Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H]2CCCC[C@H]2N2CCCC2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cccc([C@H]2CCCC[C@H]2N2CCCC2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 84.6 %

Procedure:
(2) A solution of cis-2-(3-methoxyphenyl)-1-pyrrolidinocyclohexane (2.5g) in dichloromethane was added cautiously to an ice-cold solution of boron tribromide (3 ml) in dichloromethane (15 ml). The mixture was set aside at room temperature for 18 hours and was hydrolysed with water. The aqueous layer was collected, made alkaline with ammonia and extracted with ether. The ether extracts were washed, dried (Na2SO4) and evaporated. The residue was crystallised from aqueous ethanol to give cis-2-(3-hydroxyphenyl)-1-pyrrolidinocyclohexane (2.0g), m.p. 125° to 127° C, identical to (b)(1) above.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH:11](=[N:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOP(=O)(CN)OCC
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: CCOP(=O)(CN=Cc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
Diethyl aminomethylphosphonate (4.03 g., 24.1 mmole) is stirred in an ice bath while benzaldehyde (2.50 ml., 24.5 mMol) is added dropwise over a period of 5 minutes. After having been stirred an additional 15 minutes at 0°C., the mixture is diluted with absolute ethanol (20 ml.) and evaporated in vacuo. The residue is dissolved in dry benzene (20 ml.) and evaporated to give diethyl N-benzylidene-aminomethylphosphonate (6.073 g.) as a pale yellow oil: ir (CCl4) 1639, 1250, 1062, 1037, and 971 cm-1 ; nmr (CDCl3)τ8.68 (t, 6, J=7 Hz, CH3), 5.93 (d of d, 2, J=17.5 Hz and J=1 Hz, CH2), 5.85 (d of q, 4, J=8 Hz and J=7 Hz, CH2CH3), 2.65 (m, 3, ArH), 2.29 (m, 2, ArH), and 1.75 (t of d, 1, J=1 Hz and J=5 Hz, =CH).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]1[CH2:54][CH:53]2[CH:49]([CH2:50][NH:51][CH2:52]2)[CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:51]4[CH2:52][CH:53]5[CH2:54][CH2:47][CH2:48][CH:49]5[CH2:50]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C1CC2CNCC2C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CC3CCCC3C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3,4-(1,3-propanediyl)pyrrolidine (BetaPharm) to give the title product. LC-MS (ES+) 758 [(M+H)+].
Reaction SMILES: Cl.[CH3:2][N:3]([C@@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1)[C:4]1[N:5]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.[C:43]([Cl:47])(=[O:46])[CH:44]=[CH2:45]>CN1C(=O)CCC1>[C:43]([N:30]1[CH2:31][CH2:32][CH2:33][C@@H:28]([N:3]([CH3:2])[C:4]2[N:5]=[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:21])=[CH:16][CH:15]=3)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=2)[CH2:29]1)(=[O:46])[CH:44]=[CH2:45].[ClH:47]
Reactant: C=CC(=O)Cl
Reactant: CN(c1cnc(C(N)=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1)[C@@H]1CCCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C=CC(=O)N1CCC[C@@H](N(C)c2cnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-5-(methyl(piperidin-3-yl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (92) (40 mg, 0.084 mmol) in NMP (3 mL) was added DIEA (150 μL, 0.84 mmol) and then acryloyl chloride (23 mg, 0.25 mmol). The mixture was stirred at RT for 1.5 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (93) as an HCl salt (25 mg). MS found for C25H31N7O4 as (M+H)+ 494.1, (M−H)− 492.3. UV: λ=275, 280, 313, 343, 369 nm.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C1NCCn2c1cc1cc(O)ccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Temperature: 0 °C
Yield: 47.7 %

Procedure:
To the solution of 0.5 g (2.5 mmol) 8-hydroxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1, intermediate a)) in 10 mL tetrahydrofuran, 0.6 g (3.0 mmol) 1-(tert-butoxycarbonyl)-4-hydroxypiperidine and 0.78 g (3.0 mmol) triphenylphosphine were added. The solution was cooled to 0° C., 0.68 g (3.0 mmol) di-tert-butyl azodicarboxylate were added and the cooling bath was removed. After 18 hours the reaction mixture was evaporated and the residue was flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give 0.46 g (49%) of the desired compound as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([O:18][CH2:19][C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[F:28])=[CH:16][C:15]([N:29]2[C:37](=[O:38])[NH:36][C:35]3[C:30]2=[N:31][C:32]([CH:41]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[N:33][C:34]=3[O:39][CH3:40])=[C:14]([Cl:52])[CH:13]=1)(C(C)(C)C)(C)C.[Si](OCCOC1C(OCC2C(OC)=CC=CC=2F)=CC(N)=C(Cl)C=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:52][C:14]1[CH:13]=[C:12]([O:11][CH2:10][CH2:9][OH:8])[C:17]([O:18][CH2:19][C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[F:28])=[CH:16][C:15]=1[N:29]1[C:37](=[O:38])[NH:36][C:35]2[C:30]1=[N:31][C:32]([CH:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[N:33][C:34]=2[O:39][CH3:40]
Reactant: CCOC(=O)C(C(=O)OCC)c1nc(OC)c2[nH]c(=O)n(-c3cc(OCc4c(F)cccc4OC)c(OCCO[Si](C)(C)C(C)(C)C)cc3Cl)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cccc(F)c1COc1cc(N)c(Cl)cc1OCCO[Si](C)(C)C(C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1nc(OC)c2[nH]c(=O)n(-c3cc(OCc4c(F)cccc4OC)c(OCCO)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a solution of 9-{-4-[2-(tert-butyldimethylsilyloxy)ethoxy]-2-chloro-5-(2-fluoro-6-methoxybenzyloxy)phenyl}-2-bis(ethoxycarbonyl)methyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.32 g), which was prepared in a similar manner to that described in Example 310 using 4-[2-(tert-butyldimethylsilyloxy)ethoxy]-2-chloro-5-(2-fluoro-6-methoxy-benzyloxy)aniline instead of 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline, in tetrahydrofuran (4.2 mL) was added tetra(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 8.4 mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-ethyl acetate/methanol=9/1) to give 9-[2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-4-(2-hydroxyethoxy)-phenyl]-2-bis(ethoxycarbonyl)methyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.24 g). To this material were added tetrahydrofuran (7 mL), methanol (3.5 mL), water (3.5 mL) and lithium hydroxide monohydrate (0.31 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=7/3) to give the title compound (0.14 g).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[C@@H:15]([CH2:16][N:17]4C(=O)C5=CC=CC=C5C4=O)[CH2:14][N:13]([CH3:28])[CH2:12][C@H:11]3[C:6]=2[CH:5]=[C:4]([O:29][CH3:30])[CH:3]=1.O.NN.Cl>CO>[NH2:17][CH2:16][C@@H:15]1[CH2:14][N:13]([CH3:28])[CH2:12][C@H:11]2[C:6]3[CH:5]=[C:4]([O:29][CH3:30])[CH:3]=[C:2]([Br:1])[C:7]=3[O:8][CH2:9][C@H:10]12
Reactant: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@H](CN3C(=O)c4ccccc4C3=O)[C@H]1CO2
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@@H](CN)[C@H]1CO2

Procedure:
To suspension of 0.305 g (±)-[4R*,4aS*,10bR*]-7-bromo-1,3,4,4a,5,10b-hexahydro-9-methoxy-2-methyl-4-(phthalimidomethyl)-2H-[1]benzopyrano[4,3-c]pyridine in 40 ml MeOH, is added 0.102 ml hydrazine hydrate. The mixture is refluxed 12 hours, cooled, acidified to pH 1 with 12N HCl, and concentrated to a 3 ml volume under reduced pressure. The residue is partitioned between 10 ml 2N NaOH and CH2Cl2 (40 ml). The organic phase is dried over MgSO4, filtered, and evaporated to dryness in vacuo to yield the title compound; m.p. HCl salt 277°-279° dec.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]1[N:28]=[CH:29][S:30][CH:31]=1>C(#N)C>[CH2:1]([C:4]1[N:5]([CH2:26][C:27]2[N:28]=[CH:29][S:30][CH:31]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: BrCc1cscn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cscn1
Yield: 82.3 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.150 g, 0.595 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (1.90 g, 0.0595 mmol) and 4-(bromomethyl)-1,3-thiazole (0.159 g, 0.893 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.171 g, 82% yield): 1H NMR (400 MHz, CDCl3) δ 8.81-8.80 (d, J=4.0 Hz, 1H), 7.78 (m, 2H), 6.68 (d, J=4.0 Hz, 1H), 6.63 (s, 1H), 5.51 (s, 2H), 2.80-2.76 (t, J=8.0 Hz, 2H), 1.82-1.76 (q, J=8.0 Hz, 2H), 1.06-1.02 (t, J=8.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([OH:23])=O)=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.[CH3:31][N:32](C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)[CH3:33].CNC>C(Cl)Cl>[CH2:19]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][NH:10][C:9]1[C:4]2[N:5]([C:24]([CH3:25])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[C:7]([C:21]([N:32]([CH3:33])[CH3:31])=[O:23])[CH:8]=1)[CH3:20]
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCc1cccc(C)c1CNc1cc(C(=O)N(C)C)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.4 %

Procedure:
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU)(0.14 g, 0.44 mmol) were added to methylene chloride (10 ml). Dimethylamin (0.063 g, 1.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 4 h. An additional amount of dimethylamin (0.1 ml) was added and the mixture was stirred at room temperature for 20 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography using methylene chloride:methanol (9:1) as eluent. The oily product was treated with heptane and the solid that formed was filtered off to give 0.1 g (62%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]([F:37])([F:36])[C:20]1[N:24]3[CH:25]=[C:26]([C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)[CH:27]=[C:28]([F:29])[C:23]3=[N:22][N:21]=1)=[CH:14][CH:13]=2)C1C=CC=CC=1.FC(F)(F)C(O)=O.C(Cl)Cl>CO>[F:37][C:19]([F:36])([C:20]1[N:24]2[CH:25]=[C:26]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)[CH:27]=[C:28]([F:29])[C:23]2=[N:22][N:21]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([OH:8])=[CH:18]2
Reactant: Cn1cc(-c2cc(F)c3nnc(C(F)(F)c4ccc5ncc(OCc6ccccc6)cc5c4)n3c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1cc(-c2cc(F)c3nnc(C(F)(F)c4ccc5ncc(O)cc5c4)n3c2)cn1
Temperature: 65 °C
Yield: 43.9 %

Procedure:
To a flask charged with 3-(benzyloxy)-6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline (10 mg, 20 μmol) was added trifluoroacetic acid (1.5 mL, 20 mmol). The resulting solution was heated at 65° C. for 18 h. The solution was concentrated for purification by MPLC using 98:2 CH2Cl2: MeOH to 90:10 CH2Cl2: MeOH gradient to afford 6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol (3.6 mg, 44% yield) as a colorless solid. LRMS (ESI) m/z calcd for C20H14F3N6O (M+H) 411.1, found 411.3.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[CH:6][CH:5]=1.O[NH:31][C:32]([CH:34]1[CH2:36][CH2:35]1)=[NH:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:34]1([C:32]2[N:33]=[C:26]([CH:12]3[CH2:11][CH:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:29])[F:1])=[CH:9][CH:8]=4)[CH2:15][N:14]([C:16]([N:18]4[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]4)=[O:17])[CH2:13]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
Reactant: N=C(NO)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N1CCS(=O)(=O)CC1)N1CC(c2ccc(OC(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 mg (0.23 mmol) of the compound from Example 37A and 46 mg (0.46 mmol) of N-hydroxycyclopropanecarboximidamide were initially charged in 0.8 ml of DMF and reacted with 132 mg (0.35 mmol) of HATU and 0.12 ml (90 mg, 0.69 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was taken up in 3.0 ml of DMF and converted in a microwave at 180° C. for 2 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 46 mg (37% of theory)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[C:18](Cl)[N:17]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C(OCC)(=O)C.O>[NH2:15][C:16]1[N:17]=[C:18]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[CH:19]=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: N#Cc1ccc(Cl)nc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(C#N)c(N)n2)C1
Temperature: 130 °C

Procedure:
2.15 g (10.7 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate, 1.50 g (9.77 mmol) of 2-amino-6-chloropyridine-3-carbonitrile (Example 7A) and 1.89 g (14.7 mmol) of diisopropylethylamine were suspended in 6 ml of DMSO and heated in a microwave reactor at 130° C. for 8 h. The reaction mixture was diluted with ethyl acetate (100 ml) and water (40 ml), and the organic phase was separated off and washed with saturated sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (mobile phase: cyclohexane-ethyl acetate 4:1 to 1:1). This gave 2.04 g (60% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:15][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[Cl:1]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc(CCO)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCBr)c(Cl)c1
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a stirred solution of 2-chloro-4-nitrophenethyl alcohol (1.17 g) in dichloromethane (15 ml) were added carbon tetrabromide (2.12 g) and triphenylphosphine (1.67 g) at room temperature, and the mixture was stirred for 15 minutes. The solvent was removed in vacuo, and purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=9/1) gave 1-(2-bromo-ethyl)-2-chloro-4-nitrobenzene (1.30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([C:13]1[N:14]([S:20](=[O:25])(=[O:24])[N:21]([CH3:23])[CH3:22])[CH:15]=[C:16]([CH2:18][OH:19])[N:17]=1)#[N:12].C(N(CC)CC)C.O>ClCCl>[C:11]([C:13]1[N:14]([S:20](=[O:24])(=[O:25])[N:21]([CH3:22])[CH3:23])[CH:15]=[C:16]([CH2:18][O:19][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:17]=1)#[N:12]
Reactant: CN(C)S(=O)(=O)n1cc(CO)nc1C#N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1cc(COC(=O)c2ccc(Cl)cc2)nc1C#N
Reaction time: 0.75 h

Procedure:
4-Chlorobenzoyl chloride (0.83 g) was added to a solution of 2-cyano-4-hydroxymethyl-1-(dimethylsulphamoyl)-imidazole (1.5 g) in dichloromethane (50 ml), containing triethylamine (1.0 ml) at 0°. The mixture was stirred for 45 minutes whilst the temperature was allowed to rise to room temperature. The mixture was added to water and the organic phase was separated, washed, dried and concentrated under reduced pressure. The residue was recrystallised from a mixture of diisopropyl ether and ethyl acetate to give 2-cyano-4-(4-chlorobenzoyloxy-methyl)-1-(dimethylsulphamoyl)imidazole, m.p. 94≥-96°. (Compound 1)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][OH:19])[C@H:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13]2)[C:9]([F:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+]>O.CO.[Pd]>[F:26][C:9]1[C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][OH:19])[C@H:14]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:13]2)=[N:11][CH:2]=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)c(N2CC[C@@H](CO)[C@H](c3ccccc3)C2)nc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc(N2CC[C@@H](CO)[C@H](c3ccccc3)C2)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To a mixture of 488 mg of methyl rel-2-chloro-5-fluoro-6-[(3R,4R)-4-(hydroxymethyl)-3-phenylpiperidin-1-yl]nicotinate, 428 mg of ammonium formate, and 12 mL of methanol was added 70 mg of 10% palladium/carbon while suspending it in 1 mL of water and 6 mL of methanol. The reaction mixture was vigorously stirred at 60° C. for 2 hours. After cooling to room temperature, the insolubles were filtered on a celite layer, and the filtrate was concentrated under reduced pressure. To the obtained residue was added chloroform, followed by washing with saturated aqueous sodium bicarbonate The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 283 mg of methyl rel-5-fluoro-6-[(3R,4R)-4-(hydroxymethyl)-3-phenylpiperidin-1-yl]nicotinate as a colorless foamy substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl>[Cl:23][C:17]1[CH:16]=[C:15]([C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:24])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Agent: Cl
Product: COc1ccc(C(=O)C2CCNCC2)cc1Cl
Yield: 90.3 %

Procedure:
To a solution of 4-(3-chloro-4-methoxy-benzoyl)-piperidine-1-carboxylic acid tert-butylester (1.1 g, 3.1 mmol) in 20 mL of 6N HCl, the reaction mixture was stirred at ambient temperature for 18 hours, then solvent was removed by reduced pressure to yield the title product (0.75 g, 2.8 mmol). MS (ESI) m/z 254.0 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.39 min.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:26][CH2:27][S:28][CH3:29])[C:13]([O:15][C:16]([CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1>O.[Pd]>[NH2:11][C@@H:12]([CH2:26][CH2:27][S:28][CH3:29])[C:13]([O:15][C:16]([CH2:19][N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)([CH3:18])[CH3:17])=[O:14]
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)CN1CCOCC1
Agent: [Pd]
Solvent: O
Product: CSCC[C@H](N)C(=O)OC(C)(C)CN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A solution of HCO2NH4 (5.6 g, 88.5 mmol) in water (10 ml) was added dropwise to a suspension of compound 2-(morpholinomethyl)prop-2-yl (2S)-2-(benzyloxycarbonylamino)-4-methylsulfanylbutyrate (7.5 g, 17.7 mmol) and 10% palladium on carbon (7.5g) in DMP (80 ml). The mixture was stirred at ambient temperature for 18 h. After filtration through Celite, the titrate was evaporated to dryness, neutralised with ammonia in diethyl ether to pH 9 and extracted with more ether. After evaporation the compound was purified by flash column chromatography eluting with a gradient of 1-5% ethanol/dichloromethane to give 2-(morpholinomethyl)prop-2-yl (2S)-2-amino-4-methylsulfanylbutyrate (50%).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[O:32])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCC1

Procedure:
The title compound, off-white solid (70 mg, 69%), MS (ISP) m/z=409.4 [(M+H)+], mp 180° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and cyclobutanecarboxylic acid.