Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[Na+].[Na+].[CH:10]12[CH:18]=[CH:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH2:12][CH:11]2[C:19](Cl)=[O:20]>>[CH:10]12[CH:16]=[CH:15][CH:14]([CH2:17][CH2:18]1)[CH2:13][CH2:12][CH:11]2[C:19]([CH:2]([C:1]([OH:7])=[O:6])[C:3]([OH:5])=[O:4])=[O:20]
Reactant: O=C(Cl)C1CCC2C=CC1CC2
Reactant: O=C([O-])CC(=O)[O-]
Agent: [Na+]
Product: O=C(O)C(C(=O)O)C(=O)C1CCC2C=CC1CC2
Yield: 87.5 %

Procedure:
To a solution containing sodium malonate (17.1 g) which was prepared according to the same procedure as in Example 7, bicyclo[3,2,2]non-8-ene-2-carbonyl chloride (18.4 g) obtained in Preparation Example 3 is slowly added, and the reaction mixture is reacted at −20° C. in a nitrogen atmosphere for 1 hour, and further reacted at 45° C. for 8 hours. Then, the mixture is worked up as in the procedure of Example 1, to obtain 22 g of the pure title compound (purity: 99%, yield: 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[S:21])[N:14]([CH3:20])[CH2:15][C:16]([O:18]C)=[O:17])=[CH:8][CH:7]=[CH:6]2.COCCO.[OH-].[Na+].Cl>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[S:21])[N:14]([CH3:20])[CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=[CH:6]2
Reactant: COC(=O)CN(C)C(=S)c1cccc2c(C(F)(F)C(F)(F)F)c(OC)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: COCCO
Solvent: CCCCCC
Product: COc1ccc2c(C(=S)N(C)CC(=O)O)cccc2c1C(F)(F)C(F)(F)F
Temperature: 0 °C
Yield: 18 %

Procedure:
The N-[[6-methoxy-5-(pentafluoroethyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine, methyl ester (2.3 g, 5.46 mmol), 2-methoxyethanol (50 ml) and 2N aqueous sodium hydroxide (5.46 ml) were mixed at 0° C. and the mixture stirred at room temperature for 3 hours (until disappearance of the ester spot in t.l.c. with ethyl acetate/hexane 1:1). The mixture was cooled to 0° C., neutralized to pH 8 with 1N aqueous hydrochloric acid, evaporated, the residue triturated with water, the neutral material extracted with ethyl acetate and the aqueous layer acidified with 1N aqueous hydrochloric acid to pH3. The product was extracted with ethyl acetate, the extract washed with water, dried over anhydrous MgSO4 and evaporated. The residue was purified by crystallization from chloroform/hexane to obtain 700 mg of the first crop and an additional 568 mg of the crude material from the mother liquor. Recrystallization of the first crop afforded 400 mg of the pure N-[[6-methoxy-5-(pentafluoroethyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine. The recrystallization of mother liquor gave further 291 mg. mp. 164°-165° C. Anal. Calcd: C, 50.13% H, 3.46% N, 3.44% Found: C, 49.42%, H, 3.58% N, 3.40%. nmr (DMSO): δ2.95 (s, 3H, N--CH3); δ3.97 (s, 3H, OCH3); δ4.9 (q, 2H, CH2); δ7.1-8.4 (m, 5H, Har). ir (nujol): 1700, 1723, 1750 cm-1 uv, λmax(ε): 338 (3990), 269 (13,000), 227 (45,400) ms: m/e 407 (M+), 363, 319.
Reaction SMILES: F[C:2](F)(F)S(OC)(=O)=O.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[CH2:22]([NH2:25])[C:23]#[CH:24].[OH-].[Na+]>C(#N)C.C(Cl)Cl>[CH3:2][N:17]1[C:23]([CH3:24])=[CH:22][N:25]=[C:16]1[C:15]1[CH:18]=[CH:19][C:12]([C:11]([F:20])([F:21])[F:10])=[CH:13][CH:14]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: C#CCN
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)n1C
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A mixture of methyl trifluoromethanesulfonate (3.3 ml) and p-trifluoromethylbenzonitrile (5.17 g) was heated at 65° C. for 31/2 hours, then cooled to 5° C. The mixture was then dissolved in 10 ml of acetonitrile, and 2 ml of propargylamine in 10 ml of acetonitrile was added. The mixture was stirred at room temperature for 16 hours, then cooled to 5° C. and 3 ml of concentrated sodium hydroxide added (about 1 equivalent), followed by 40 ml of methylene chloride. The organic layer was separated, the solvent evaporated under reduced pressure, and 50 ml of toluene added. The mixture was refluxed for 3 hours, cooled, the solvent evaporated under reduced pressure, and the residue recrystallized from isopropyl ether, to yield 4.6g of 1,5-dimethyl-2-(4-trifluoromethylphenyl)imidazole, a compound of Formula (6), m.p. 130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:11]=[CH:10][CH:17]=[CH:16][C:13]=2[CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A heterogeneous mixture of 4-chlorophenol (14.1 g, 0.11 mmol), 4-fluorobenzaldehyde 12.4 g, 0.1 mmol) and CS2CO3 (65.0 g, 0.20 mmol) in DMF (400 mL) was stirred at 90° C. for 6 h. The reaction mixture was poured into water (1.2 L) and extracted with ethyl acetate (2×200 mL). The organic phase was washed with water (2×100 mL), dried over magnesium sulfate and concentrated to give essentially pure 4-chlorophenoxybenzaldehyde, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[NH4+].[Cl-].C(O)(=O)C>CO.O.[Fe]>[Cl:1][C:2]1[CH:15]=[C:14]([CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1)[NH2:16]
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(Cc2ccc(N)cc2Cl)CC1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of 1-(2-chloro-4-nitrobenzyl)-4-methylpiperazine (0.96 g, 3.6 mmol) in MeOH/water (4:1, 50 mL) was added 1.80 g (33.7 mmol) of NH4Cl and 1.47 g (26.3 mmol) of Fe dust and the mixture heated at reflux under an atmosphere of N2 for 2 h (HPLC indicated no progress). To this was added 4 mL of glacial acetic acid and the mixture heated at reflux for an additional 2 h. The reaction mixture was cooled to ambient temperature, filtered, and the filtrate concentrated. The residue was partitioned between EtOAc and saturated aq. NaHCO3, the separated aqueous layer was extracted with EtOAc, and the combined organics washed with brine and dried over Na2SO4. Upon concentration, the crude product was purified by silica gel chromatography (eluted with 5-7% MeOH/DCM; silica gel deactivated with 1% triethylamine/DCM) to provide 0.53 g of product.
Reaction SMILES: N[NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Cl[C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[IH:22]>>[I:22][C:15]1[CH:20]=[C:19]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([NH2:2])=[O:4])=[CH:6][CH:7]=2)[N:18]=[CH:17][N:16]=1
Reactant: NNC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Product: NC(=O)c1ccc(-c2cc(I)ncn2)cc1

Procedure:
The compound was prepared according to Example 1 using 4-aminocarbamoylphenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:18])[NH:13]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:33]([NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH3:34]>O.C(OCC)(=O)C>[CH:36]1([N:35]([CH2:33][CH3:34])[C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)=[O:3])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCNC1CCCCC1
Reactant: CC(COc1cccc2c1CCC(=O)N2)CC(=O)O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(C(=O)CC(C)COc1cccc2c1CCC(=O)N2)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.6 Grams of 5-(3-carboxy-2-methylpropoxy)-3,4-dihydrocarbostyril and 1.6 ml of triethylamine are added to 200 ml of ethyl acetate, followed by dropwise addition of 1.0 ml of ethyl chloroformate under external ice cooling and agitation while maintaining the internal temperature at 10° to 20° C. Thereafter, the mixture is agitated at room temperature for 1 hour, added with 1.4 g of N-ethylcyclohexylamine and further agitated for 1.5 hours. The reaction solution is poured into water to separate the liquid, and the organic layer is washed with dilute aqueous NaOH solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na2SO4. After filtering off the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ligroin-benzene, obtaining 1.5 g of 5-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 114°-115.5° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][N:20]3[CH:24]=[C:23]([CH2:25][C:26]([O:28]CC)=[O:27])[C:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:21]3)=[CH:15][CH:14]=2)[N:10]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][N:20]3[CH:24]=[C:23]([CH2:25][C:26]([OH:28])=[O:27])[C:22]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:21]3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cn2cc(CC(=O)O)c(-c3ccccc3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
After a mixture of ethyl [1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (578 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain [1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetic acid (467 mg, yield: 86%). This was recrystallized from acetone-hexane. Melting point: 135–136° C.
Reaction SMILES: [N+](C1OC([C:9]2[N:13]3N=C(Cl)C=C[C:12]3=[N:11][N:10]=2)=CC=1)([O-])=O.[N+:19]([C:22]1[O:36][C:25]([CH:26]=[N:27][NH:28][C:29]2[N:34]=[N:33][C:32](Cl)=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20].[C:37]([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>>[N+:19]([C:22]1[O:36][C:25]([C:26]2[N:34]3[N:33]=[C:32]([NH:10][N:11]=[CH:12][N:13]([CH3:9])[CH3:37])[CH:31]=[CH:30][C:29]3=[N:28][N:27]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(-c2nnc3ccc(Cl)nn23)o1
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(C=NNc2ccc(Cl)nn2)o1
Agent: [Pb+4]
Product: CN(C)C=NNc1ccc2nnc(-c3ccc([N+](=O)[O-])o3)n2n1

Procedure:
The preparation of 3-(5-nitro-2-furyl)-6-chloro-s-triazolo[4,3-b]pyridazine was carried out by the oxidative cyclization of 1-(5-nitro-furfurylidene)-2-(3-chloro-6-pyridazinyl) hydrazine (m.p. 250° - 254°C.) with lead tetraacetate. The yield was 79% and the product, after recrystallization from dimethyl formamide, melted at 222° - 226°C.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(=O)(O)[O-]>CN(C)C(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH:29][CH2:3][C:4]2[N:5]=[C:6]3[C:11](=[N:12][CH:13]=2)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]3[NH2:15])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: COc1ccc(CCN)cc1OC
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: COc1ccc(CCNCc2cnc3nc(N)nc(N)c3n2)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (55 mg, 0.1638 mmol) in anhydrous N,N dimethylacetamide was added 2-(3,4-dimethoxyphenyl) ethylamine hydrochloride (55 ul, 0.32 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 3.8 mg product was obtained. Yield: 19.6%; 1H NMR (500 MHz, DMSO-d6): δ 2.75943–2.79062 (t, J=7.37 Hz, 2H), 2.92110–2.95356 (t, J=7.365 Hz, 2H), 3.72197(s, 3H), 3.75135(s, 3H), 4.54559(s, 2H), 6.74441–6.77765 (dd, J1=8.26 Hz, J2=1.955 Hz, 1H), 6.84994 (s, 1H), 6.88406–6.90401 (dd, J1=8.195 Hz, J2=1.735 Hz, 1H); 8.87126(s, 1H); ESI-MS: m/z 356 (M++1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([OH:11])=[O:10].C(C(C#N)=C(C#N)C#N)#N>CC(N(C)C)=O>[C:9]([C:12]1[CH:19]=[CH:18][C:15]([C:16]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1)([OH:11])=[O:10]
Reactant: Nc1ccccc1S
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: N#CC(C#N)=C(C#N)C#N
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(-c2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-aminothiophenol (300 mg, 2.4 mmol) in DMA (3 mL) was added to resin-bound 4-carboxybenzaldehyde (subn. 0.60 mmol/g, 400 mg, 0.24 mmol), followed by TCNE (307 mg, 2.4 mmol). The suspension was shaken at 25° C. for 24h. The resin was filtered, washed with DMA and DCM, and dried under high vacuum. The resin-bound benzothiazole was cleaved from the solid support with 20% (v/v) TFA in DCM (2×5 mL, 15 min) and the combined filtrates were evaporated to give the title compound. 1H NMR (d6-DMSO) δ 7.52 (t, 1H, J=7.6 Hz), 7.60 (t, 1H, J=7.0 Hz), 8.12 (d, 2H, J=8.4 Hz), 8.23 (d, 2H, J=8.4 Hz), 8.00-8.40 (m, 2H). MS (API-ES+) m/z 256 (M+H).
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:39])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:17])(OCC1C=CC=CC=1)=O.[ClH:40].[H][H]>[Pd].CC(O)C>[ClH:40].[NH2:11][CH2:12][C:13](=[O:39])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:17]
Reactant: O=C(CCC(=O)OCCCCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NCC(=O)CCC(=O)OCCCCCCCCCCC(=O)O
Yield: 51.7 %

Procedure:
This compound was prepared from the product of 13b (0.60 g; 1.1 mmol), 12 M HCl (0.09 mL; 1.1 mmol), 10% Pd/C (100 mg), hydrogen gas, and 2-propanol (25 mL) using the procedure in Example 8d. 0.20 g (51%) product was obtained (white solid).
Reaction SMILES: [O:1]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH2:28][CH2:29][NH:30][CH:31]=[N:32][NH2:33])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][CH:19]4[CH:18]([O:34][Si](C(C)(C)C)(C)C)[CH:17]=[CH:16][C@@H:15]35)[Si](C(C)(C)C)(C)C.C(#N)C>O1CCCC1>[O:23]1[C@@H:19]2[C@@:20]34[CH2:24][CH2:25][N:26]([CH2:27][CH2:28][CH2:29][NH:30][CH:31]=[N:32][NH2:33])[C@@H:14]([C@@H:15]3[CH:16]=[CH:17][C@@H:18]2[OH:34])[CH2:13][C:12]2=[C:21]4[C:22]1=[C:9]([OH:1])[CH:10]=[CH:11]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1OC1C(O[Si](C)(C)C(C)(C)C)C=C[C@H]4[C@@H](C2)N(CCCNC=NN)CC[C@]314
Solvent: C1CCOC1
Solvent: CC#N
Product: NN=CNCCCN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Yield: 73 %

Procedure:
3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-(N-aminoiminomethyl-aminopropyl)morphinan was deprotected using 40% HF in a 10:1 mixture of acetonitrile and tetrahydrofuran as described before. The precipitate was filtered and washed with acetonitrile, methylenechloride followed by methanol. KRS-2-47 was obtained as a white powder in 73% yield (70 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:34][CH2:35]1)[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 54.8 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-cyclopropyl-4-(piperazin-1-yl)benzamide (128 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 25-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 15 mL) and dried in vacuum to afford (S)-3-chloro-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (120.4 mg, 0.250 mmol, 54.9% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.60 (m, 2 H) 0.61-0.72 (m, 2 H) 1.84-2.01 (m, 3 H) 2.12-2.23 (m, 1 H) 2.51-2.57 (m, 4 H) 2.77-2.86 (m, 1 H) 3.02 (br. s., 4 H) 3.35-3.46 (m, 3 H) 3.54-3.64 (m, 1 H) 3.95-4.03 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.16 (d, J=8.34 Hz, 1 H) 7.63 (d, J=1.77 Hz, 1 H) 7.75 (dd, J=8.34, 2.02 Hz, 1 H) 7.85 (d, J=2.02 Hz, 1 H) 8.39 (d, J=4.04 Hz, 1 H) 10.45 (s, 1 H). [M+H] calc'd for C25H29ClN6O2, 481; found, 481.
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[C:31]4[N:30]=[CH:29][N:28](COCC[Si](C)(C)C)[C:27]=4[CH:26]=[C:25]([C:40]([F:43])([F:42])[F:41])[CH:24]=3)[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].O.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:13][N:10]1[CH2:11][CH2:12][C:7]([CH2:20][O:21][CH2:22][C:23]2[C:31]3[N:30]=[CH:29][NH:28][C:27]=3[CH:26]=[C:25]([C:40]([F:42])([F:41])[F:43])[CH:24]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1.[C:46]([OH:48])([C:45]([F:50])([F:49])[F:44])=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c2ncn3COCC[Si](C)(C)C)(c2ccccc2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3[nH]cnc23)(c2ccccc2)CC1

Procedure:
tert-Butyl 4-phenyl-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methoxy)methyl)piperidine-1-carboxylate was treated with trifluoroacetic acid: water (9:1, 3 ml) at ambient temperature for 15 min at which time LC-MS analysis revealed completion of the reaction (HPLC method 10: tR=2.5 min, 520(MH)+). The volatiles were evaporated and dried under vacuo. The residue was treated with formaldehyde (0.1 mL, 3.6 mmol), acetic acid (cat.) and sodium cyanoborohydride (25 mg, 0.4 mmol) at ambient temperature for 2 h. The reaction was complete by LC-MS analysis (HPLC method 9: tR=2.7 min, 534(MH)+). The solvent was evaporated and the residue was treated with trifluoroacetic acid /dichloromethane (1:1, 4 ml) at ambient temperature for 3 h. LC-MS analysis (HPLC method 1: tR=2.0 min, 404(MH)+). The solvent was evaporated and the residue was purified by Prep HPLC (HPLC method 15). Fractions containing required product were combined and evaporated to give the title compound as a TFA salt. (6 mg, yield for 5 steps from (6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methanol, 13.2% yield). 1H-NMR (CD3OD, 500 MHz) δ 8.85 (s, 1H), 7.99 (s, 2H), 7.57 (s, 1H), 7.43-7.27 (m, 5H), 4.85 (s, 2H), 3.52 (s, 2H), 3.45 (m, 2H), 2.85 (m, 2H), 2.75 (s, 3H), 2.69-2.66 (m, 2H), 2.19 (m, 2H); 19F NMR (471 MHz, CD3OD) δ −62.9, −77.6; LC/MS (HPLC method 1): tR=2.1 min, 404(MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]([CH3:43])[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][N:24]([CH3:43])[CH3:23])=[CH:29][CH:30]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Reactant: CN(C)CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc(OCCN(C)C)cc4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanamine (Combi-Blocks, Cat. No. PN-3972). LCMS (M+H)+=487.0/489.0.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:28].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[ClH:21].[OH:8][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[O:28])[CH2:11][CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: COc1ccc(C(=O)CCCCCCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CCCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Product: Cl
Reaction time: 82 h

Procedure:
A mixture of 27.6 g (0.1 mole) of α,α-diphenyl-4-piperidinemethanol, 26.5 g (0.11 mole) of 6-chloro-4'-methoxycaprophenone, 20 g of potassium bicarbonate, and 0.1 g of potassium iodide in 300 ml of toluene and 45 ml of water is stirred on a steam bath for about 82 hours then worked up by the procedure described in Example 5 to give 6-[4-(α-hydroxy-α-phenylbenzyl)piperidino]-4'-methoxycaprophenone hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][NH:6][C:7](=[O:25])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][C:17]1[C:18]([O:23]C)=[N:19][CH:20]=[CH:21][CH:22]=1.S(Cl)(Cl)=O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][NH:6][C:7](=[O:25])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][C:17]1[C:18](=[O:23])[NH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ncccc1CCN1CCCCC1CC(=O)NCc1cccc(F)c1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: O=C(CC1CCCCN1CCc1ccc[nH]c1=O)NCc1cccc(F)c1
Yield: 92.6 %

Procedure:
370 mg of N1-(3-fluorobenzyl)-2-[1-[2-(2-methoxy-3-pyridyl)ethyl]-2-piperidyl]acetamide obtained in Example 177, 0.44 ml of thionyl chloride and 5 ml of ethanol were stirred at 100° C. for 2 hours. The solvent was evaporated, and to the residue was added an aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and dried over sodium sulfate. Then the drying agent was filtered off, and the solvent was evaporated, to give 330 mg of white crystals.