Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccccc4O)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccccc4O)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(2-hydroxyphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: B(O)O.[F:4][C:5]([F:26])([F:25])[CH2:6][N:7]1[C:12](=[O:13])[C:11](Cl)=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:9]=[N:8]1.[F-:27].[Cs+].N>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:4][C:5]([F:26])([F:25])[CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:17]2[CH:18]=[CH:19][C:20]([F:27])=[C:15]([CH3:10])[CH:16]=2)=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:9]=[N:8]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cl)cc1
Reactant: [F-]
Agent: [Pd]
Agent: N
Agent: OBO
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2c(-c3ccc(S(C)(=O)=O)cc3)cnn(CC(F)(F)F)c2=O)ccc1F

Procedure:
The boronic acid (231 mg, 1.5 mmol), prepared in example 210A, 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (500 mg, 1.36 mmol), tetrakis-(triphenylphosphine)-palladium(0) (47 mg, 0.041 mmol), and CsF (413 mg, 2.72 mmol) were stirred at reflux in DME (20 mL) under N2 for 5 hours. TLC (1:1 hexanes/ethyl acetate) indicated that all the starting material was consumed. Volatiles were removed in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. An off white powder was obtained (yield: 275 mg, 46%). mp 88-91° C.; 1H NMR (300 MHz, CDCl3, a mixture of rotamers) δ 2.2, 2.25 (2d, J=1.5 Hz, 3H) 3.05, 3.09 (2 s, 3H) 4.78-4.92 (m, 2H) 6.61-6.8 (m, 1H) 6.82-6.98 (m, 1H) 7.35 (d, J=9 Hz, 1H) 7.78 (d, J=9 Hz, 1H) 7.86-8.09 (m, 4H). MS (DCI/NH3), m/z 441 (M+H)+. Anal. calc. for C20H16F4N2O3S.0.5 H2O: C, 53.45; H, 3.81; N, 6.23. Found C, 53.17; H, 3.65; N, 5.88.
Reaction SMILES: B(F)(F)F.CCOCC.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[F:20])[NH:16][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14]2.[CH3:26][C:27]1[CH:28]=[C:29]([S:34]N2C(=O)CCC2=O)[CH:30]=[C:31]([CH3:33])[CH:32]=1.ClCCl>[Cl-].[Na+].O.C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[F:20])[NH:16][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]2[S:34][C:29]1[CH:30]=[C:31]([CH3:33])[CH:32]=[C:27]([CH3:26])[CH:28]=1
Reactant: Cc1cc(C)cc(SN2C(=O)CCC2=O)c1
Reactant: CCOC(=O)c1cc2cc(Cl)c(F)cc2[nH]1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(F)c(Cl)cc2c1Sc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.4 %

Procedure:
Boron trifluoride ethyl etherate (0.135 g, 0.12 mL, 0.001 mol) was added to a mixture of ethyl 5-chloro-6-fluoroindole-2-carboxylate (0.75 g, 0.0031 mol), N-(3,5-dimethylphenylthio)-succinimide (0.78 g, 0.0033 mol) and anhydrous dichloromethane (20 mL) under dry argon atmosphere. After stirring at room temperature for 2 hours was added boron trifluoride ethyl etherate (0.27 g, 0.24 mL, 0.002 mol) and then reaction was heated at 45° C. for 2 hours. After cooling reaction was diluted chloroform and brine while shaking. Organic layer was separated, washed with saturated solution of sodium hydrogen carbonate, then with brine and dried. The solvent was evaporated to give 1.2 g (100%) of satisfactory pure title compound, mp 170-173° C. (from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[CH3:12][N:11]([CH3:13])[C:8]1[CH:7]=[C:3]2[C:4]([O:6][C:16](=[O:15])[NH:1][C:2]2=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)c1ccc(N)c(C(=O)O)c1
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1ccc2[nH]c(=O)oc(=O)c2c1

Procedure:
To the mixture of 8.9 g of 2-amino-5-dimethylaminobenzoic acid in 60 mL of dioxane, under stirring and external cold water cooling 10 mL of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 50 mL of ether. The product is stirred for 5 minutes in the mixture of 50 mL of methanol and 5 mL of triethylamine, filtered off, washed with 30 mL of methanol. After drying 7 g of the title product is obtained, m.p.: 258° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][CH2:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(#N)C>[C:14]([N:1]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][CH2:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCNc2ccccc2CN1
Solvent: CC#N
Product: CC(=O)N1CCC(=O)NCc2ccccc21
Temperature: 80 °C

Procedure:
2,3,5,6-Tetrahydro-1H-benzo[b][1,5]diazocin-4-one (prepared as in J. Am. Chem. Soc. 2004, 126, 3529-3533) (1.00 g, 5.68 mmol) was dissolved in anh acetonitrile (50 ml). Acetic anhydride (587 μL, 6.25 mmol) was added and the reaction mixture was heated to 80° C. for 16 h. The reaction mixture was concentrated, triturated with ether, and filtered to afford title compound as a beige solid. (1.063 g, 86%) mp 236-239° C.; LCMS: m/z=219.30 (M+H+), HPLC (95% purity); 1H NMR (400 MHz, DMSO-d6) δ 7.82 (m, 1H), 7.38 (m, 4H), 4.64 (m, 1H), 4.29 (m, 1H), 3.87 (m, 1H), 2.92 (m, 1H), 2.57 (m, 1H), 2.26 (m, 1H), 1.69 (s, 3H).
Reaction SMILES: C([O-])(O)=O.[Na+].I[CH2:7][CH2:8][F:9].[I:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)=[O:19])=[CH:13][CH:12]=1>CN(C=O)C.O>[F:9][CH2:8][CH2:7][N:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[CH2:21][NH:20][C:18](=[O:19])[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([I:10])=[CH:16][CH:15]=1
Reactant: FCCI
Reactant: O=C(Cc1ccc(I)cc1)NC[C@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(I)cc1)NC[C@H]1CCCN1CCF
Temperature: 90 °C
Yield: 80.8 %

Procedure:
In a sealed tube, 0.53 g of NaHCO3 (6.4 mmol) and 0.49 g of 1-iodo-2-fluoroethane (2.8 mmol) are added to 0.88 g (2.6 mmol) of the compound obtained from step 1.10 dissolved in DMF (6 ml). The sealed tube is heated at 90° C. for 5 hours. The reaction mixture is cooled, the DMF is then evaporated off under reduced pressure, and the residue obtained is taken up in water (10 ml) and extracted with ethyl acetate (20 ml×2). The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol, 1% NH4OH), with a gradient of 0% to 10% methanol. 0.82 g of compound is obtained, in the form of a beige-coloured powder. Yield=85%. Melting point: 96° C. MH+: 391 (tr: 5.1 min., condition 1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=3)[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(C)(C)C3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)O)cc3)CC2)C1

Procedure:
reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate and aqueous sodium hydroxide at about 55° C. to about 75° C., and isolating or not isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.C([O-])=O.[NH4+].C([BH3-])#[N:22].[Na+]>[Cl-].[Zn+2].[Cl-]>[NH2:22][CH:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C2CCN(CC2)C1Cc1cccnc1
Reactant: [BH3-]C#N
Agent: O=C[O-]
Agent: [Cl-]
Agent: [NH4+]
Product: NC1C2CCN(CC2)C1Cc1cccnc1

Procedure:
Another illustration of derivatization of saturated ketone intermediates is the reductive amination to give amines. Thus, 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one reacts with ammonium formate, zinc chloride and sodium cyanoborohydride to give 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as predominantly the cis diastereomer. Likewise, reaction of 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one with methylamine and sodium cyanoborohydride provides 3-(methylamino)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane. These amine derivatives can be used as a template for library formation by reacting them with a variety of acylating agents (e.g., acid chlorides, acid anhydrides, active esters, and carboxylic acids in the presence of coupling reagents) and isocyanates to produce 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes with amide and urea substituents in the 3-position of the 1-azabicyclo[2.2.2]octane, both of which classes are compounds of the present invention. Commercially unavailable isocyanates can be prepared in situ from corresponding amines and triphosgene in the presence of triethylamine. Such derivatives can be produced as single enantiomers, using the single enantiomers of 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane and 3-(methylamino)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as starting materials. For instance, the (2R,3R)- and (2S,3S)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes can be produced by resolution of the cis 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane, for example, using diastereomeric amides. Thus, when the cis amine is reacted with a chiral acid such as (S)—N-(tert-butoxycarbonyl)proline using a suitable coupling agent such as diphenylchlorophosphate, a pair of diastereomeric amides, separable by reverse phase chromatography, is produced. The separated proline amides can then be deprotected, for example, by treatment with trifluoroacetic acid (to remove the tert-butoxycarbonyl protecting group) and then the proline can be cleaved from the desired amine, for example, using Edman degradation conditions (i.e., phenylisothiocyanate, followed by trifluoroacetic acid).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15]([O:17]CC)=O)=[C:4]([C:7](=O)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][CH:6]=1.[CH3:20][NH:21][NH2:22]>CCO>[Br:1][C:2]1[C:3]2[C:15](=[O:17])[N:21]([CH3:20])[N:22]=[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[C:4]=2[S:5][CH:6]=1
Reactant: CCOC(=O)c1c(Br)csc1C(=O)c1ccncc1
Reactant: CNN
Solvent: CCO
Product: Cn1nc(-c2ccncc2)c2scc(Br)c2c1=O
Yield: 44.8 %

Procedure:
A suspension of ethyl 4-bromo-2-isonicotinoylthiophene-3-carboxylate (5.2 g, 15.94 mmol) and methyl-hydrazine (2.2 g, 47.8 mmol) in EtOH (40 mL) was heated to reflux overnight. After removal of the solvent, the crude product was purified by silica gel column and eluted with 5:1 PE/EtOAc to give the title compound as a white solid (2.3 g, 44.8% yield). LC-MS (Method C): m/z 322 (M+H)+, Rt: 1.75 min. 1H NMR (400 MHz, DMSO-d6): δ=8.80-8.78 (m, 2H), 8.28 (s, 1H), 7.81-7.80 (m, 1H), 3.81 (s, 3H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.BrC1[CH:14]=[CH:15][C:16]([O:19][C@H:20]2[CH:27]3[CH2:28][N:23]4[CH2:24][CH:25]([CH2:29][CH:21]2[CH2:22]4)[CH2:26]3)=[N:17][CH:18]=1.C1(B(O)O)C=CC=CC=1>>[C:1]1([C:11]2[CH:14]=[CH:15][C:16]([O:19][C@H:20]3[CH:27]4[CH2:28][N:23]5[CH2:24][CH:25]([CH2:29][CH:21]3[CH2:22]5)[CH2:26]4)=[N:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Brc1ccc(OC2C3CC4CC2CN(C4)C3)nc1
Agent: OB(O)c1ccccc1
Product: c1ccc(-c2ccc(OC3C4CC5CC3CN(C5)C4)nc2)cc1

Procedure:
Prepared from the product of Example 9F (496 mg, 1.60 mmol) and phenylboronic acid (480 mg, 3.1 mmol; Aldrich) according to Method B: 1H NMR (300 MHz, methanol-D4) δ ppm 1.75 (s, 1H), 2.00-2.25 (m, 6H), 2.98 (d, J=12.9 Hz, 2H), 3.15 (s, 2H), 3.51 (d, J=12.9 Hz, 2H), 5.33 (s, 1H), 6.90-6.96 (m, 1H), 7.30-7.38 (m, 1H), 7.40-7.48 (m, 2H), 7.54-761 (m, 2H), 7.94 (dd, J=8.6, 2.5 Hz, 1H), 8.35 (d, J=2.4 Hz, 1H), MS (ESI) m/z=307 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.[Cl-].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: COc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ccccc2OC)c1
Yield: 63.8 %

Procedure:
Methyl 3-bromobenzoate (1.99 g, 9.25 mmol), tetrakis(triphenylphosphine) palladium(O) (110 mg), sodium carbonate (2.04 g, 19 mmol in 5 ml water) and toluene (10 ml) were degassed under nitrogen in a 25 ml flask fitted with a reflux condenser. 2-Methoxybenzeneboronic acid (1.46 g, 9.61 mmol) in toluene (1 ml) was added and the mixture was heated at reflux for two days then mixed with 1:1 saturated sodium chloride/ethyl acetate (15 ml). The organic materials were separated, dried (MgSO4) then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient hexane to 8:1 hexane/ethyl acetate) which gave methyl 3-(2-methoxyphenyl)benzoate (1.43 g, 64%), m.p.: 92°-93° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl.O>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(C)cccc1COCCCOCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(COCCCOCc2ccc3ccccc3n2)c1C(=O)O
Temperature: 90 °C

Procedure:
Methyl 2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoate (3.3 g, 8.7 mmol, EXAMPLE 35a) is dissolved in ethanol (81 mL). 10 N NaOH (9 mL, 90 mmol) is added and the contents are heated to 90° C. overnight. The reaction is cooled to r.t., and the volume reduced under vacuum. 2 N HCl (45 mL, 90 mmol) is added, and the pH is adjusted to ˜4. The contents are poured into water (400 mL) and extracted with dichloromethane (3×200 mL). The organic layers are combined, washed with brine (2×300 mL), dried over MgSO4, filtered and reduced under vacuum to dryness. The crude material is purified by flash chromatography (silica, 3% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, 2H), 7.86 (d, 1H), 7.73 (dd, 1H), 7.60-7.50 (m, 2H), 7.26-7.11 (m, 3H), 5.01 (s, 2H), 4.70 (s, 2H), 3.84 (t, 2H), 3.73 (t, 2H), 2.50 (s, 3H), 1.89 (quintet, 2H). MS (ESI) 366 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.C(N(CC)CC)C>CS(C)=O>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[N:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
0.500 g (3.18 mmol) of ethyl piperidine-4-carboxylate, 0.866 g (4.77 mmol) of 2-chloro-5-trifluoromethylpyridine and 0.483 g (4.77 mmol) of triethylamine were reacted in dimethyl sulfoxide at 60° C. overnight. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness to yield crude ethyl 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylate.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22](=O)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[CH3:2][C:3]1[C:11]([C:12]2[S:14][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:22]([CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:13]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)C(Cl)C(=O)C1CCOCC1
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1C1CCOCC1
Yield: 79.3 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (400 mg, 1.8 mmol) produced in Example 11-B(v), ethyl 2-chloro-3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (1.0 g, 4.3 mmol) produced above and 2-propanol (40 mL) as starting materials and in the same manner as in Example 11-B(vi), the title compound (530 mg, 81%) was obtained as a yellow solid.
Reaction SMILES: [Na].[N:2]1([C:8]([NH2:10])=[NH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[CH:25]=[C:26]([OH:27])[N:10]=[C:8]([N:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[N:9]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N=C(N)N1CCCCC1
Agent: [Na]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(O)nc(N3CCCCC3)n2)CC1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
Sodium (1 mol) was dissolved in anhydrous ethanol (400 mL). To the obtained solution, Piperidine-1-carboxamidine (0.5 mol) was carefully added in portions. Then 4-(2-ethoxycarbonyl-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.5 mol) was added dropwise, and the mixture was stirred at reflux for 4-6 h (monitored by TLC), cooled to room temperature, concentrated, diluted with water (300 mL) and acidified with acetic acid to pH-4. The formed precipitate was collected by filtration, washed with water and dried to afford 4-(6-hydroxy-2-piperidin-1-yl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (89 g, 49%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:62]=[CH:61][C:53]2[NH:54][C:55]([C@@H:57]([NH2:60])[CH2:58][OH:59])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:60][C@H:57]([C:55]1[NH:54][C:53]2[CH:61]=[CH:62][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][OH:59])=[O:7]
Reactant: N[C@@H](CO)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CO)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CC=CC1
Yield: 100 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxyethylamine in tetrahydrofuran. Yield: 100%; Rf value: 0.40 (silica gel; dichloromethane/methanol=9:1); C22H21ClN4O3 (424.89); mass spectrum: (M+H)+=425/427 (chlorine isotope) and (M+H)+=423/425 (chlorine isotope).
Reaction SMILES: C([O:8][CH2:9][C:10]([C:13]1[S:17][C:16]([NH2:18])=[N:15][N:14]=1)([CH3:12])[CH3:11])C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:18][C:16]1[S:17][C:13]([C:10]([CH3:12])([CH3:11])[CH2:9][OH:8])=[N:14][N:15]=1
Reactant: CC(C)(COCc1ccccc1)c1nnc(N)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CO)c1nnc(N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
To a solution of 5-(2-benzyloxy-1,1-dimethyl-ethyl)-1,3,4-thiadiazol-2-ylamine (15.0 g, 57.0 mmol) in DCM (100 mL), boron tribromide (1N in DCM, 15.0 mL, 162.0 mmol) is added slowly at 0° C. The reaction mixture is warmed up to room temperature and stirred for 3 h. After cooling the reaction mixture to 0° C., ice water is added. The two phases are separated and the pH of the water phase is adjusted to ˜13 with NaOH and extracted with n-BuOH. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 10.0 g of 2-(5-amino-1,3,4-thiadiazol-2-yl)-2-methyl-propan-1-ol as a brown solid; m/z 174 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9](=[S:11])[NH:10][C:4]=2[CH:3]=1.[OH-].[K+].I[CH3:15]>CCO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9]([S:11][CH3:15])=[N:10][C:4]=2[CH:3]=1
Reactant: S=c1[nH]c2cnc(Cl)cc2[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirring solution of 6-chloro-1H-imidazo[4,5-c]pyridine-2(3H)-thione (1.49 g, 8.03 mmol) and potassium hydroxide (540 mg, 9.63 mmol) in anhydrous EtOH (49.7 mL) was added iodomethane (0.50 mL, 8.03 mmol). The reaction solution was stirred at RT for 3.5 h, and then partitioned between EtOAc (64 mL) and 2N HCl (11.3 mL). The aqueous layer was separated, and the pH was adjusted to a slightly basic pH with the addition of saturated NaHCO3, followed by extraction with EtOAc (100 mL). The combined organic layers were concentrated, and dried under vacuum to afford the title compound as a solid. LC-MS: calculated for C7H6ClN3S 199.00 observed m/e: 200.04 (M+H)+ (Rt 1.12/2.0 min).