Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:22][CH2:23][CH:24]1[CH2:26][CH2:25]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH:24]1([CH2:23][NH:22][C:18]([CH:16]2[CH2:15][C:14]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:2]([Cl:1])[CH:3]=3)([OH:21])[CH2:17]2)=[O:19])[CH2:26][CH2:25]1
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: NCC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(NCC1CC1)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added aminomethylcyclopropane (0.112 ml, 1.29 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (101 mg, 43% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C20H27ClN2O2, 362.9, found, 363.2 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.44-7.38 (m, 2H), 7.28 (dd, J=7.9, 2.6 Hz, 1H), 6.40 (br apt t, J=5.4 Hz, 1H), 3.69 (s, 2H), 3.10-3.04 (m, 2H), 2.76-2.68 (m, 3H), 2.57-2.42 (m, 6H), 1.78-1.69 (m, 4H), 0.94-0.84 (m, 1H), 0.48-0.40 (m, 2H), 0.18-0.12 (m, 2H); 100 MHz 13C NMR (CDCl3) δ 176.7, 146.1, 135.3, 133.9, 130.8, 126.3, 123.6, 74.0, 56.7, 54.3, 44.9, 41.1, 40.7, 33.1, 23.7, 10.8, 3.7.
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2=[O:18])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20]1.[CH2:26]([OH:28])[CH3:27]>C(OCC)(=O)CC>[O:19]1[CH:23]=[CH:22][C:21]([CH:24]2[C:26](=[O:28])[C:27]3[C:14]([C:13]([O:12][CH2:11][CH3:10])=[O:18])=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][CH:1]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:20]1
Reactant: CCO
Reactant: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Reactant: O=Cc1ccoc1
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccoc1)C(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 5.5 %

Procedure:
A mixture of (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (948 mg, 4 mmol) and furan-3-carbaldehyde (422 mg, 4.4 mmol) in ethyl propionate (30 mL) was cooled to 0° C. Then a solution of sodium ethanoxide in ethanol [sodium (368 mg, 16 mmol) in ethanol (20 mL)] was added dropwise. After the addition, the mixture was stirred at room temperature for 2 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:1) to give ethyl 3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (80 mg, yield: 5%). LC-MS (ESI) m/z: 362 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:8]([OH:10])=[O:9])[N:6]=1.[Cl:32]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:32])=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)c(Cl)s1
Yield: 70.9 %

Procedure:
To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(triphenylmethoxyimino)ace tic acid (5.81 g, 13.47 mmol) in DMF (30 mL) at room temperature (1 mL) was added N-chlorosuccinimide (1.80 g, 13.47 mmol). After overnight reaction the reaction mixture was poured into water (about 500 mL) and the resulting precipitate was filtered, washed with water and then with ethyl acetate and dried in vacuum to afford 4.43 g (71%) of the title compound. 13C NMR (CDCl3) δ108.5, 125.6, 126.2, 126.6, 12.3, 134.7 141.8, 146.5, 162.1, 163.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[O:33][CH3:34]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:19][C:18]=2[O:33][CH3:34])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1nc(-c2ccc(N)c(OC)c2)oc1C
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2OC)nc1Cl
Yield: 70.4 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.135 g, 0.78 mmol), thionyl chloride (4 mL), methyl 2-(4-amino-3-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (105d) (0.3 g, 1.03 mmol) and pyridine (5 mL), to obtain 0.23 g of the title compound as a colorless solid (71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[N-:13]=[N+]=[N-].[Na+].C1C=CC=CC=1.COP(OC)OC.[Cl:30]CCl>CO.CO.ClCCl>[ClH:30].[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH2:13])[CH:5]=1
Reactant: ClCCl
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(CBr)c1
Agent: COP(OC)OC
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cccc(CN)c1
Product: Cl
Reaction time: 8 h
Yield: 83 %

Procedure:
Methyl-3-bromomethylbenzoate (5.72 g, 0.025 mol, Ryan Chemicals (Maybridge)), sodium azide (3.25 g, 0.05 mol), and tetra n-butylbromide (0.4 g, 0.00125 mol) were added to 100 mL dry benzene in a 250-mL round-bottom flask equipped with a condenser and calcium chloride drying tube in an atmosphere of argon. The mixture was then heated at reflux for 24 h and monitored by TLC (Bakerflex) using dichloromethane, 2% methanol, and 5% methanol/dichloromethane as solvents. The mixture was cooled, the inorganic salts were removed by filtration, and washed with benzene. The filtrate was added to a 250-mL separatory funnel and was then washed three times with water, once with brine, and dried with magnesium sulfate. The drying agent was removed by filtration, and the volume of the clear colorless filtrate was reduced to ~50 mL in a 100-mL round-bottom flask. The solution was saturated with argon and 3.1 g (0.025 mol) trimethylphosphite was added by drop over 10 min. The reaction bubbled during the addition (loss of nitrogen) and was mildly exothermic (once it was necessary to cool on ice with a calcium chloride drying tube in place to keep the temperature below 30° C.). The reaction was followed in the TLC system above and after 18 h, it was necessary to add ~200 mg of additional trimethylphosphite. The reaction was complete after stirring overnight. Anhydrous HCl was then bubbled into the solution with vigorous stirring. After 2 h, a precipitate formed and alter 4 h, the reaction was complete. The white solid was removed by filtration. It was then added to 200 mL ether in a 500-mL Erlenmeyer flask and vigorously stirred for 5 min. After filtration, the solid was dissolved in a minimum amount of boiling methanol and ether was added until the solution was slightly turbid. Cooling, filtering, and drying in vacuo gave 4.2 g (83%) of methyl-3-aminomethylbenzoate hydrochloride, mp 177°-178° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C1(C)C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C@@H:1]1[CH2:2][C@H:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccccn1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccccn1
Yield: 44 %

Procedure:
A solution of 2-vinylpyridine (13-1) (2 g, 19.0 mmol) in toluene (40 ml) was treated with ethyl diazoacetate (1.97 ml, 19.0 mmol) and stirred at reflux overnight. The mixture was concentrated in vacuo, and the residue was purified by gradient elution on silica gel (0-50% EtOAc/hexanes) to elute peak 1; the solvent gradient was then ramped to 100% EtOAc to elute peak 2. This yielded the 13-3 (1.6 g, 44%) as the first eluting diastereomer, and the corresponding cis diastereomer 13-2 (914 mg, 25%) as the second eluting diastereomer, both as yellow oils. 1H NMR (500 MHz, CDCl3): δ 8.44 (m, 1H), 7.56 (dt, J=7.6, 1.7 Hz, 1H), 7.22 (dd, J=7.8, 1.0 Hz, 1H), 7.08 (ddd, J=7.6, 4.9, 1.2 Hz, 1H), 4.17 (q, J=7.3 Hz, 2H), 2.58 (ddd, J=10.0, 6.1, 3.9 Hz, 1H), 2.25 (ddd, J=9.5, 5.6, 3.9 Hz, 1H), 1.61, (m, 2H), 1.28 (t, J=7.1 Hz, 3H). LC/MS: m/z (M+H)=192.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])=[CH:14][CH:15]=1)=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:39][CH:40]=2)[CH2:30][CH2:29]1>C(Cl)Cl.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=4[F:26])=[CH:14][CH:15]=3)=[O:3])=[N:39][CH:40]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2nccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 143.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 1 h at reflux. Title compound: ESI-MS: 517.1 [M+H]+; tR=3.37 min (System 1); TLC: Rf=0.11 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([OH:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[N+:12]([O-])([OH:14])=[O:13].OS(O)(=O)=O>>[N+:12]([C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([OH:9])=[N:5][CH:6]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1ncccc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a mixture of 3-(trifluoromethyl)pyridin-2-ol (2 g, 12.26 mmol) and nitric acid (1.644 mL, 36.8 mmol) was added H2SO4 (12.03 g, 123 mmol) at 0° C. Then the mixture was stirred at 25° C. for 16 h. The mixture was then warmed to 60° C. for 5 h, cooled and added to 150 g of ice. The mixture was extracted with EA (2×100 mL) and washed with H2O (100 mL) to give the organic layer. The combined organic extract was washed with brine, dried over Na2SO4 and concentrated to yield a brown solid of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.2 g, 8.99 mmol, 73.3% yield): 1H NMR (400 MHz, CD3OD) δ 8.91 (d, J=2.43 Hz, 1H), 9.42 (d, J=2.43 Hz, 1H); ES-LCMS m/z 209.0 (M+H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([C:24]2[C:25]([C:33]3[CH:34]=[C:35]([NH:39][C:40](=[O:49])[C:41]4[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=4[F:48])[CH:36]=[CH:37][CH:38]=3)=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)[CH:21]=[CH:20][N:19]=1>>[F:48][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:41]=1[C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:25]2[C:24]([C:22]3[CH:21]=[CH:20][N:19]=[C:18]([NH:16][C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:11]=4)[N:23]=3)=[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]3[N:26]=2)[CH:34]=1)=[O:49]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCN4CCOCC4)c3)n2)c1)c1c(F)cccc1F

Procedure:
The title compound was prepared from (3-{[2-(4-morpholinyl)ethyl]oxy}phenyl)-amine and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide in a manner analogous to Example 27, Step D. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.55 (s, 1H), 8.84 (d, 1H), 8.48 (d, 1H), 8.27 (d, 1H), 8.01 (s, 1H), 7.81 (d, 1H), 7.59 (m, 1H), 7.49 (m, 3H), 7.35 (d, 1H), 7.25 (m, 3H), 7.13 (t, 2H), 6.51 (d, 2H), 4.0 (m, 2H), 3.54 (m, 4H), 2.64 (m, 2H), 2.41 (m, 4H). HRMS calculated C36H32F2N7O3 [M+H]+ 648.2535, found 648.2528.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:18][C:19]2[CH:20]=[C:21]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27]3)=[O:23])[CH:28]=[CH:29][C:30]=2[CH3:31])=[O:17])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C(O)c1ccc(OCc2ccccc2)cn1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccc2)cn1

Procedure:
The title compound was prepared from 5-(benzyloxy)pyridine-2-carboxylic acid and 3-amino-N-cyclopropyl-4-methylbenzamide according to the method described for Example 1; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.32 (s, 2H), 7.39 (m, 4H), 7.51 (m, 2H), 7.57 (m, 1H), 7.71 (m, 1H), 8.13 (m, 1H), 8.22 (m, 1H), 8.36 (m, 1H), 8.48 (s, 1H), 10.16 (s, 1H); Mass Spectrum: M+Na+ 424.
Reaction SMILES: C(CN[C:6]1([C:16]#[N:17])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)C=C.[CH2:18]([Mg]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+].[CH2:29]1[CH2:33]OC[CH2:30]1>>[CH2:33]([NH:17][CH2:16][C:6]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][CH2:8][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:14][CH2:15]1)[CH:29]=[CH2:30]
Reactant: C=CCCNC1(C#N)CCC2(CC1)OCCO2
Reactant: Cl[Mg]Cc1ccccc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCNCC1(Cc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.50 g 8-(allylmethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 35 ml analytical grade tetrahydrofuran was added dropwise to 14.8 ml 2.0 molar benzylmagnesium chloride solution in THF under a nitrogen atmosphere and the mixture was stirred overnight at room temperature. For working up, 25 ml saturated ammonium chloride solution were added, while cooling with ice, the phases were separated, the aqueous phase was extracted three times with 25 ml diethyl ether each time, the combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. The crude allyl-(8-benzyl-1,4-dioxaspiro[4.5]dec-8-yl)methylamine obtained (5.41 g) was stirred, without further purification, with a mixture of 13 ml conc. hydrochloric acid (32 per cent by weight) and 7.5 ml water for 24 hours at room temperature. The reaction mixture was then first washed three times with 50 ml diethyl ether each time and then rendered alkaline by addition of sodium hydroxide solution (32 per cent by weight), while cooling with ice, and extracted three times with 100 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 3.55 g 4-(allylmethylamino)-4-benzylcyclohexanone were obtained.
Reaction SMILES: C([Cl:4])(=O)C.C(O[C:10](=O)[N:11]([C@H:13]([C:15](=[O:44])[NH:16][C@H:17]([C:21]([N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:24]1[C:33](=[O:43])[NH:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:42])=[O:22])[CH:18]([CH3:20])[CH3:19])[CH3:14])C)(C)(C)C>CO>[ClH:4].[Cl:42][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:35]=1[NH:34][C:33]([C@@H:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31][CH2:32][N:23]1[C:21](=[O:22])[C@@H:17]([NH:16][C:15](=[O:44])[C@@H:13]([NH:11][CH3:10])[CH3:14])[CH:18]([CH3:19])[CH3:20])=[O:43]
Reactant: CC(=O)Cl
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl)C(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A solution of acetyl chloride (552 mg, 500 μL, 7.03 mmol, Eq: 115) in MeOH (2 mL) was added to a vial containing ((S)-1-{(S)-1-[(S)-1-(2-chloro-6-fluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-methyl-propylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (36 mg, 61.1 μmol, Eq: 1.00). The mixture was stirred at RT for 1 h. The solvent was evaporated and the resulting solid was dissolved in MeCN (3 mL) and water (1 mL) which was lyophilized to give (S)-2-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2-chloro-6-fluoro-phenyl)-amide hydrochloride (30 mg) as a white powder, m/z=489 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH:6]([OH:23])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:10][CH2:9]1.[CH3:28][CH:29]1[CH2:35][C:34](=[O:36])[O:33][C:31](=[O:32])[CH2:30]1.[Li+].[OH-].C1COCC1.O>O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][CH:6]([OH:23])[CH2:5][O:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][C:34]([CH2:35][CH:29]([CH3:28])[CH2:30][C:31]([OH:33])=[O:32])=[O:36])[CH2:13][CH2:12]1
Reactant: Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC1CC(=O)OC(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CC(=O)O)CC(=O)Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol (75 uL, 0.2M/NMP) was mixed with 3-methyl glutaric anhydride (3 eq, 225 uL 0.2M /NMP) to get a product containing both esther and amide. After evaporation of the mixture it was treated with 3 eq 0.5M LiOH in (THF/water 1:4) for two hours at 80° C. to hydrolyse the esther. The reaction mixture was diluted with more water (2 mL) and the desired product was extracted with 5×500 uL EtOAc which was evaporated to dryness.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:9]1[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH3:15])[CH:14]=1>CN(C=O)C.[Cl-].[Na+].O>[CH3:15][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[N+:16]([O-:18])=[O:17])[O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cccnc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Rinse 35% oil dispersion of KH (12 g, 11 mmol) with 100 mL hexanes twice and dry under vacuum before cooling in an ice bath. Add 100 mL dry DMF then a solution of 3-hydroxypyridine (10 g, 105 mmol) in 100 mL DMF dropwise. Treat with a solution of 5-fluoro-2-nitrotoluene (16.3 g, 105 mmol) in 50 mL DMF to obtain a dark solution. Stir at ambient temperature for 1 hour, pour the mixture into 1 liter of brine and extract twice with 200 mL of EtOAc. Combine the extracts and wash twice with 500 mL brine, dry over MgSO4 and concentrate to 24 g of a dark oil. Purification by chromatography 20% EtOAc in hexanes give the title compound as an oil: ISMS 231 (M+1); C12H10N2O3: calcd: C, 62.61; H, 4.38; N, 12.17; found: C, 62.63; H, 4.58; N, 12.06.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CNc1ccc(CC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNc1ccc(CC(=O)O)cc1
Reaction time: 3 h
Yield: 46.8 %

Procedure:
Methyl 2-(4-(methylamino)phenyl)acetate (721 mg. 4.0 mmol) was dissolved in tetrahydrofuran (10 mL) and treated with a 1 M aqueous solution of lithium hydroxide (4.4 mmol). After 3 hours, the mixture was acidified with 1 N aqueous hydrochloric acid and concentrated to remove tetrahydrofuran. The aqueous phase was extracted with dichloromethane (2×20 mL) and the organic layer was dried and concentrated to give 2-(4-(methylamino)phenyl)acetic acid (309 mg, 1.87 mmol).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:36]=[O:37].O>O1CCCC1>[CH2:7]([N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]1[CH:21]=[CH:22][C:2]([CH:36]=[O:37])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
In an argon atmosphere, the obtained 4-bromo-N,N-dibenzylaniline (425 mg, 1.21 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to −78° C. A 1.6 M n-butyl lithium hexane solution (1.1 mL, 1.8 mmol) was added thereto, and, 5 minutes thereafter, dimethylformamide (0.186 mL, 2.4 mmol) was further added thereto, followed by stirring for 5 minutes. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (9:1 hexane/ethyl acetate) to obtain 4-(dibenzylamino)benzaldehyde (192 mg, 53%).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[C:6]([O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:2][O:3][N:4]([CH3:5])[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([O:10][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:12])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of N-methoxymethanamine hydrochloride (5.00 g) in N,N-dimethylformamide (200 mL) was added triethylamine (7.1 mL), and the mixture was stirred at room temperature for 30 min. [4-(tert-Butoxycarbonyl)phenyl]acetic acid (10.0 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.2 g) and 1-hydroxybenzotriazole (8.60 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (9.50 g, yield 80%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 280 (MH+).