Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH:9]([CH3:10])[CH2:8][N:7](C(OCC)=O)[CH2:6][CH:5]1[CH3:16])[CH3:2]>[OH-].[Na+]>[CH2:1]([NH:3][CH:4]1[CH:5]([CH3:16])[CH2:6][NH:7][CH2:8][CH:9]1[CH3:10])[CH3:2]
Reactant: CCNC1C(C)CN(C(=O)OCC)CC1C
Agent: [Na+]
Agent: [OH-]
Product: CCNC1C(C)CNCC1C

Procedure:
The Mixture A of isomers of 4-ethylamino-1-carbethoxy-3,5-dimethylpiperidine (2.1 g, 0.92 mmol) was stirred in 5 N NaOH solution (20 ml) at 100° C. for 96 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to afford Mixture A of isomers of 4-ethylamino-3,5-dimethyl piperidine as oil. Yield 1.34 g (93.2%), C9H20N2, m/z 157 (M+1), PMR (CDCl3): 0.94 (dd, 9H), 1.45 (m, 1H), 1.66 (m, 1H), 1.94 (m, 3H, D2O exchangeable), 2.36 (m, 1H), 2.44-2.74 (m, 3H), 3.0 (dd, 1H), 3.5 (m, 1H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23](=[O:29])[NH:24][CH2:25][CH2:26][O:27][NH2:28])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.CO>[C:1]1([C:7](=[N:28][O:27][CH2:26][CH2:25][NH:24][C:23](=[O:29])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])[C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1c[nH]c2cnccc12
Reactant: CC(C)(C)OC(=O)NCCON
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCON=C(c1ccccc1)c1c[nH]c2cnccc12
Yield: 89 %

Procedure:
tert-Butyl 2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methylene]amino]oxy]ethylcarbamate (429.2 mg, 89%) was prepared as a white foam using phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (Reference Example 8) and tert-butyl[2-(aminooxy)ethyl]carbamate following the procedure described for Example 104: Rf 0.42 (90:10 methylene chloride/methanol); 1H NMR (300 MHz, CD3OD) δ1.38-1.39 (9H, s), 3.40-3.44 (2H, m), 3.17-3.20 (1H, t, J=5.7 Hz), 3.26-3.28 (1H, t, J=5.3 Hz), 6.50-6.80 (1H, m), 7.30-7.50 (5H, m), 7.86-8.32 (2H, m), 8.76 (1H, s); ESI MS m/z 381 [C21H24N4O3+H]+; HPLC (Method A) 96.8% (AUC), tR=17.7 min.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[N:4][CH:3]=1.Cl.Cl[CH2:17][C:18]1[C:19]([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[N:20][CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:14][O:13][CH2:12][CH2:11][O:10][C:5]1[CH:6]=[C:7]([C:2]([O:1][CH2:17][C:18]2[C:19]([C:24]3[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=3)=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:3][N:4]=1)[CH:8]=[O:9]
Reactant: Cn1nccc1-c1ncccc1CCl
Reactant: COCCOc1cc(C=O)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C=O)c(OCc2cccnc2-c2ccnn2C)cn1
Temperature: 60 °C
Yield: 25.4 %

Procedure:
A mixture of 5-hydroxy-2-(2-methoxyethoxy)isonicotinaldehyde (125 mg, 0.63 mmol, 1 eq.), 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine hydrochloride salt (120 mg, 0.63 mmol, 1 eq.), and Cs2CO3 (410 mg, 1.26 mmol, 2 eq.) in DMF (3.0 mL) was heated at 60° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(2-methoxyethoxy)-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (59 mg, 25%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.59 (dd, J=4.7, 1.6 Hz, 1H), 7.87 (dd, J=7.9, 1.3 Hz, 1H), 7.73 (s, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.27 (dd, J=7.9, 4.8 Hz, 1H), 7.00 (s, 1H), 6.25 (d, J=1.9 Hz, 1H), 5.02 (s, 2H), 4.26 (dd, J=5.4, 3.9 Hz, 2H), 3.80 (s, 3H), 3.57 (dd, J=5.4, 3.9 Hz, 2H), 3.28 (s, 3H). LRMS (M+H+) m/z 387.1.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[S:27]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.OS(C(F)(F)F)(=O)=O.[OH-].[Na+]>C(Cl)Cl>[C:30]1([S:27]([C:21]2[C:20]3[C:24](=[CH:25][CH:26]=[C:18]([O:17][CH:14]4[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]4)[CH:19]=3)[NH:23][N:22]=2)(=[O:28])=[O:29])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNCC3)cc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
A solution of 4-[3-(1-naphthylsulfonyl)-1H-indazol-5-yloxy]piperidin-1-ylcarboxylic acid benzyl ester (1.78 g, 3.29 mmol) and anisole (1.1 mL, 9.9 mmol) in methylene chloride at 0° C. was treated with triflic acid (2.05 mL, 23.2 mmol), stirred at 0° C. under nitrogen for 1.5 hours, treated with 2.5 N sodium hydroxide and extracted with warm ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography with 0.5-0.75% ammonium hydroxide/5.0-7.5% methanol in chloroform to give 3-(1-naphthylsulfonyl)-5-(piperidin-4-yloxy)-1H-indazole as a dark orange semi-solid, 0.860 g, (64.2% yield). A portion of the semi-solid (160 mg) was dispersed in methanol and chloroform, treated with ethereal HCl and concentrated in vacuo for 12 hours at 82° C. to yield the title product as a light orange solid, 0.151 g, mp 174-6° C. (dec), Mass spectrum (+EI, [M+H]+) m/z 408. 1HNMR (500 MHz, DMSO-d6): δ14.11-14.19 (br, 1H), 8.66-8.80 (br, m, 3H), 8.55-8.57 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.70-7.73 (m, 1H), 7.54-7.63 (m, 3H), 7.31 (d, 1H, J=2.07 Hz), 7.12-7.15 (m, 1H), 4.69-4.73 (m, 1H), 3.19-3.29 (m, 2H), 3.06-3.13 (m, 2H), 2.02-2.07 (m, 2H), 1.75-1.83 ppm (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+]>CS(C)=O>[NH2:2][C:1]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[O:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)COc1ccccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1oc2ccccc2c1N
Temperature: 25 °C
Yield: 56.2 %

Procedure:
A solution of methyl 2-(2-cyanophenoxy)ethanoate (3.82 g, 20 mmol) in DMSO (40 mL) is added dropwise to a suspension of NaH (0.84 g, 21 mmol) and DMSO (10 mL) stirred under N2 at 25° C. After 10 min the mixture is poured onto ice water and extracted with ether. The combined extracts are washed with water, saturated brine and dried (MgSO4). After removal of the solvent under reduced pressure, methyl 3-aminobenzo[b]furan-2-carboxylate (2.15 g, 56%) is obtained as a yellow solid. 1H NMR (DMSO) δ7.95 (1H, d, J=7.7 Hz), 7.48 (2H, d, J=3.4 Hz), 7.29-7.22 (1H, m), 6.40 (2H, brs), 3.80 (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH:3]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]1C[CH:26]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].CN(C)C(COCCCCCCCC)COCCCCCCCCC1CC1CCCCCCC(OC)=O>>[CH3:36][N:2]([CH3:1])[CH:3]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: CCCCCCCCC1CC1CCCCCCCCOCC(COCCCCCC(=O)OC)N(C)C
Agent: CCCCCCCCOCC(COCCCCCCCCC1CC1CCCCCCC(=O)OC)N(C)C
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COCCCCCC(=O)OC)N(C)C

Procedure:
Ketone (q) may also be carried forward to methyl 6-(2-(dimethylamino)-3-((8-(2-octylcyclopropyl)octyl)oxy)propoxy)hexanoate (Compound 22) in a manner analogous to that described above for Compound 2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27]>C(NCC)C.CCOC(C)=O>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][CH2:2][N:11]([CH2:12][CH3:13])[CH2:8][CH3:7]
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCCBr)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: CCN(CC)CCCc1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
A solution of 0.290 g (0.603 mmol) (E)-N-[4-(3-bromo-propyl)-3-chloro-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide (Z45d) in 2 mL diethylamine was heated to 100° C. in a sealed reaction vessel in the microwave for 5 min. The reaction mixture was diluted with EtOAc, the org. phase was washed with water, dried over sodium sulphate and evaporated down i. vac. The residue was triturated with ether, the precipitate was filtered off, washed with ether and dried in a HV.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3].[CH:28]1(Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:23]([CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:24]([O:26][CH3:27])=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(CC(C)C)c1
Reactant: BrC1CCCCCC1
Product: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)c(CC(C)C)c1)C1CCCCCC1

Procedure:
10 g (0.0275 mol) of methyl 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]acetate are reacted, in analogy to the procedure of Example 1, with 10.04 g (0.055 mol) of cycloheptyl bromide and 6.17 g (0.055 mol) of potassium tertiary butylate to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([OH:26])[CH2:24][OH:25])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:35]=[C:36]=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:26][C:36](=[O:37])[NH:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:36](=[O:37])[NH:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](CSC[C@H](O)CO)NC(=O)OCc1ccccc1
Reactant: CCCCCCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCC
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-dihydroxypropylthio)propanoate (13) was stirred in anhydrous benzene (0.1 M) under nitrogen at room temperature. Octyl isocyanate (2.02 eq) and DMAP (dimethylaminopyridine, 2.02 eq) were added and the resulting mixture heated to 40° C. and stirred overnight. The reaction mixture was concentrated to remove benzene then reconstituted in DCM and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-50% EtOAc/Hex to afford the title product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]=O)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[C:14]([O:18][C:19]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19](=[O:20])[CH:21]=[CH:12][CH2:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]2)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1cc(CC=O)cc2cn[nH]c12
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(CC=CC(=O)OC(C)(C)C)cc2cn[nH]c12
Reaction time: 15 h
Yield: 51.5 %

Procedure:
Tetrahydrofuran (8 mL) was added to a flask containing (7-methyl-1H-indazol-5-yl)-acetaldehyde (1.94 mmol, 1.0 equiv) and (tert-butoxycarbonyl-methylene)triphenylphosphorane (1.46 g, 3.88 mmol, 2.0 equiv) at room temperature under nitrogen. The resulting yellow solution was stirred overnight (15 h). LCMS indicated completion. The mixture was partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography to afford the desired product as a yellow oil (272 mg, 51.5% for two steps). MS (ESI) [M+H]+=273; 1H NMR (400 MHz, CDCl3) δ 12.3 (br., 1H), 8.06 (s, 1H), 7.36 (s, 1H), 7.04 (m, 1H), 6.96 (s, 1H), 5.74 (dd, J=15.6 and 1.6 Hz, 1H), 3.54 (d, J=6.8 Hz; 2H), 2.57 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[N:7]=1)(=[O:5])[CH3:4].Br.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O.C(OCC)(=O)C>[C:13]([NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[O:5])[CH2:4][Br:1])[N:7]=1)(=[O:15])[CH3:14]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc(C(C)=O)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(C(=O)CBr)n1

Procedure:
Bromine (1.9 ml) was added dropwise to a mixture of 2-acetyl-6-acetylaminopyridine (6.6 g) and 30 wt % hydrogenbromide-acetic acid solution (7.4 ml) in acetic acid (66 ml) at ambient temperature under stirring and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 2-acetylamino-6-bromoacetylpyridine (8.57 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3c(Cl)nccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1nccc2c(NC3CCNCC3)cccc12

Procedure:
Deprotection was performed (room temperature, 2 hours) by using Intermediate 84 (81.9 mg) and a mixed solution of trifluoroacetic acid and methylene chloride (1:1, 2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (2 ml) and diethyl ether (6 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (64 mg) as yellow powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10](I)[N:9]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](I)[CH:23]=[CH:22][N:21]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:19])[CH:25]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(I)n1
Reactant: Clc1cc(I)ccn1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-iodo-6-trifluoromethyl-pyrimidine (example A.3) (1.21 g, 3.15 mmol) and commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (765 mg, 3.2 mmol) according to the general procedure IVc protocol a. Obtained as a light yellow solid (0.53 g, 45%). MS (ISP) 369.8 [(M+H)+]; mp 151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[O:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:36][CH:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: NC1CCOCC1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3CCOCC3)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with tetrahydro-2H-pyran-4-amine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=497.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15](=[O:17])[NH2:16])[NH:9]2.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>>[OH:1][CH:2]([CH2:18][NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15](=[O:17])[NH2:16])[NH:9]2
Reactant: CC(C)(C)N
Reactant: Cc1cc(OCC2CO2)c2cc(C(N)=O)[nH]c2c1
Product: Cc1cc(OCC(O)CNC(C)(C)C)c2cc(C(N)=O)[nH]c2c1
Reaction time: 24 h
Yield: 55 %

Procedure:
1.5 g of 4-(2,3-epoxypropoxy)-2-carbamoyl-6-methyl indole in 25 ml tert.-butylamine is heated to boiling for 24 hours. The solution is then evaporated and the residue dissolved in chloroform. The chloroform solution is washed with water, dried and evaporated. The residue is suspended in hot acetic ester and mixed with 0.8 g benzoic acid. A clear solution will result here, from which a precipitate deposits. This is aspirated and recrystallized from 100 ml acetic ester. There is obtained 1.5 g (55% of theory) 4-(2-hydroxy-3-tert.-butylaminopropoxy)-2-carbamoyl-6-methyl indole as benzoate; m.p. 213°-214° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].[Cl:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[CH:34]=[CH2:35]>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH:35]=[CH:34][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][C:28]=2[Cl:27])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(I)cc1-c1ccccc1C
Reactant: C=Cc1cnccc1Cl
Solvent: CN1CCCC1=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cnccc2Cl)cc1-c1ccccc1C
Yield: 46.5 %

Procedure:
N-[4-iodo-2-(2-methylphenyl)benzoyl]methionine methyl ester (2.1 g, 4.34 mmol), 4-chloro-3-vinylpyridine (1.4 g, 10 mmol), and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with methylene chloride 1:1, 177 mg, 0.22 mmol) were combined in NMP (9 mL) and TEA (3 mL) and heated at 100° C. for 5 hours. The mixture was concentrated and purified by flash chromatography (50% EtOAc in hexanes) to give 1.0 g of the title compound. MS m/e 495 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.61 (m, 2H), 1.90 (m, 2H), 2.15 (m, 6H), 3.69 (s, 3H), 4.65 (m, 1H), 5.95 (m, 1H), 7.3-7.5 (m, 9H), 7.69 (m, 1H), 8.05 (m, 1H), 8.45 (s, 1H).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:21][N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=1)=[O:19]
Reactant: CNc1ccccc1
Reactant: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Agent: Cl
Solvent: ClCCl
Product: CN(C(=O)c1cc(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Phenylquinoline-4-carboxylic acid chloride hydrochloride (10.7 g) is added in portions over a period of 15 minutes, with stirring, to a solution of N-methylaniline (12.8 g) in methylene chloride (75 ml), cooled to 0° C. The mixture is stirred for 2 hours 30 minutes at 10° C. The solution obtained is washed with a 20% strength solution of acetic acid in water (120 ml). The acetic acid solution is extracted with methylene chloride (100 ml). The organic phases are combined, washed with water (3×100 ml), dried over magnesium sulphate and evaporated under reduced pressure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:29][O:30][CH3:31])[C:20]([NH:22][C:23]([CH3:28])([CH3:27])[C:24]#[C:25][CH3:26])=[O:21].O>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)[O:11][CH:19]([CH2:29][O:30][CH3:31])[C:20]([NH:22][C:23]([CH3:28])([C:24]#[C:25][CH3:26])[CH3:27])=[O:21])#[N:2]
Reactant: COc1cc(O)cc(C#N)c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1cc(C#N)cc(OC)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
3-Cyano-5-methoxyphenol (prepared as described in J. Med. Chem. (1993), 36, No 16, 2367; 0.119 g) in dry N,N-dimethylformamide (3 ml) containing anhydrous potassium carbonate (0.168 g) and 2-bromo-N-(4-methylpent-2-yn-4-yl) 3-methoxypropionamide (0.210 g) were stirred and heated to 80° C. for 5 hours. The mixture was cooled to ambient temperature, stored for 2 days then poured into water and extracted with ethyl acetate. The organic phases were combined, washed with water, dried over magnesium sulphate then evaporated under reduced pressure to give a brown gum. The gum was fractionated by chromatography (silica; hexane/ethyl acetate 3:2 by volume) to give the required product (0.110 g) as a colourless gum.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH:3]=[CH2:4].I[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C)CCN(C)C.Cl>C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=1)[CH:3]=[CH:4][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1
Reactant: C=CC(C)(C)COCc1ccc(F)c(Oc2ccccc2)c1
Reactant: COc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Product: COc1ccc(C=CC(C)(C)COCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 160 °C
Yield: 9 %

Procedure:
A stirred mixture of 3,3-dimethyl-4-(4-fluoro-3phenoxybenzyloxy)but-1-ene (0.27 g), p-iodoanisole (0.21 g), palladium (II) diacetate (0.02 g), tri-o-toluylphosphine (0.054 g) and tetramethylethylenediamine (0.1 g) was heated at 160° C. for 24 hours. After cooling, the mixture was poured into dilute aqueous hydrochloric acid, and extracted into ethyl acetate, the extracts combined, washed with water, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent to yield a brown oil. The crude product was distilled through a kugelrohr apparatus to give 3,3-dimethyl-1-(4-methoxyphenyl)-4-(4-fluoro-3-phenoxybenzyloxy)but-1-ene (0.033 g), as an oil, containated by 30% of 3,3-dimethyl-2(4-methoxyphenyl)-4-(4-fluoro-3-phenoxybenzyloxy)but-1ene.