was added to ensure homogeneity, and the resulting solution was stirred at rt for 18 h. The mixture was then poured into H2O, and the pH was adjusted to neutral by the addition of conc. NH4OH. The solid which formed was collected by filtration to afford the title com-pound (0.65 g, 78%) as a tan solid, which was recrystallized from MeOH: mp 250-252° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH2:22])O1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]2[C:3](=[C:4]([NH2:5])[N:22]=[C:21]3[C:20]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:6]=1
Reactant: COc1ccc(Br)c(C#N)c1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c(N)nc1ccccc12
Yield: 68 %

Procedure:
2-Bromo-5-methoxybenzonitrile (1.32 g, 6.23 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.36 g, 6.23 mmol), bis(triphenylphosphine)palladiumdichloride (0.437 g, 0.623 mmol) and potassium phosphate monohydrate (4.30 g, 18.68 mmol) were added to toluene (30 mL) and water (3 mL). The reaction mixture was degassed with bubbled nitrogen gas for 30 minutes before being refluxed under nitrogen for 15 h. After cooling, the reaction mixture was filtered through Celite® and the organic layer was extracted with ethyl acetate. After removal of the solvents, the crude material was triturated with 40 mL of DCM followed by 50 mL of hexanes to give 8-methoxyphenanthridin-6-amine (0.95 g, 68%) as a light yellow solid. The product was confirmed by GC/MS and NMR.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[I:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[I:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc(I)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(I)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
2-Chloro-5-nitro-pyridine (60 grams, 0.38 mol) and 4-iodo-phenol (83.5 grams, 0.38 mol), 50% aqueous sodium hydroxide (475 mL) and toluene (475 mL) were added to a flask and stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and concentrated hydrochloric acid was added to adjust the pH to two. The aqueous layer was separated from the toluene layer and extracted with diethyl ether (3×400 mL). The diethyl ether and toluene solution were combined and washed with 1M sodium hydroxide (2×300 mL). The organic layer was concentrated under vacuum to yield 96.5 grams of crude product. This material was recrystallized from hexanes and ethyl acetate to provide 85.3 grams (66%) of the title compound. MS m/z: ESI+ 343.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:15]2[C:19](=[O:20])[CH:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:33][CH:32]=4)=[CH:24][CH:23]=3)[O:17][C:16]2=[O:42])C=CC=CC=1>ClCCl>[CH3:41][S:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([CH2:21][CH:18]3[O:17][C:16](=[O:42])[NH:15][C:19]3=[O:20])=[CH:23][CH:24]=2)=[CH:36][CH:35]=1)(=[O:39])=[O:40]
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC3OC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC3OC(=O)NC3=O)cc2)cc1
Yield: 88.2 %

Procedure:
1 ml trifluoroacetic acid was added to a solution of 0.214 g (0.33 mmole) 3-triphenylmethyl-5-([4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl]methyl)oxazolidine-2,4-dione in 10 ml dichloromethane. After stirring for 45 minutes at room temperature 20 ml more of dichloromethane was added, the reaction mixure was washed twice with water, dried (sodium sulfate) and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica gel using heptane:ethyl acetate:acetic acid (10:10:1) as eluent to give 0.118 g (yield 88%) of 5-([4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl]methyl)oxazolidine-2,4-dione.
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C[S-:25].[Na+]>CN(C=O)C>[NH2:22][C:19]1[C:20]2[N:21]=[C:13]([C:4]3[N:3]([CH3:23])[C:2]([SH:25])=[N:6][C:5]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:14][C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: C[S-]
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(S)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
2-(2-Bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (80 mg) and sodium thiomethoxide (58 mg) in DMF (5 mL) were heated at 80° C. for 2 hours under an inert atmosphere. After cooling to ambient temperature the reaction mixture was concentrated in vacuo, then dissolved in 2M NaOH (5 mL) and washed with DCM (5 mL). The aqueous layer was acidified to pH 4 with 2M HCl, the solid precipitate washed with water (5 mL) then diethyl ether (10 mL) and dried under high vacuum to give the title compound as a yellow solid (44 mg, 65%);
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[S:13][C:14]([C:21](Cl)=[O:22])=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:11][C:12]1[S:13][C:14]([C:21]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=1
Reactant: O=C(Cl)c1sc(Cl)nc1C(F)(F)F
Reactant: OCCOc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCCOc1ccccc1)c1sc(Cl)nc1C(F)(F)F

Procedure:
6.3 g (0.045 mol) of 2-phenoxyethanol are added slowly while stirring to a solution of 11 g (0.44 mol) of 2-chloro-5-chlorcarbonyl-4-trifluoromethyl-thiazole in 100 ml of absolute toluene. The solution is then cooled to 0°-5° and 3.6 g (0.045 mol) of triethylamine are added dropwise while stirring. Triethylamine-hydrochloride precipitates from the reaction mixture. After everything is added, the suspension is stirred for 20 hours at room temperature and then poured onto ice-water. The organic phase is separated, dried over sodium sulfate and concentrated in a rotatory evaporator. The residue cristallizes. In order to purify it, the crystals are suspended in petrol-ether, filtered and dried. In this manner 8.7 g (57% of the theoreticl yield) of the title compound are obtained, m.p. 70°-72°.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[N:13][C:12]2[N:11]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:26][CH2:27][CH2:28][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:36](C=O)C>C(Cl)Cl>[CH3:1][C:2]1[CH:14]=[N:13][C:12]2[N:11]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH2:36])=[O:24])=[N:21][CH:22]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:26][CH2:27][CH2:28][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(=O)O)nc2)CCN2CCCC12
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(N)=O)nc2)CCN2CCCC12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-[2-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza-cyclopenta[c]fluoren-6-yl)-ethyl]-pyridine-2-carboxylic acid (400 mg, 1.063 mmol) was dissolved in 15 mL DCM and cooled at 0° C. Oxalyl chloride (669 mg, 5.315 mmol) and catalytic amount of DMF was added and the reaction mixture was stirred at RT for 1 h. The reaction was monitored by LCMS. The reaction mixture was concentrated and aqueous ammonia was added at 0° C. The reaction mixture was warmed to RT and stirred for 1 h. The reaction mixture was concentrated to obtain the crude product that was purified by reverse phase chromatography to obtain 2.5 mg of 5-[2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza-cyclopenta[c]fluoren-6-yl)-ethyl]-pyridine-2-carboxylic acid amide as the TFA salt. 1H NMR TFA:—CD3OD: 8.2 (s, 2H), 7.95 (d, 1H), 7.8 (s, 1H), 7.6 (d, 1H), 5.0 (t, 1H), 4.6 (m, 2H), 3.62 (m, 1H), 3.5 (m, 2H), 3.3 (m, 3H), 2.8 (d, 1H), 2.63 (m, 2H), 2.4 (s, 3H), 2.2 (m, 2H), 2.1 (m, 1H). Separation by chiral HPLC provides enantiomers II-243a-b.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].C([O-])([O-])=O.[K+].[K+].Br[CH:22]([CH3:24])[CH3:23]>CN(C=O)C.CCOC(C)=O>[CH:22]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14])([CH3:24])[CH3:23]
Reactant: CC(C)Br
Reactant: COCc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1cc(C(=O)OC)ccc1OC(C)C
Temperature: 90 °C
Yield: 98.4 %

Procedure:
Methyl 4-hydroxy-3-(methoxymethyl)benzoate (9.50 g; 48.42 mmol; 1 eq.) was dissolved in DMF (142.50 mL). Then K2CO3 (26.77 g; 193.68 mmol; 4 eq.) and 2-bromopropane (18.18 mL; 193.68 mmol; 4 eq.) were added to the reaction mixture. It was heated to 90° C. for 3 hours. The reaction mixture was cooled to RT and diluted with EtOAc. It was washed with water (3×), brine, dried over MgSO4 and concentrated affording the title compound as a yellow oil (11.35 g, 98%). 1H NMR (DMSO-d6, 300 MHz) δ 7.95-7.84 (m, 2H), 7.13-7.11 (d, J=8.63 Hz, 1H), 4.81-4.69 (sept, J=6.07 Hz, 1H), 4.39 (s, 2H), 3.81 (s, 3H), 3.36 (s, 3H), 1.31-1.29 (d, J=6.01 Hz, 6H). LC/MS (Method B): 239.2 (M+H)+. HPLC (Method A) Rt 4.25 min (Purity: 95.8%).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].N1C=CC=CC=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[C:14]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(N)C(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC(C)(C)C(=O)O
Reaction time: 1 h
Yield: 63724.3 %

Procedure:
A suspension of 41.2 g (0.4 mmol) of alpha -aminoisobutyric acid, 100 ml pyridine, and 100 ml water is stirred at 0°-5° C. and 45.0 ml (0.45 mmol) of acetic anhydride is added over a period of 30 min. Solution is observed after 1 hr and the mixture is allowed to stand at room temperature for 10 hrs. The reaction mixture is diluted with 500 ml water and evaporated in vacuo. The residue is then recrystallized from water, dried in vacuo affording 37.0 g alpha-acetamidoisobutyric acid.
Reaction SMILES: [Si]([O:8][CH:9]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[CH2:10][CH2:11][CH:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:13]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH:9]([OH:8])[CH2:10][CH2:11][CH:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:13]2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.5 g of 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (3) were dissolved in 65 ml of tetrahydrofuran. 0.74 ml of acetic acid and 8.03 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran were added and the mixture was stirred at room temperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoride solution were then added, and the mixture was stirred at reflux temperature for another 3 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using n-heptane/ethyl acetate 2/1. This produced 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (4) of molecular weight 430.48 (C26H23FN2O3); MS (ESI): 431.24 (M+H+).
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=1)(=[O:5])=[O:4].[ClH:24]>CN(C=O)C.O.[Pd]=O>[ClH:24].[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 20.5 h

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]-ethenesulphonamide (10 kg) and 10% palladium oxide on charcoal (10 kg, 50% wet paste, added as two charges) in DMF (50 L), water (35 L) and 2N hydrochloric acid (15.75 L) was hydrogenated at atmospheric pressure over 20.5 h. The catalyst was removed by filtration. The filter cake was washed with water (40 L). The filtrate was concentrated in vacuo to approximately 30 L and cooled to 18°. Ethyl acetate (70 L) was added over 1 h and the resulting suspension cooled to 5° and aged for 1 h. The product was collected by filtration, washed with ethyl acetate (20 L) and dried in vacuo at 40°-50° overnight (8.87 kg, 79.0% of theory). A portion (0.2 kg) of the solid was recrystallised from hot IMS/water (4:1) (1 L) and obtained as fine, off-white crystals (0.143 kg), 71.7% of theory).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C>[C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][C@@H:11]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
A 1 L 3-neck round bottom flask equipped with a mechanical stirrer and addition funnel was charged with 252B (14.7 g, 39 mmol) and acetonitrile (200 mL) and acetic acid (100 mL). The solution was cooled to 0° C. and Na(OAc)3BH (33.3 g, 157 mmol) was added in three portions over 2 hours. The reaction was stirred for two hours at this temperature after the final addition. The mixture was then cooled to −10° C. and slowly quenched by addition of 1 N NaOH (100 mL), 4 N NaOH (100 mL), 6 N NaOH (100 mL) followed by 50% NaOH (50 mL). The reaction was warmed to room temperature and the layers were separated. The aqueous layer was extracted with CH2Cl22 (2×250 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (10% to 30% EtOAc/hexane gradient) on silica gel afforded 6.0 g (yield: 41%) of Compound 252C.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[C:12]2[N:13]=[C:14]([NH:23][N:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=1)C1C=CC=CC=1.[H][H]>CO.C(Cl)Cl.[Pd]>[OH:8][C:9]1[CH:33]=[C:12]2[N:13]=[C:14]([NH:23][N:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(OCc4ccccc4)cc3n2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(O)cc3n2)c1
Yield: 68.9 %

Procedure:
There was dissolved N-(2-benzyloxy-7-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidin-5-yl)-N′-(3-methyl-benzylidene)-hydrazine (50.7 mg, 0.115 mM) in a mixed solvent of methanol/methylene chloride (1:2) (3 mL), then 10% palladium on carbon (10.1 mg) was added to the solution and the mixture was stirred for 3 hours in a hydrogen gas atmosphere. The reaction liquid was filtered, the solvent was distilled off, and the resulting residue was purified by the reversed phase HPLC and then subjected to a desalting operation to thus give the title compound (27.8 mg, yield: 69%).