Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: CNC(=O)C=Cc1ccc(O)cc1
Reactant: COc1cccc(CBr)c1
Product: CNC(=O)C=Cc1ccc(OCc2cccc(OC)c2)cc1
Yield: 60 %

Procedure:
The title compound is prepared in analogy to example 11 b) from 3-(4-hydroxy-phenyl)-N-methyl-acrylamide and 1-bromomethyl-3-methoxy-benzene. Yield=60%. Colorless solid. MS: m/e=298.2 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:13]([N:20]=[C:21]=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O.C(N(CC)CC)C.C(Cl)(Cl)Cl.CO>[CH2:13]([NH:20][C:21]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=NCc1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1c[nH]c2ccccc12)NCc1ccccc1
Reaction time: 2 h

Procedure:
Tryptamine (1.04 g, 6.5 mmol) was dissolved in a mixture of acetone (20 ml) and triethylamine (1 ml) under a nitrogen atmosphere. Benzyl isocyanate (952 mg, 7.15 mmol, 0.88 ml) was swiftly added dropwise at 0° C. and the mixture was then subsequently stirred for 2 h, while cooling with ice, and at RT for 2 h. A subsequent TLC in chloroform/methanol 20:1 showed only small amounts still of tryptamine. The mixture was concentrated i. vac. The residue obtained was purified by flash chromatography with 100 g of silica gel and chloroform/methanol 20:1→9:1→4:1.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.[CH3:24][O:25][C:26](=[O:31])[C:27](OC)=[O:28]>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:27]([C:26]([O:25][CH3:24])=[O:31])=[O:28])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reactant: COC(=O)C(=O)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To a solution of N-phenylsulfonyl indole (5.14 g, 20 mmol) in dry THF (100 ml) under argon, and cooled to -65° C., was added t-butyl lithium (13 ml, 22 mmol, 1.7 M in pentane). The solution was allowed to warm to 0° C. and stirred for 1 hr. The above solution was added via canula to a stirred solution of dimethyloxalate (9.5 g, 80 mmol) in THF (250 ml) at 0° C. After 4 hrs at 0° C. the mixture was quenched with saturated aqueous NH4CI and extracted with ethyl acetate (3×100 ml). The dried (MgSO4) extract was evaporated in vacuo, and the residue purified by chromatography over silica gel eluting with hexane/ethyl acetate (b 10:1) to give the α-keto ester 12 (2.3 g, 34%). M.p. 111-112° C. (from ethyl acetate). IR (CHCl3) 3680, 3619, 3415, 3019, 1743, 1692, 1600, 1537 and 1372 cm-1. λmax (ε) (MeOH) 208 (23930), 265 (4460), 275 (4170), 312 (10040) nm. 1H NMR (CDCl3) δ8.06 (1H, d, J=8.5 Hz), 7.78 (2H, d, J=7.5 Hz), 7.58 (1H,d, J=8 Hz), 7.51-7.37 (5H, m), 7.29 (1H, t, J=7.6 Hz), 3.99 (3H, s). 13C NMR (CDCl3) δ177.2, 161.3, 138.5, 136.7, 135.8, 134.1, 129.0, 128.7, 128.5, 127.0, 124.8, 123.4, 122.2, 115.3, 53.3. Anal. calcd for C17H13NO5S C, 59.47; H, 3.82; N, 4.08. Found C, 59.42; H3.84; N, 3.99%.
Reaction SMILES: [OH:1][C:2]1([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([C:35]#[N:36])=[CH:34][C:28]=3[N:27]=2)[C:12]2[C:13]3[C:5](=[CH:6][N:7](S(C4C=CC(C)=CC=4)(=O)=O)[C:8]=3[C:9]([CH3:15])=[CH:10][C:11]=2[CH3:14])[CH2:4][CH2:3]1.CCN(CCOC(C1(CCC(C)C)CCCCC1)=O)CC.[OH-].[K+]>CCO>[OH:1][C:2]1([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([C:35]#[N:36])=[CH:34][C:28]=3[N:27]=2)[C:12]2[C:13]3[C:5](=[CH:6][NH:7][C:8]=3[C:9]([CH3:15])=[CH:10][C:11]=2[CH3:14])[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(C)cc(C)c42)C(O)(c2nc4cc(C#N)ccc4[nH]2)CC3)cc1
Agent: CCN(CC)CCOC(=O)C1(CCC(C)C)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)c2[nH]cc3c2c1C(O)(c1nc2cc(C#N)ccc2[nH]1)CC3
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
(±)-2-(5-Hydroxy-6,8-dimethyl-1-tosyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile (41 mg, 0.083 mmol) in EtOH (0.83 mL) was treated with isomylamine (190 μL, 1.65 mmol) and KOH (46.3 mg, 0.826 mmol) and heated in a microwave for 30 minutes at 100° C. After 30 minutes an additional aliquot of isomylamine (190 μL, 1.65 mmol) and KOH (46.3 mg, 0.826 mmol) were added and the reaction heated in a microwave. After 30 minutes the reaction was complete. It was directly loaded onto a column and purified using FCC eluting with heptane:EtOAc 1:2 to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.59 (br. s., 1H), 7.89-7.95 (m, 1H), 7.55-7.72 (m, 1H), 7.34-7.55 (m, 1H), 7.01 (s, 1H), 6.56 (s, 1H), 6.15 (m, 1H), 2.89-2.90 (m, 2H), 2.27-2.45 (m, 5H). HRMS calcd. for C21H18N4O (M+H)+ 343.1554. found 343.156.
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)=[N:12][CH:13]=2)[CH:5]=1.O[CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]1[CH3:33]>>[N:14]1([C:11]2[N:12]=[CH:13][C:8]([O:7][CH2:6][C:4]3[CH:5]=[N:1][N:2]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]4[CH3:33])[N:3]=3)=[CH:9][CH:10]=2)[CH:18]=[N:17][N:16]=[N:15]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1O
Reactant: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Product: CC1CN(C(=O)OC(C)(C)C)CCC1n1ncc(COc2ccc(-n3cnnn3)nc2)n1

Procedure:
The title compound was synthesized from Intermediate 13 and tert-butyl 4-hydroxy-3-methylpiperidine-1-carboxylate in a manner similar to that described in Example 69. The compounds were isolated as a mixture of four stereoisomers. Characterized by LCMS (ES+-MS found: 464 (M+Na), 442 (M+H)).
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:25][CH2:24][N+:19]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:26][C:27]1[N:28]=[C:29]([CH3:33])[NH:30][C:31]=1[Cl:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:26][C:27]1[N:28]=[C:29]([CH3:33])[N:30]([CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[CH2:18][CH2:17][N:16]([C:13]3[N:12]=[CH:11][C:10]([O:9][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:15][N:14]=3)[CH2:25][CH2:24]2)[C:31]=1[Cl:32]
Reactant: c1ccc(COc2cnc(N3CC[N+]4(CCCC4)CC3)nc2)cc1
Reactant: Cc1nc(Cl)c(Cl)[nH]1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncc(OCc3ccccc3)cn2)CC1
Yield: 68.9 %

Procedure:
A mixture of 3.59 g (8.85 mmol) of 8-(5-benzyloxy-2-pyrimidinyl)-8-aza-5-azoniaspiro [4.5]decane bromide, 1.47 g (9.73 mmol) of 4,5-dichloro-2-methylimidazole and 4.89 g (35.41mmol) of potassium carbonate in 72 ml of dimethylformamide is refluxed for 12 hours and filtered hot. The dimethylformamide is evaporated and the product is chromatographed on silica gel, yielding 2.90 g (69%) of 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]-1-piperazinyl}-5-benzyloxypyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O>[Si:17]([O:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCc1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A solution containing 3 g (18 mmol) of 4-nitrophenethyl alcohol, 5.2 ml (20 mmol) of tert-butylchlorodiphenylsilane, 3.05 g (45 mmol) of imidazole and 438 mg (3.5 mmol) of N,N-dimethylaminopyridine in dimethylformamide (20 ml) was stirred under a nitrogen atmosphere at room temperature for 3 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (40 ml) and 2M hydrochloric acid (40 ml). The ethyl acetate layer was separated, washed with saturated aqueous sodium bicarbonate (40 ml), dried over magnesium sulfate, filtered and evaporated to give 6.56 g of 4-[2-(tert-butyldiphenylsilyloxy) ethyl]nitrobenzene as a yellow gum.
Reaction SMILES: [CH2:1]=[CH:2][S:3]([O-:6])(=[O:5])=[O:4].[Na+:7].[CH3:8][NH:9][CH3:10]>>[CH3:8][N:9]([CH3:10])[CH2:1][CH2:2][S:3]([O-:6])(=[O:5])=[O:4].[Na+:7]
Reactant: CNC
Reactant: C=CS(=O)(=O)[O-]
Agent: [Na+]
Product: CN(C)CCS(=O)(=O)[O-]

Procedure:
Sodium ethylenesulfonate (18.2 ml, 25% aqueous solution w/w) and dimethylamine (4.43 ml, 40% aqueous solution w/w) were heated in a sealed finger tube at 105° C. for 48 h before concentrating in vacuo to yield the subtitle compound as a white solid. Yield: 9.80 g.
Reaction SMILES: [C:1]([C:5]1[NH:16][C:8]2=[N:9][CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[NH:16][C:8]2=[N:9][CH:10]=[C:11]([NH2:13])[CH:12]=[C:7]2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2cc(N)cnc2[nH]1
Temperature: 30 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 2-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (2.3 g, 0.01 mol) in MeOH (50 mL) was added Raney Ni (0.23 g, 10%) under N2 protection. The mixture was stirred under hydrogen atmosphere (1 atm) at 30° C. for 1 h. The catalyst was filtered off and the filtrate was concentrated to dryness under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 1:2) to give 2-tert-butyl-1H-pyrrolo[2,3-b]pyridin-5-amine (1.4 g, 70%). 1H-NMR (MeOD, 400 MHz) δ 7.71 (s, 1H), 7.27 (s, 1H), 5.99 (s, 1H), 1.37 (s, 9H). MS (ESI) m/e (M+H+) 190.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([N:28]=[CH:29][N:30]=4)[C:24]([Br:27])=[CH:25][N:26]=3)=[CH:16][CH:15]=2)[C:10](=[O:31])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:27][C:24]1[N:23]2[N:28]=[CH:29][N:30]=[C:22]2[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]3=[O:31])=[CH:15][CH:16]=2)=[N:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNCCN1c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Yield: 77.3 %

Procedure:
A solution of 4-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (0.252 mg, 0.6 mmol) in 2:1 DCM:TFA (4.8 mL) is stirred for 1 hour at room temperature. The mixture is then diluted with DCM and basified with sat. NaHCO3. The aqueous layer is extracted with DCM (3×) and the organic layers are combined, dried over MgSO4, filtered and concentrated to afford the title compound as a solid (180 mg, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>O1CCOCC1>[CH:12]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[CH2:13]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)OC)nc1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
The title compound was prepared by following general procedure 2. Methyl 5-bromopyridine-2-carboxylate (4.0 g, 18.5 mmol) was dissolved in 160 mL dioxane. Vinyltributyltin (11.7 g, 37 mmol) was added to this solution at 25° C., followed by addition of dichlorobis(triphenylphosphine) palladium (1.5 g, mmol). The reaction mixture was degassed and purged with nitrogen for 5 min. and then heated at 100° C. for 2 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by SiO2 chromatography (100-200 mesh, eluent: hexane-50% ethyl acetate-hexane gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 2 g of methyl 5-vinylpyridine-2-carboxylate as a pale yellow oil (solid at −20° C.). TLC Rf 0.3 in 40% Ethyl acetate:Hexane.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH:43]([C:46]1[CH:47]=[CH:48][C:49]([O:81][CH3:82])=[C:50]([C:52]2[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=2[CH2:62][NH:63][C:64]2[N:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])=[CH:66][N:65]=2)[CH:51]=1)([CH3:45])[CH3:44].Br[C:84]1[CH:89]=[C:88]([C:90]([F:93])([F:92])[F:91])[CH:87]=[C:86]([C:94]([F:97])([F:96])[F:95])[CH:85]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:91][C:90]([F:92])([F:93])[C:88]1[CH:89]=[C:84]([N:63]([CH2:62][C:53]2[CH:54]=[C:55]([C:58]([F:61])([F:59])[F:60])[CH:56]=[CH:57][C:52]=2[C:50]2[CH:51]=[C:46]([CH:43]([CH3:45])[CH3:44])[CH:47]=[CH:48][C:49]=2[O:81][CH3:82])[C:64]2[N:65]=[CH:66][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])=[CH:68][N:69]=2)[CH:85]=[C:86]([C:94]([F:95])([F:96])[F:97])[CH:87]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(OCCCC(=O)OC(C)(C)C)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
To toluene (1 ml) are added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (62 mg) and palladium acetate (II) (16 mg) and the mixture is stirred under nitrogen atmosphere at room temperature for 5 minutes. To the mixed solvent is added the mixed solution of tert-butyl 4-{2-[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg), 1-bromo-3,5-bis-trifluoromethyl-benzene (126 mg) and toluene (1.5 ml), and the mixture is degassed under reduced pressure and thereto is added sodium tert-butoxide (51 mg) and the mixture is stirred under nitrogen flow at 80° C. overnight. The reaction solution is allowed to cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=10:1) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-phenyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (204 mg). MS (m/z): 772 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])[CH2:8][CH2:7]1.[OH-].[K+]>C(O)C>[C:18]([O:17][C:15]([N:13]([CH2:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([CH2:5][CH2:4][C:3]([OH:22])=[O:2])[CH2:7][CH2:8]1)[CH3:14])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)CC[C@H]1CC[C@H](CN(C)C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C[C@H]1CC[C@H](CCC(=O)O)CC1)C(=O)OC(C)(C)C

Procedure:
0.990 g (3.16 mmol) trans-3-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexyl}-propionic acid methyl ester and 660 mg potassium hydroxide were dissolved in 5.0 ml of ethanol and the reaction mixture heated at reflux for 3 hours. It was then evaporated, subsequently poured into 50 ml of an ice/water mixture, acidified with aqueous hydrochloric acid to pH 5 and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure giving 0.900 g (95%) trans-3-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexyl}-propionic acid as colorless viscous oil, MS: 299 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.[CH2:15]([O:17][C:18](=[O:36])[C@@H:19]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:20][NH:21][C:22](=[O:25])[CH2:23][NH2:24])[CH3:16].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:36])[C@@H:19]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH2:20][NH:21][C:22](=[O:25])[CH2:23][NH:24][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:16]
Reactant: CCOC(=O)[C@H](CNC(=O)CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CCCCNc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)CCCCNc1ccccn1)NS(=O)(=O)c1ccccc1

Procedure:
Acid 3-3 (186 mg, 0.55 mmol), amine 3-6 (150 mg, 0.46 mmol), NMM (0.20 mL, 1.8 mmol) and BOP (302 mg, 0.68 mmol) were combined in 3 mL DMF. After 5 d the DMF was removed on a rotary evaporator, the residue was diluted with EtOAc, then washed with water, sat. NaHCO3, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 25% i-PrOH/EtOAc) provided 3-7 as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][CH:10]([C:12]1[CH:13]=[N:14][C:15]([F:19])=[CH:16][C:17]=1[I:18])[CH3:11])([CH3:6])([CH3:5])[CH3:4].[F:21][CH2:22][CH2:23]I>C(Cl)(Cl)Cl.C(O)(C)C>[F:19][C:15]1[N:14]=[CH:13][C:12]([CH:10]([N:9]([CH2:23][CH2:22][F:21])[C:8](=[O:20])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[CH3:11])=[C:17]([I:18])[CH:16]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1I
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CC(c1cnc(F)cc1I)N(CCF)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
Add sodium hydride (58.9 mg, 2.46 mmol) to a solution of [1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (300 mg, 819 μmol) at 0° C. Stir the mixture at 0° C. to RT for 1 h. Add 1-fluoro-2-iodo-ethane (570 mg, 3.28 mmol). Stir the mixture at RT for 4 h and then at 50° C. overnight. Dilute the mixture with chloroform/IPA (3/1, 100 mL) and wash with water/aqueous saturated sodium chloride. Dry the organic phase over sodium sulfate and concentrate in vacuo to give the crude product. Purify the crude product by FCC (20% ethyl acetate in hexane) to give 140 mg of the title compound (41%). MS (ES) m/z 413 [M+1]+.
Reaction SMILES: Cl.Cl.[CH:3]([C@@H:5]1[C@H:10]([CH2:11][CH2:12][C@@H:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[OH:14])[CH2:9][CH2:8][NH:7][CH2:6]1)=[CH2:4].[OH-].[Na+].C=O.C1(C)C(CO)=CC=CC=1.C(NCC)C>O>[CH2:3]([C@H:5]1[C@H:10]([CH2:11][CH2:12][C@@H:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[OH:14])[CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:4]
Reactant: C=C[C@H]1CNCC[C@H]1CC[C@H](O)c1ccnc2ccc(OC)cc12
Agent: C=O
Agent: Cc1ccccc1CO
Agent: Cl
Solvent: CCNCC
Solvent: O
Product: CC[C@@H]1CNCC[C@H]1CC[C@H](O)c1ccnc2ccc(OC)cc12
Temperature: 120 °C

Procedure:
A mixture of 6 g of 3-[3(R)-ethenyl 4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(S)-propanol dihydrochloride, 15 ml of a normal aqueous solution of sodium hydroxide, 1.2 ml of a 0.4% aqueous solution of formaldehyde and 60 ml of water was heated at 120° C. for 24 hours in an autoclave. After cooling, the reaction medium was made alkaline by addition of sodium hydroxide lye and extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The oily residue obtained was subjected to high pressure liquid chromatography (support: silica gel; eluant: 100/7.5/3.75 toluene-methanol-diethylamine mixture). The separated fractions containing the desired product were evaporated. There was thus recovered 2.6 g of an oil which, by the action of HCl in ethanol, was converted into the dihydrochloride. After three recrystallizations of this last product in ethanol, 0.7 g of 3-[3(S)-ethenyl 4(R)-piperidyl]-1-(6-methoxy-4-quinolyl)-1(S)-propanol were obtained in the form of the dihydrochloride melting at 204° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:27][CH3:28])=[CH:8][C:9]([O:25][CH3:26])=[C:10](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2.[CH3:33]CN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CO>[CH3:33][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([C:14](=[O:15])/[CH:13]=[CH:12]/[C:10]2[CH:11]=[C:6]([C:5]3[S:1][C:2]4[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=4[CH:4]=3)[C:7]([O:27][CH3:28])=[CH:8][C:9]=2[O:25][CH3:26])=[CH:17][CH:18]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)/C=C/c2cc(-c3cc4ccccc4s3)c(OC)cc2OC)cc1
Yield: 34 %

Procedure:
The title compound was prepared by esterification of 4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid (Ex-3) with methanol in the presence of EDCI and DMAP. Yellow solid, 34% yield, m.p. 149–151° C. 1H-NMR (300 MHz, CDCl3): 8.17 (d, 2H, J=6.7 Hz), 8.10 (d, 1H, J=15.8 Hz), 8.05 (d, 2H, J=6.7 Hz), 7.95 (s, 1H), 7.82 (m, 2H), 7.67 (s, 1H), 7.57 (d, 1H, J=15.8 Hz), 7.33 (m, 2H), 6.58 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 3.97 (s, 3H). MS m/z=458 ([M]+, 100%). HRMS (EI) Calcd. for C27H22O5S: 458.118 Found: 458.1196.
Reaction SMILES: CN(C)C1C=C([CH:9]=[C:10]([CH3:12])[N:11]=1)C(O)=O.Cl[C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:24])[N:23]=1)[C:18]([OH:20])=[O:19].C(N)(C)C>>[CH:10]([NH:11][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([CH3:24])[N:23]=1)[C:18]([OH:20])=[O:19])([CH3:12])[CH3:9]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: Cc1cc(C(=O)O)cc(N(C)C)n1
Solvent: CC(C)N
Product: Cc1cc(C(=O)O)cc(NC(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-dimethylamino-6-methyl-isonicotinic acid starting from 2-chloro-6-methyl-isonicotinic acid and isopropylamine; LC-MS: tR=0.52 min, [M+1]+=195.09.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:34])=[C:15]([CH3:33])[C:16]=1[C:17]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28]C)=[C:21]([CH:30]([CH3:32])[CH3:31])[CH:20]=1)=[O:18].[B]>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:34])=[C:15]([CH3:33])[C:16]=1[C:17]([C:19]1[CH:20]=[C:21]([CH:30]([CH3:31])[CH3:32])[C:22]([OH:28])=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=1)=[O:18]
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc4ccccc4c3)oc(C)c2C)cc1C(C)C
Agent: [B]
Solvent: ClCCl
Product: Cc1oc(Cc2ccc3ccccc3c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Yield: 53.7 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (1.04 g, 2.29 mmol) and 1M boron tribroride/CH2Cl2 (4.81 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 0.542 g (54%) of the title compound. 1H NMR (DMSO-d6) δ1.12 (d, 12 H), 1.82 (s, 3 H), 2.18 (s, 3 H), 3.31 (septet, 2 H), 4.02 (s, 2 H), 7.22 (dd, 1 H), 7.43-7.50 (m, 4 H), 7.55 (s, 1 H), 7.76-7.86 (m, 3 H), 9.12 (s, 1 H).