Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])=[CH:6][CH:5]=1)([O-])=O>Cl.C(OCC)(=O)C.[OH-].[Na+]>[NH2:1][C:4]1[S:8][C:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])=[CH:6][CH:5]=1
Reactant: C=CCOC(=O)c1ccc([N+](=O)[O-])s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1ccc(N)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.6 %

Procedure:
To a solution of allyl 5-nitro-2-thiophenecarboxylate (3.2 g, 15 mmol) in concentrated hydrogen chloride (35 ml) were added under cooling SnCl2.H2O (10.1 g, 45 mmol). The mixture was stirred for 3.5 hours at ambient temperature, diluted with ethyl acetate and basified to pH 10 with 5N NaOH. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (3:7) to give the title compound as a yellow oil (1.94 g, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[CH:18])=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:20])([CH3:19])[CH2:8][CH:7]=1)=[O:5])[CH3:2].[CH3:21][O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[C:18][C:28]3[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:32])=[CH:26][CH:27]=3)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:19])([CH3:20])[CH2:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc2c(cc1C)C(C(=O)OCC)=CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)OC)cc3)c(C)cc21

Procedure:
Following General Procedure B and using 6-ethynyl-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 185, 0.126 g, 0.47 mmol), 4-iodo phenyl acetic acid methyl ester (0.13 g, 0.47 mmol), triethyl amine (2 mL), copper(I)iodide (0.029 g, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10-12% ethyl acetate in hexane as the eluent, the title compound was obtained as a viscous oil (0.144 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:37]([CH2:39][NH2:40])[OH:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:40][CH2:39][CH2:37][OH:38])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (d, J=5.05 Hz, 4 H), 1.60-1.75 (m, 4 H), 2.41 (d, J=11.16 Hz, 2 H), 3.34-3.42 (m, 4 H), 3.45 (t, J=5.58 Hz, 2 H), 3.53-3.63 (m, 2 H), 4.16-4.24 (m, 4 H), 4.93 (t, J=4.21 Hz, 1 H), 7.11-7.18 (m, 2 H), 7.37-7.45 (m, 2 H), 8.00 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.41 (t, J=6.00 Hz, 1 H), 17.20 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [S:1]1[C:5]([C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7])=[CH:4][CH:3]=[N:2]1.Cl>CO>[S:1]1[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccns1
Agent: Cl
Solvent: CO
Product: NNC(=O)c1ccns1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,1-dimethylethyl 2-(5-isothiazolylcarbonyl)hydrazinecarboxylate (I83) (480 mg, 1.973 mmol) in HCl (2 ml, 8.00 mmol) (4M in 1,4-dioxan) was stirred at room temperature under argon for 18 hours (overnight). After this time, the mixture was concentrated under reduced pressure to give a pale yellow coloured solid. The solid was dissolved in MeOH and passed through and SCX cartridge, eluting initially with MeOH and then with 2M NH3 in MeOH. The NH3/MeOH fractions were concentrated under reduced pressure to give a yellow coloured solid in 217 mg.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:15]2[CH2:16][C:13](=[C:4]([C:5]3[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=3)[CH2:3][OH:2])[CH2:14]2)=[CH:26][CH:27]=1
Reactant: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.11 g (4.45 mmol) of methyl{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate in 40 mL of hexanes and 40 mL of CH2Cl2 was added a solution of 26.7 mL (26.7 mmol) of DIBAL-H (1M solution in THF), followed by stirring for 1 h at −78° C. The reaction mixture was warmed to rt for 1.5 h, quenched by addition of 8 g of sodium sulfate decahydrate, and stirred for 1 h at rt. The quenched reaction was filtered and the organic layer was concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid. 1NMR(CDCl3) δ 3.99 (s, 2H), 4.03 (s, 2H), 4.35 (s, 2H), 4.54 (s, 1H), 6.70-6.80 (m, 3H), 7.30-6-7.40 (m, 8H); Mass Spectrum: m/e=446 (M+1 35Cl, 35Cl) and 448 (M+1 35Cl, 37Cl).
Reaction SMILES: Cl.C([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([NH:25][C:26]3[CH:41]=[CH:40][C:29]([O:30][C:31]4[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=4)=[C:28]([Cl:42])[CH:27]=3)=[N:22][CH:21]=[N:20][C:19]=2[CH:18]=[CH:17]1)(=O)C1C=CC=CC=1.[CH3:43][C:44]([NH2:47])([CH3:46])[CH3:45].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[ClH:42].[C:44]([NH:47][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([O:30][C:29]2[CH:40]=[CH:41][C:26]([NH:25][C:23]3[C:24]4[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][OH:10])[CH:17]=[CH:18][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:27][C:28]=2[Cl:42])=[CH:32][CH:33]=1)([CH3:46])([CH3:45])[CH3:43]
Reactant: O=C(O)c1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)cc1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)NC(=O)c1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoic acid hydrochloride (183 mg), 2-methylpropan-2-amine (0.038 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg), 1-hydroxybenzotriazole monohydrate (55 mg), triethylamine (0.050 mL) and N,N-dimethylformamide (3 mL) was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (1 mL), 1N aqueous sodium hydroxide solution (0.6 mL) was added and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution (0.3 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (118 mg) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>>[NH:2]=[C:1]([N:37]1[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:30])(=[O:31])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccc(S(N)(=O)=O)cc3)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)Nc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 33.8 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide following procedure C and using 1 equivalent of 1-methylpiperazine as secondary amine and 1 equivalent of DIEA as base. The product was purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:10])[CH3:9])=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C([Li])CCC.CN([CH:23]=[O:24])C>>[C:11]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]([CH3:10])[CH3:9])[CH:23]=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CN(C)c1ccc(Br)cc1C(C)(C)C
Agent: [Li]CCCC
Product: CN(C)c1ccc(C=O)cc1C(C)(C)C
Yield: 60.9 %

Procedure:
In a manner analogous to example 1 d, the process is carried out by a reaction of 4.1 g (16 mmol) of (4-bromo-2-tert-butylphenyl)dimethylamine with 9.6 ml (24 mmol) of a 2.5M solution of n-butyllithium and 1.9 ml (24 mmol) of DMF. 2 g of 3-tert-butyl-4-dimethylaminobenzaldehyde are obtained in the form of a yellow oil (yield=100%).
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1.[Li+].[Cl-:24].O>CN(C=O)C>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:7]([CH2:6][Cl:24])=[CH:8][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1
Reactant: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCl)cc1-c1ccccc1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A solution of thionyl chloride (10.0 g, 84.0 mmol) in DMF (10 mL) was added dropwise to a solution of 4-hydroxymethyl-2-phenylbenzoic acid, methyl ester (12.1 g, 50 mmol), prepared as in Example 158C, and LiCl (2.33 g, 55.0 mmol) in DMF (40 mL). After 1 hour, the reaction mixture was poured into H2O and the resulting mixture was extracted with ether (3×). The combined organic extracts were rinsed with H2O (2×), saturated aqueous NaHCO3 (3×) and brine, dried (MgSO4) and concentrated under reduced pressure to provide the desired compound (10.8 g, 83%) as a clear, colorless oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:13]([CH2:16][OH:17])([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C:13]([CH2:14][O:15][S:35]([CH3:34])(=[O:37])=[O:36])([CH2:16][O:17][S:35]([CH3:34])(=[O:37])=[O:36])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[O:27][S:35]([CH3:34])(=[O:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn([C@@H]2OC(CO)(CO)[C@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@H](OCc3ccccc3)[C@H]2OS(C)(=O)=O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
To a solution of nucleoside 5 (1100 mg, 2.91 mmol) in anhydrous tetrahydrofuran (20 cm3) was added anhydrous pyridine (5 cm3) followed by methanesulfonyl chloride (1.2 ml, 15.5 mmol). The mixture was stirred under a nitrogen atmosphere for 18 h at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and dissolved in ethyl acetate. The organic phase was washed with saturated aqueous solution of sodium hydrogen carbonate (3×10 cm3) and dried (Na2SO4). The organic phase was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (2% methanol, v/v) as elutxnt to afford nucleoside 11 (908 mg, 51%). δC (CDCl3) 163.3, 150.6, 135.6, 134.6, 128.7, 128.3, 112.2, 87.9, 85.0, 83.1, 80.9, 77.2, 76.9, 76.6, 73.3, 66.6, 66.2, 38.6, 37.6, 37.6, 12.2.
Reaction SMILES: [I:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:34].[OH-].[Na+]>N1C=CC=CC=1.O>[I:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]2[S:34][C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]5)[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CC1CCC(N2CCN(c3ccc(C(=O)NNC(=O)c4ccc(I)cc4)cc3)CC2)CC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC1CCC(N2CCN(c3ccc(-c4nnc(-c5ccc(I)cc5)s4)cc3)CC2)CC1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 119.7 %

Procedure:
A suspension of N′-(4-iodobenzoyl)-4-[4-(4-methylcyclohexyl)-1-piperazinyl]benzohydrazide (22.95 g) in pyridine (459 ml) was treated with phosphorus pentasulfide (11.2 g) and stirred at 120° C. for 2.5 hours. The reaction mixture was added a solution of sodium hydroxide (510 g) in water (9200 ml). The resulting precipitate was collected, washed with acetone. The powder was recrystallized from THF (800 ml) and dried to give 1-[4-[5-(4-iodophenyl)-1,3,4-thiadiazol-2-yl]phenyl]-4-(4-methylcyclohexyl)piperazine (16.42 g).
Reaction SMILES: [NH:1]1[N:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[C:3](=O)O1.[C:10]([Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])#C>>[CH2:21]([Sn:12]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[C:10]1[CH:3]=[C:4]2[CH2:8][CH2:7][CH2:6][N:5]2[N:1]=1)[CH2:22][CH2:23][CH3:24]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1ONN2CCCC12
Product: CCCC[Sn](CCCC)(CCCC)c1cc2n(n1)CCC2

Procedure:
The title compound was prepared from 5,6-dihydro-4H-pyrrolo [1,2-c][1,2,3]oxadiazolone (prepared by the method described in Tet Letters, 24, (10), 1067, 1983) and ethynyltributyltin by the procedure described in Example 5, Preparation 3; δH (CDCl3)0.8-1.7 (27H, m), 2.62 (2H, q), 2.85 (2H, t), 4.17 (2H, t), 6.02 (1H, s).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]#N)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:33].[Na+].[K+]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH:20]=[O:33])[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C#N)CC2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=O)CC2)CC1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A solution of 2.3 g of trans-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexanecarbonitrile in 100 ml of methylene chloride was placed at -78° C. in a sulphonation flask under argon gasification and treated within 3 minutes with 10.5 ml of a 1.5M solution of diisobutylaluminium hydride in toluene. The mixture was subsequently stirred at -78° C. for a further 4 hours, then treated cautiously with 50 ml of 10% potassium sodium tartrate solution and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (2.1 g) on silica gel with 5% ethyl acetate/petroleum ether gave 1.95 g (84.4%) of trans-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexanecarboxaldehyde which contained about 10% of the corresponding epimeric cis aldehyde in accordance with NMR spectroscopic analysis and which was reacted without additional purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.[N:14]1([C:19]2[N:24]=[CH:23][N:22]=[C:21]([N:25]=[C:26](SC)SC)[CH:20]=2)[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:14]1([C:19]2[N:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3[O:13][C@:5]4([CH2:4][N:3]=3)[CH:10]3[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]3)[CH2:6]4)[CH:20]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1cc(-n2ccnc2)ncn1)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cn(-c2cc(NC3=NC[C@@]4(CN5CCC4CC5)O3)ncn2)cn1
Yield: 85.4 %

Procedure:
A suspension of (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (419 mg, 1.8 mmol), dimethyl 6-(1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (404 mg, 1.5 mmol), and cesium carbonate (1.24 g, 3.8 mmol) was stirred in DMF (3.8 mL) at 75° C. for 2 h. The reaction was concentrated and purified by flash chromatography on a 40 g silica gel cartridge with 0 to 3% [9:1 MeOH/NH4OH] in CHCl3 to yield (R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (417 mg, 83% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.40 (1H, br. s.), 8.60 (1H, d, J=1.01 Hz), 8.37 (1H, t, J=1.01 Hz), 7.55 (1H, t, J=1.39 Hz), 7.16 (1H, dd, J=1.39, 0.88 Hz), 6.84 (1H, br. s.), 3.98 (1H, d, J=9.57 Hz), 3.64 (1H, d, J=9.57 Hz), 3.34 (1H, dd, J=14.98, 1.64 Hz), 2.69-3.04 (5H, m), 2.08-2.21 (2H, m), 1.67-1.78 (1H, m), 1.43-1.62 (2H, m). LCMS: RT=0.26 min, MH+=326.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[CH:12](=[O:15])[CH2:13][CH3:14].N1C=CC=CC=1C(O)CCC>>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([CH:12]([OH:15])[CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=1
Reactant: CCC=O
Reactant: FC(F)(F)c1cccc(Br)n1
Agent: CCCC(O)c1ccccn1
Product: CCC(O)c1cccc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-bromo-6-(trifluoromethyl)pyridine (purchased from Oakwood Products Inc., West Columbia, S.C.) and propionaldehyde following the procedure as described above for the synthesis of 1-(pyridin-2-yl)butan-1-ol (Example 231, Step A). Mass Spectrum (ESI) m/z=206.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:22])=[C:18]([CH:21]=1)[CH:19]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:19][C:18]2[CH:21]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=2[CH3:22])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(F)cc1C=O
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(F)ccc2C)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and 5-fluoro-2-methyl-benzaldehyde (1.38 g, 10 mmol) in ethanol (10 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(5-fluoro-2-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.0 g, 70%) as a white solid: LC/MS m/e calcd for C17H16FNO2 (M+H)+: 285.3, observed: 286.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(N[C@H](C(O)=O)C(C)C)(OC(C)(C)C)=O.C([O-])(=O)C.[K+]>CC(O)=O.CC(O)=O.[Pd].C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]3([C:13](=[O:15])[O:14][C:6]=2[CH:7]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: O=C(O)C1(c2ccc(Br)cc2)CCCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: Ic1ccccc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Oc2cc(Br)ccc2C12CCCC2
Temperature: 90 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A vial was charged with 1-(4-bromophenyl)cyclopentanecarboxylic acid (200 mg, 0.743 mmol), iodobenzene diacetate (359 mg, 1.11 mmol), Boc-L-valine (48.4 mg, 0.223 mmol), potassium acetate (146 mg, 1.49 mmol) and palladium (II) acetate trimer (8.34 mg, 5 mol %). Tert-butanol (7.4 mL) was added and the mixture was heated at 90° C. for 11 hours, then at room temperature for 8 hours. The reaction mixture was concentrated, diluted with DCM and filtered. The residue was purified by flash column chromatography on silica gel to afford 6-bromo-2H-spiro[benzofuran-3,1′-cyclopentan]-2-one 7.51 (75 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C12H1279BrO2: 267.0; found: 267.0.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH:11]=[CH:12][CH2+:13]2[C:18]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:17]=3[CH:16]=[C:15]([CH3:27])O2)=[CH:9][CH:8]=1.O.[NH2:31][NH2:32]>C(O)C>[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH:11]=[CH:12][C:13]2[C:18]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:17]=3[CH2:16][C:15]([CH3:27])=[N:32][N:31]=2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: COc1cc2c(cc1OC)[CH2+](C=Cc1ccc(O)cc1)OC(C)=C2
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)C(C=Cc1ccc(O)cc1)=NN=C(C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.5 g (10.6 mM) of 1-(4-hydroxystyryl)-3-methyl-6,7-dimethoxy-2-benzopyrylium perchlorate (m.p. 298° to 300° C. d.) are suspended in 90 ml of 99.5% ethanol, 1.6 ml (31.8 mM) of 100% hydrazine hydrate are added, and the solution is stirred for 2 hours at room temperature. After evaporation at reduced pressure the residue is suspended in 100 ml of water, filtered, washed with 3×5 ml of water, the crude product is resuspended in hot water, filtered, washed with 3×5 ml of water and dried at 80° to 100° C. Yield 2.65g, m.p. 205° to 207° C. (decomp.). This crude product is purified by refluxing in 12 ml of ethanol and subsequent drying. Yield 2.37 g (66.4%), m.p. 209° to 211° C. (decomp.).