Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:17]1[CH:22]=NC2N(O)N=[N:25][C:19]=2[CH:18]=1.CCN(C(C)C)C(C)C.C1(N)CCC1>CN(C=O)C.C(Cl)CCl>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:25][CH:19]1[CH2:18][CH2:17][CH2:22]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: NC1CCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)NC1CCC1
Reaction time: 2 h

Procedure:
To a solution of 4.98 g N-Boc-cis-4-hydroxy-L-proline in 50 ml DMF were added 4.13 g EDC, 2.93 g HOAt, 3.75 ml DIPEA and 1.53 g cyclobutylamine at 0° C. After stirring for 2 h the reaction mixture was concentrated, the residue was dissolved in ethyl acetate and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was pure enough for the subsequent transformation. Yield: 3.32 g colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:49][CH2:50][C:51]1[N:56]=[CH:55][C:54]([C:57](O)=[O:58])=[CH:53][CH:52]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:57]([C:54]1[CH:55]=[N:56][C:51]([CH2:50][OH:49])=[CH:52][CH:53]=1)=[O:58])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)c1ccc(CO)nc1
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: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
2-Aminophenyl carbamic acid t-butyl ester (Reference Compound No. 1-1, 0.60 g, 2.9 mmol), N,N-diisopropylethylamine (1.5 mL, 8.6 mmol), and HATU (1.1 g, 2.9 mmol) were added to a suspension of 6-hydroxymethylpyridine-3-carboxylic acid (Reference Compound No. 10-1) in DMF (10 mL), and then the reaction mixture was stirred at room temperature for 2 hours. Water (200 mL) was added thereto, the whole was extracted with ethyl acetate (100 mL, 50 mL), and then the organic layer was washed with brine (100 mL) twice. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 0.66 g of the title reference compound as a brown oil. (Yield 67% in 2 steps)
Reaction SMILES: [Na].C(=O)(O)O.[NH2:6][C:7]([NH2:9])=[NH:8].[CH2:10]([O:12][C:13](=[O:37])[NH:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][C:24]([C:33]#N)=[CH:25][NH:26]C2C=CC=CC=2)=[CH:17][C:16]=1[O:35][CH3:36])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:37])[NH:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][C:24]2[C:25]([NH2:26])=[N:8][C:7]([NH2:9])=[N:6][CH:33]=2)=[CH:17][C:16]=1[O:35][CH3:36])[CH3:11]
Reactant: N=C(N)N
Reactant: CCOC(=O)Nc1c(OC)cc(CC(C#N)=CNc2ccccc2)cc1OC
Agent: O=C(O)O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Nc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reaction time: 1 h

Procedure:
A solution of 360 mg. of sodium in 100 ml. of absolute ethanol was treated with 2.8 g. of guanidine carbonate and 2.0 g. of 4-(3-anilino-2-cyano-allyl)-2,6-dimethoxy-carbanilic acid ethyl ester and boiled under reflux for 20 hours. The solution was diluted with 100 ml. of water and the alcohol removed under vacuum. After standing at room temperature for 1 hour, the precipitate was removed by filtration with suction, washed with water and dissolved in about 200 ml. of boiling ethanol. The solution was chromatographed on 100 g. of silica gel using ethanol/ethyl acetate (1:1) and there was obtained 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-carbanilic acid ethyl ester which, after recrystallization from ethanol, had a melting point of 228° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1C(=O)N([Br:22])C(=O)C1.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:22][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH2:1][N:2]([CH3:3])[CH2:14][CH2:13][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1CCc2c(Br)c3ccccc3n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3.7 g) in 40 mL of CHCl3 cooled at 0° C. was added 4 g of NBS in two portions. After stirring for 2 h at r.t., the reaction mixture was treated with 30 mL of water and 20 mL of saturated aqueous solution of NaHCO3, and then extracted with 200 mL of CH2Cl2. The extract was dried over Na2SO4 for 2 days, and then filtered through a pad of silica gel, concentrated to give 4 g of the title compound as a light brown solid.
Reaction SMILES: [FH:1].[CH3:2][N:3]=[C:4]=[O:5].[Cl:6][CH2:7][C:8]([C:12]#[N:13])([S:10]Cl)[CH3:9].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:2][N:3]([S:10][C:8]([C:12]#[N:13])([CH3:9])[CH2:7][Cl:6])[C:4]([F:1])=[O:5]
Reactant: CN=C=O
Reactant: F
Reactant: CC(C#N)(CCl)SCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(SC(C)(C#N)CCl)C(=O)F
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
To a mixture of 3.53 g of anhydrous hydrogen fluoride in 150 ml of toluene cooled to -50° C. was added dropwise 10.05 g of methyl isocyanate. After stirring for 1.5 hr. at 0° C., 30.0 g of approximately 85 percent pure 1-chloro-2-cyano-2-propanesulfenyl chloride was added followed by dropwise addition of 17.8 g of triethylamine. During the addition of base the temperature was maintained between 0° and 10° C. After stirring for an additional 1 hr., the precipitated salt was removed by filtration and the filtrate was concentrated to yield 26.5 g of a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-:18])=[O:17])[C:8](Cl)=[N:7][C:6]=1[CH3:20])[CH3:2].[NH3:22]>CO>[NH2:22][C:8]1[N:7]=[C:6]([CH3:20])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])=[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: N
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Solvent: CO
Product: CCCCNc1c(C(=O)OCC)c(C)nc(N)c1[N+](=O)[O-]

Procedure:
177.9 g. of 4-butylamino-6-chloro-2-methyl-5-nitronicotinic acid ethyl ester (0.5 Mol.) and 500 ml. of methanol are heated in an autoclave together with 300 ml. of aqueous ammonia (30%) at about 60° for 10 hours. After this time, the solvent is distilled off and the residual 6-amino-4-butylamino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester is recrystallized from methanol, yield: 135 g., m.p. 98°-99°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]([N:13]([C:26]2[C:31]([N+:32]([O-])=O)=[CH:30][CH:29]=[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])[N:27]=2)C(C2N(C)N=C(C(C)(C)C)C=2)=O)=O)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Fe]>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[NH:32][C:31]3[C:26]([N:13]=2)=[N:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:43])([F:42])[F:44])=[CH:29][CH:30]=3)[N:8]([CH3:10])[N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)N(C(=O)c1cc(C(C)(C)C)nn1C)c1nc(-c2ccccc2C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cn1nc(C(C)(C)C)cc1-c1nc2nc(-c3ccccc3C(F)(F)F)ccc2[nH]1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid (5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-[3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (339 mg, 0.554 mmol, prepared as described in the previous step) was taken up in acetic acid (10 mL), treated with iron powder (124 mg, 2.22 mmol), and heated to 90° C. for 15 h. The resulting mixture was concentrated to a volume of 3 mL, treated with saturated aqueous NaHCO3 (75 mL) and extracted twice with EtOAc (75 mL, 40 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:19 v/v for 5 min, then 1:19 to 1:4 v/v over 40 min) to yield 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-5-(2-trifluoromethyl-phenyl)-1H-imidazo[4,5-b]pyridine as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 8.13 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.61-7.68 (m, 1H), 7.52-7.59 (m, 2H), 7.40 (d, J=8.1 Hz, 1H), 6.56 (s, 1H), 4.37 (s, 3H), 1.37 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H20F3N5: 400.2 (M+H). Measured: 400.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(COc2ccc(Br)cc2C(=O)Nc2cccnc2)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(COc2ccc(-c3cnn(C)c3)cc2C(=O)Nc2cccnc2)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-({[3-(methyloxy)phenyl]methyl}oxy)-N-3-pyridinylbenzamide ((may be prepared as described in Example 18; 120 mg, 0.29 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66.5 mg, 0.32 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.58 ml, 0.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.13 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined, evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 24 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[F:11][Sb-:12]([F:17])([F:16])([F:15])([F:14])[F:13].[CH3:18][N:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S([O-])([O-])(=O)=O.[Mg+2]>[N+](C)([O-])=O>[F:11][Sb-:12]([F:17])([F:16])([F:15])([F:14])[F:13].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N+:19]([CH3:26])([CH3:18])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: CN(C)c1ccccc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C[N+](C)(C)c2ccccc2)cc1
Yield: 70 %

Procedure:
13.81 g (0.1 mol) of 4-methoxybenzylalcohol and 35.78 g (0.1 mol) of N,N-dimethylaniline hexafluoroantimonate were dissolved in 100 g of nitromethane and, after the addition of 12.04 g (0.1 mol) of magnesium sulfate, allowed to react at 80° C. for 4 hours. After the completion of the reaction, the mixture was filtered and the filtrate was concentrated. The precipitated white solid was washed with ether and dried to give the titled compound. Yield: 70%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([N:7]([CH2:10][CH3:11])CC)=[O:6].[Li]CCCC.C(C1[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:28])=[CH:25][CH:24]=1)#N>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:4]2[C:3]=1[CH:15]=[C:10]([C:11]1[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH2:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[O:28])=[CH:25][CH:24]=1)[NH:7][C:5]2=[O:6]
Reactant: CN1CCC(CNC(=O)c2ccc(C#N)cc2)CC1
Reactant: CCN(CC)C(=O)c1cccc(Cl)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(CNC(=O)c2ccc(-c3cc4c(Cl)cccc4c(=O)[nH]3)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
3-Chloro-N,N-diethyl-2-methyl-benzamide (150 mg, 0.66 mmol) was dissolved in anhydrous THF (2 mL) under N2 and cooled to −78° C. n-BuLi (2.5M in n-hexanes, 558 μL, 1.39 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. 4-Cyano-N-(1-methyl-piperidin-4-ylmethyl)-benzamide (180 mg, 0.66 mmol) in anhydrous THF (2 mL) was added dropwise to the reaction mixture and stirred at −78° C. continued for 1 h. The reaction mixture was poured into ice/water, allowed to warm to RT and extracted with CH2Cl2 (×3) and the organic phase dried (MgSO4). The solution was filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC-MS to afford 4-(5-chloro-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(1-methyl-piperidin-4-ylmethyl)-benzamide as a white solid (37 mg, 13%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:32]([C:34]1[C:35]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N:36][CH:37]=[CH:38][N:39]=1)#[CH:33].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][C:35]1[C:34]([C:32]#[C:33][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)=[N:39][CH:38]=[CH:37][N:36]=1)[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1nccnc1CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nccnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 51.1 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I43) (140 mg, 0.306 mmol), ethyl 2-(3-ethynylpyrazin-2-yl)acetate (I101) (64 mg, 0.34 mmol), bis(triphenylphosphine)palladium(II) chloride (11 mg, 5 mol %) and DMF (2 mL) were loaded into a microwave tube and degassed with a nitrogen for ten minutes. Copper(I) iodide (3 mg, 5 mol %) and triethylamine (0.192 mL, 1.38 mmol) were added under nitrogen and the resulting mixture heated under microwave irradiation (120° C./15 minutes). The cooled mixture was concentrated, and the residue evaporated onto silica gel. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I102) (95.5 mg, 52% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.47 (s, 1H), 8.87 (d, J=0.5 Hz, 1H), 8.76-8.71 (m, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 4.15-3.99 (m, 6H), 2.80 (s, 2H), 2.70-2.63 (m, 1H), 1.80-1.70 (m, 2H), 1.55-1.44 (m, 2H), 1.42 (s, 9H), 1.14 (t, J=7.1 Hz, 3H). LCMS Method C: rt 6.73 min; m/z 633.1 [M+Na]+, 555.0 [M−tBu+2H]+, 511.1 [M-Boc+2H]+; m/z 609.1 [M−H]−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[C:11](F)=[CH:12][C:13]([F:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Br:9][C:10]1[C:11]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][C:13]([F:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(Br)c(F)cc1F
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Br)c(Oc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
A mixture of 4-chlorophenol (94.7 mg, 0.74 mmol), methyl 5-bromo-2,4-difluorobenzoate (Preparation 18, 168 mg, 0.67 mmol), and potassium carbonate (277 mg, 2.01 mmol) in dimethyl sulfoxide (3 mL) was stirred for 16 hours at room temperature under a nitrogen atmosphere. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were successively washed with aqueous sodium hydroxide solution (1.0 M, 20 mL), brine (2×30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colourless oil (199 mg, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:38]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:38][C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C(c2ccc(Cl)c(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccc(Cl)c(Cl)c2)[C@@H](N)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of the compound (14.4 g) obtained in step 5 in toluene (120 mL) was added DPPA (16.5 g) and triethylamine (8.36 mL) at room temperature, and the mixture was stirred at 100° C. for 2 hr. The reaction solution was cooled, 8N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried, and concentrated under reduced pressure to give tert-butyl (3R*,4S*)-3-amino-4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate (13.3 g, 100%) as an orange oil.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:33]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1>C1COCC1.CCCCC>[CH:2](=[C:33]1[CH2:34][CH2:35][C:36](=[O:39])[CH2:37][CH2:38]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)CC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=C1CCC(=Cc2ccccc2)CC1
Reaction time: 5 h
Yield: 120 %

Procedure:
To a mechanically stirred suspension of 15.24 g (0.035 mole) of benzyltriphenylphosphonium bromide in 150 ml of THF there was added first 22 ml of 1.61 N n-butyllithium in pentane and then 5.0 g (0.032 mole) of cyclohexane-1,4-dione, ethylene monoketal in 50 ml of THF. Following 5 hours' heating at reflux the mixture was allowed to cool and was then washed in turn with water and brine. The organic layer was concentrated, and the residue was chromatographed on 1 liter of silica gel, eluting with 20% ethyl acetate in Skellysolve® B, to afford 7.15 g (97%) of 4-benzylidenecyclohexanone, ethylene ketal as an oil, the nmr spectrum of which is in consonance with the structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:33][CH3:34])=[CH:11][C:12]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)=[C:13]([CH:15]([O:23]C(=O)C)[C:16](=[O:22])[NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO.C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]1[C:10]([O:33][CH3:34])=[CH:11][C:12]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)=[C:13]([CH:15]([OH:23])[C:16]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2noc(C)n2)c(C(OC(C)=O)C(=O)NC(C)(C)C)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1cc(-c2noc(C)n2)c(C(O)C(=O)NC(C)(C)C)cc1OCc1ccccc1
Yield: 100.4 %

Procedure:
A mixture of acetic acid [5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-tert-butylcarbamoyl methyl ester (Reference example 12-1) (604 mg), a 5 mol/L aqueous solution of sodium hydroxide (1 mL) and methanol (8 mL) was stirred at room temperature for 1.5 hours. Ethyl acetate and water were added to the mixture. The separated organic layer was washed with water, an aqueous solution of sodium bicarbonate successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (552 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCc1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2c(c1)OCO2
Yield: 100.5 %

Procedure:
A solution of alcohol (a) (1.90 g, 11 mmol) in dichloromethane (25 ml) was treated at 0° C. with triethylamine (1.9 ml, 13.7 mmol) and methanesulfonyl chloride (1.1 ml, 13.7 mmol). After 1.5 hours at room temperature the mixture was partitioned between dichloromethane and water. The organic extract was dried and evaporated to give a yellow oil (2.7 g, 96%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][NH:9][C:10](=O)[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:4]([C:10]([CH3:11])=[N:9][N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NNc1ncccc1Br
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nnc2c(Br)cccn12
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a solution of 0.17 g (0.74 mmol) of N′-(3-bromopyridin-2-yl)acetohydrazide from step A above in 40 mL of anhydrous toluene was added 3 mL of glacial acetic acid and the resulting mixture was heated to reflux for 20 h employing a Dean-Stark trap. The reaction mixture was cooled to ambient temperature then evaporated to dryness in vacuo to afford the title compound (0.13 g, 84%) LC-MS: m/z (ES) 212, 214 (MH)−.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
Benzene (1 mL), cinnamoyl chloride (0.160 mg), and aluminium chloride (150 mg) were reacted in carbon disulfide (5 mL) at from 0° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (35 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].N1C=CC=CC=1.[N:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:36]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: O=C(Cl)N1CCCC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCCC3)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (648 mg, 2 mmol) in dichloromethane (5 mL) and pyridine (1 mL, 12 mmol) was added a solution of pyrrolidine-1-carbonyl chloride (0.243 mL, 2.2 mmol) in dichloromethane (2 mL) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-{3-[(pyrrolidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (842 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C25H31N3O3 (M+H)+: 422.54, observed: 422.2.