Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+:10]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[CH:4][CH:3]=1.[Na+:10]
Reactant: Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc([O-])cc1

Procedure:
4-methylphenol (3.73 g, 0.035 mol) is dissolved in 10 mL THF and added dropwise to a suspension of sodium hydride (0.83 g, 0.035 mol) in 60 mL THF to produce sodium 4-methyl phenoxide. HOC6H4SO2NNaSO2CF3 (4.06 g, 0.012 mol) is dissolved in 50 mL THF and added dropwise to a suspension of sodium hydride (0.30 g, 0.012 mol) and tetra(n-butyl)ammonium bromide (0.4 g) in 50 mL THF and stirred for 16 hours to produce a sodium phenoxide solution of the sulfonimide NaOC6H4SO2NNaSO2CF3.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][NH:4][N:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][C:7]([C:6]2[C:2]([CH3:1])=[N:3][NH:4][CH:5]=2)=[O:9])[CH2:12][CH2:11]1
Reactant: Cc1n[nH]cc1C(=O)O
Reactant: NC1CC1
Product: Cc1n[nH]cc1C(=O)NC1CC1
Yield: 93.8 %

Procedure:
Following the same procedure in Example 29 (Step B and C in Method B), using 3-methyl-1H-pyrazole-4-carboxylic acid (252 mg, 2.0 mmol) and cyclopropylamine (285 mg, 5.0 mmol), provided the desired crude compound (310 mg, 94%), which was used in Step A directly.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)=[CH:2]1>CO.[Pd]>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(-c2ccoc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2ccoc2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
277 mg 4-furan-3-yl-1-nitrobenzene are dissolved in 40 ml of methanol and combined with 200 mg palladium/C. The suspension is shaken at 25° C. for 60 h under a H2 pressure of 5 bar. Then the solvent is eliminated in vacuo. The crude mixture is purified by column chromatography. The carrier material used is silica gel and the mobile phase used is a solvent mixture of cyclohexane/ethyl acetate 50/50. The suitable fractions are freed from the solvent in vacuo.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:40])/[C:10](/[CH2:28][O:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:11]/[C:12]2[CH:27]=[CH:26][C:15]([C:16]([NH:18][O:19]C3CCCCO3)=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:40])/[C:10](/[CH2:28][O:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:18][OH:19])=[O:17])=[CH:26][CH:27]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(NC(=O)/C(=C/c2ccc(C(=O)NOC3CCCCO3)cc2)COc2cccc3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN1CCC(NC(=O)/C(=C/c2ccc(C(=O)NO)cc2)COc2cccc3ccccc23)CC1
Temperature: 0 °C
Yield: 88.8 %

Procedure:
(E)-4-(3-(1-Methylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxoprop-1-enyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide obtained in Example (1-1-3) (333 mg, 0.61 mM) was dissolved in methanol (5 ml) and the resulting solution was cooled to 0° C. To the resulting solution, trifluoroacetic acid (0.23 ml, 5 eq.) was slowly added, and the resultant was reacted at room temperature for 18 hrs. After the completion of reaction, the solvent was removed under reduced pressure. The residue thus obtained was purified with a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to obtain 250 mg of the title compound as a white solid (yield 89%).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:14](=S)=[S:15]>C(O)CCC>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:3][N:4]1[CH2:5][CH2:6][NH:7][C:14]1=[S:15]
Reactant: NCCNCC(O)c1ccccn1
Reactant: S=C=S
Solvent: CCCCO
Product: OC(CN1CCNC1=S)c1ccccn1
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
N-[2-hydroxy-2-(2-pyridyl)ethyl]ethylene-diamine (17 g.) is dissolved in n-butanol (170 cc.) and carbon disulphide (21.4 g.) is added to the solution. During the addition, the temperature rises from 20° to 34° C. The mixture is stirred for 15 minutes and is then heated under reflux for 30 minutes. After concentration under reduced pressure (20 mm.Hg), the residue is taken up in ethyl acetate (100 cc.). The product which crystallises is filtered off and then dried. 1-[2-Hydroxy-2-(2-pyridyl)ethyl]imidazolidine-2-thione (16 g.), which melts at 120° C., is thus obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(C(O[NH:30][C@H:31]([C:36](O)=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])C1C=CC=CC=1)(O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]([C:36](=[O:37])[C@H:31]([CH2:32][CH:33]([CH3:35])[CH3:34])[NH2:30])[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C[C@H](NOC(C(=O)O)c1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Product: CC(C)C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Yield: 34.3 %

Procedure:
By reacting 7 g of N-(indan-2-yl)glycine tert-butyl ester with 8.5 g of N-(carboxybenzoxy)-L-leucine and treating the reaction mixture as in Reference Example 5, there is obtained 3.5 g of L-leucyl-N-(indan-2-yl)glycine tert-butyl ester as colorless amorphous powder.
Reaction SMILES: O.I([O-])(=O)(=O)=O.[Na+].[CH2:8]([O:15][CH2:16][CH:17]([OH:20])CO)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[CH2:8]([O:15][CH2:16][CH:17]=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC(O)COCc1ccccc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=CCOCc1ccccc1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Into a suspension of water (1055 g) and sodium periodate (406 g) was dropped 3-benzyloxy-1,2-propanediol (366 g, 2.0 mol) at 20 to 25° C. over a period of 21 hours, and the mixture was stirred for 2 hours. Ethyl acetate (495 ml) was added, and the mixture was filtrated and washed. The aqueous layer was extracted with ethyl acetate (825 ml) again, and the organic layers were combined, and washed with a 10% sodium thiosulfate aqueous solution (363 g). The organic layer was treated with phosphoric acid to regulate pH to around 7, then, washed twice with 5% saline (660 g) and dehydrated over anhydrous magnesium sulfate (100 g). Magnesium sulfate was filtrated off, and hydroquinone (1.3 g) was added, the solvent was distilled off, to obtain a title compound (259 g, yield 85.9%).
Reaction SMILES: [BH4-].[Na+].[C:3]([CH:7]1[C:13](=[O:14])[CH2:12][CH:11]2[O:15][CH:8]1[CH2:9][CH2:10]2)([O:5][CH3:6])=[O:4]>CO>[C:3]([CH:7]1[CH:13]([OH:14])[CH2:12][CH:11]2[O:15][CH:8]1[CH2:9][CH2:10]2)([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C1C(=O)CC2CCC1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(O)CC2CCC1O2
Reaction time: 8 h

Procedure:
NaBH4 (2.56 g, 67.7 mmol) was added to a solution of 2-carbomethoxy-8-oxabicyclo(3.2.1)octan-3-one, 3, (5.12 g, 27.8 mmol) in MeOH (100 mL) at -78° C. The reaction mixture was left at room temperature overnight. The solution was concentrated to dryness. The residue was dissolved in water (50 mL), and extracted with CH2Cl2 (100, 2×50 mL). The combined dried (MgSO4) extracts were concentrated to dryness (yield: 3.9 g). By repeated flash column chromatography four isomers were obtained from the residue (2.9 g). The major isomer was 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane (1.0 g, 26%). Some of the other isomers were isolated to be used in the following reactions but there were still mixed fractions. Other pure isomers obtained: 2β-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane (28 mg), 2β-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane (305 mg) and 2α-carbomethoxy-3β-hydroxy-8-oxabicyclo(3.2.1)octane (84 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[N:25]1([C:7]2[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:20])[F:21])[N:4]=[C:3]([C:2]([F:1])([F:24])[F:23])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1N1CCCC1

Procedure:
This compound was prepared as described in Example 37: 6.0 g (0.016 mol) of product of Example 27, 2.6 ml (0.032 mol) of pyrrolidine in 30 ml of DMF were reacted affording a brown solid which was recrystallized in hot hexane giving 5.18 g (78.1%) of product as a tan solid; mp 68.5°-70° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[C:2]2[CH:3]=[CH:4][CH:8]=[CH:9][CH:10]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1cccc(Br)c1

Procedure:
m-Bromobenzoyl chloride is reacted with benzene to form m-bromobenzophenone.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:29]2=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]2[CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:7]([C:14]1[CH:19]=[CH:18][C:17]([C:24]2[C:29]3=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]3[CH:27]=[CH:26][CH:25]=2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S1(=O)CCN2C=CC=C(Br)C2=N1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of sodium carbonate (121 mg), tetrakis(triphenylphosphine)palladium(0) (13.18 mg), (4-phenoxyphenyl)boronic acid (98 mg) and 9-bromo-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg) in DMF (dry) (10 mL) and water (2 ml) was stirred at 80° C. under N2 overnight. NH silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (116 mg) as a white solid. The solid was crystallized from DMSO (1.5 mL)-EtOH (3 mL) to give the title compound (90.7 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][OH:20])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29](OCC)=[O:30]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[NH:18][C:29](=[O:30])[O:20][N:19]=4)=[CH:16][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc2[nH]c(-c3ccc(F)cc3)nc2c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2ccc3[nH]c(-c4ccc(F)cc4)nc3c2)no1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
2-(4-Fluoro-phenyl)-N-hydroxy-1H-benzoimidazole-5-carboxamidine (501.9 mg, 1.86 mmol, example 3), triethylamine (645 μl, 4.63 mmol) and ethyl chloroformate (229 μl, 2.4 mmol) was dissolved in 35 ml of DMF. The mixture was heated to 80° C. for 7 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 118 mg (21%) of the desired product. MS: m/e=297.05 (M+H+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[O:44]1[CH:48]=[CH:47][CH:46]=[C:45]1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:45]4[O:44][CH:48]=[CH:47][CH:46]=4)[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccco1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3c2ccco2)cc1
Reaction time: 20 h
Yield: 67.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 2-furaldehyde (0.2 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 20 hours. To the reaction solution were added 2-furaldehyde (0.2 g) and sodium triacetoxyborohydride (0.22 g), and the mixture was further stirred for 3 days. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-furyl)-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 91) (150.0 mg) as yellow crystals.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH3:24][CH2:25][CH2:26][CH:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:31][CH:27]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:25][CH3:24])=[O:3])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-heptylamine (50.9 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-heptyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (36.4 mg).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.8 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-fluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.5 mg, 53.9% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.65 (m, 1H), 7.41 (s, 1H), 7.40–7.10 (m, 5H), 7.05 (m, 2H), 6.97 (apparent d, 1H, J=8.7 Hz), 6.86 (m, 2H), 6.79 (apparent dt, 1H, J=2.4, 7.9 Hz), 5.31 (apparent dd, 1H, J=4.5, 8.0 Hz), 3.39 (m, 2H), 2.97 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.5 Hz), 2.3–2.1 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 475.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]3[OH:28])=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30].[CH2:33]1COCC1.[H-].[Na+].IC>CO.O>[F:32][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH:16]3[O:28][CH3:33])=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30]
Reactant: CN1c2nc(C3CCN(C(=O)OC(C)(C)C)CC3O)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: O
Product: COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 25 °C

Procedure:
To a flask was added tert-butyl 4-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-3-hydroxypiperidine-1-carboxylate (27-1) (54 mg, 0.114 mmol), & anhydrous THF (2.5 mL). The reaction mixture was cooled to 0 C while stirring under an atmosphere of nitrogen, then added sodium hydride (60% by wt in mineral oil) (5.92 mg, 0.148 mmol) in one portion. Reaction mixture was continued to stir at 0 C for 10 minutes, then added iodomethane (8.54 μl, 0.137 mmol) and permitted to warm to room temperature. After 1 hour reaction mixture was diluted with MeOH & drops of water, then purified by reverse-phase chromatography (10-100% CH3CN:0.1% TFA in H2O) to yield tert-Butyl 4-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazole-[3,4-b]pyridin-5-yl}-3-methoxypiperidine-1-carboxylate (28-1). HRMS (M+H)+: observed=489.1983, calculated=489.1978.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:3]=1[O:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:25]=O.[BH4-].[Na+]>CO>[CH3:25][N:8]1[CH2:7][CH2:6][C:5]([O:4][C:3]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:2]=2[F:1])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9]1
Reactant: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 50 ml of methanol, was added 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine and 15 ml of a 37% aqueous formaldehyde solution. After stirring at 70° C. for two hours, the mixture was cooled, and treated (portionwise) with 2.5 g of sodium borohydride over a period of five minutes. After stirring at ambient temperature for two hours, the reaction mixture was evaporated to a semi-solid. The semi-solid was stirred with 50 ml water, then extracted with ethyl acetate. The organic layer was washed with water, followed by a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvent yielded a residue which was purified by means of a high pressure liquid chromatography (silica gel, elution with 5% methanol/dichloromethane). The desired fractions were combined, then evaporated to afford 1-methyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine as an oil. The oil was dissolved in isopropanol, and acidified to pH 1with etheral-oxalic acid. The resultant precipitate was collected and dried to give 2.5 g (47%), of 1-methyl-4-(2,3,4,5,6-pentaflurophenoxy)-4-phenylpiperidine oxalate, m.p. 152°-154° C. (dec).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:14])=[CH:12][S:13][C:7]2=[N:6][C:5]=1[CH3:15].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[C:11]([CH3:14])=[CH:12][S:13][C:7]4=[N:6][C:5]=3[CH3:15])[CH2:17][CH2:18]2)=[CH:23]1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCCl
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(c2c[nH]c3ccccc23)CC1

Procedure:
A mixture of 3.75 parts of 6-(2-chloroethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one, 3 parts of 3-(4-piperidinyl)-1H-indole, 10 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone was stirred and refluxed for 20 hours using a water-separator. The reaction mixture was filtered hot over Hyflo and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol, yielding 3.25 parts of 6-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 274.7° C. (compound 11).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[Cl:31][C:32]1[C:33]([CH:54]=O)=[C:34]2[C:40]([C:41]([OH:43])=[O:42])=[CH:39][N:38]([S:44]([C:47]3[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[C:35]2=[N:36][CH:37]=1>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[C@H:16]([NH:15][CH2:54][C:33]1[C:32]([Cl:31])=[CH:37][N:36]=[C:35]2[N:38]([S:44]([C:47]3[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[CH:39]=[C:40]([C:41]([OH:43])=[O:42])[C:34]=12)[C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[C@@H](N)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(C=O)c(Cl)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@@H](C(=O)OCc4ccccc4)C(C)(C)C)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 10 mL round bottom flask was added sodium triacetoxyborohydride (86 mg, 0.407 mmol), (R)-benzyl 2-amino-3,3-dimethylbutanoate (130 mg, 0.407 mmol) and DCM (2 mL). The mixture was stirred at room temperature for 10 min and then cooled to 0° C. 5-Chloro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (130 mg, 0.271 mmol) was added and the reaction mixture was stirred at 0° C. for 20 min to afford the title compound. [M+H] calc'd for C29H30ClN3O6S, 584; found, 584.0.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:10]=1[NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>O1CCCC1.[Pd]>[Si:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:10]=1[NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2-{[tert-butyl(dimethyl)silyl]oxy}-6-nitroaniline (8.5 g, 31.7 mmol) in tetrahydrofuran (100 mL) is added a 10% palladium on carbon (50% wet, 8.2 g), and the mixture is vigorously stirred under hydrogen atmosphere at room temperature for one hour. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (ethyl acetate/n-hexane=1/5, 1/3 and 1/1) to give the title compound as brown oil (6.95 g, yield: 92%).