Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C@@H:13]([S:28][CH2:29][C:30]1([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:31]1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21]C2CCCCO2)[CH:15]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[OH:21][CH2:20][C:16]1[CH:15]=[C:14]([C@H:13]([S:28][CH2:29][C:30]2([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:31]2)[CH2:12][CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:2]([OH:1])([CH3:4])[CH3:3])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(COC3CCCCO3)c2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(CO)c2)CC1
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 90.5 %

Procedure:
To the hydroxy ester from Step 16 (9.02 g, 17.1 mmol) in anhydrous methanol (60 mL) under nitrogen was added pyridine (50 μL) followed by pyridinium p-toluenesulfonate (1.1 g, 4.3 mmol). The reaction mixture was stirred 3.5 hours at 55° C., then at r.t. overnight before concentrating in vacuo. The residue was diluted with EtOAc (500 mL) and washed with H2O, saturated aq. NaHCO3, NaH2PO4 buffer (pH=4.5) and with brine. After drying over MgSO4 and evaporation of the solvents, the product was purified by flash chromatography (40% to 60% EtOAc in hexanes) giving 6.85 g (91%) of the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]([CH3:11])=[CH:7][C:8]([OH:10])=[O:9]>O.C(O)(=O)C>[N:1]([C:6]([CH3:11])([CH3:5])[CH2:7][C:8]([OH:10])=[O:9])=[N+:2]=[N-:3]
Reactant: CC(C)=CC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(CC(=O)O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
According to the method of S, Nagarajan and B. Ganem, J. Org. Chem., 51, 4856, (1986), sodium azide (52 g, 0.8 mol) in water (100 mL) was added to a stirred solution of 3,3-dimethylacrylic acid (20 g, 0.2 mol) in glacial acetic acid (50 mL) in one portion. The clear yellow solution was stirred for 1 h at RT, then heated in an oil bath at 95° C. for 2 days. Water (50 mL) was added to the cooled orange solution. This solution was poured into a separatory funnel and extracted with ether (5×200 mL). The combined organic extracts were dried over anhydrous MgSO4 and concentrated to an orange oil. This oil was used without further purification.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=C(C)[N+:18]=1[O-])[CH2:9][CH2:10][CH3:11]>C(O)(=O)C>[C:5]([O:4][CH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:18]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCOc1cccc(C)[n+]1[O-]
Solvent: CC(=O)O
Product: CCCCOc1cccc(COC(C)=O)n1
Temperature: 135 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
An amount 60 ml of acetic anhydride was stirred at about 120° C., and a solution of 11.1 g of 6-butoxy-α-picoline N-oxide in 25 ml of glacial acetic acid was dropwise added thereto over about one hour. After the dropwise addition, the mixture was stirred at 135° C. for 4.5 hours, acetic acid and acetic anhydride were removed by concentration under a reduced pressure, the reaction mixture was dissolved in ether, and the remaining acetic acid was neutralized with an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ether, concentrated under a reduced pressure, and separated by silica gel column chromatography (ethyl acetate:hexane=8:92) to obtain 4.89 g of the desired product (yield 35.9%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:21])=O.O>COCCOC>[NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([Cl:21])[N:7]=1
Reactant: COc1ccc(-c2c[n+]([O-])c(N)c(C#N)n2)cn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2nc(C#N)c(N)nc2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
3-Amino-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile 4-oxide (6.65 g) was dissolved in DME (133 ml). To the solution was added phosphorus oxychloride (12.6 g) at 25° C. The mixture was stirred at ambient temperature for 2 hours. To the mixture was added water (520 ml). The solution was stirred at 20-25° C. for 15 hours. The precipitated crystals were collected by filtration and dried in vacuo, to give 3-amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile as powder (4.6 g). The filtrate was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO4. Evaporation of solvent in vacuo gave oily residue. The residue was purified by chromatography on silica gel (EtOAc:n-Hexane=1:1, v/v) to give 3-amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile as powder (1.0 g).
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[N:12]=[N:11]2)=[CH:6][CH:5]=1.CO.O.O.[OH-].[Li+]>C1COCC1>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[N:11]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cn(-c2ccc(OC(F)F)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccc(OC(F)F)cc2)nn1
Temperature: 70 °C
Yield: 107.8 %

Procedure:
To a solution of ethyl 1-(4-(difluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxylate (600 mg, 2.12 mmol) in a mixture of THF (7 ml), methanol (7 ml) and water (7 ml) was added lithium hydroxide hydrate (267 mg, 6.36 mmol). The solution was heated to 70° C. for 3 h. Most of the organic solvent was removed under reduced pressure. Water was added and the solution was extracted with methyl tert-butyl ether to remove non-acid material. Then 25% aq. hydrochloric acid was added to reach acidic pH. The product precipitated and the mixture was extracted three times with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to yield a light yellow solid (583 mg, 99%). MS (ISP): 253.9 ([M−H]+); 509.2 ([2M−H]+).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CO.C(OCC)(=O)C>[C:6]([C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1csc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C#Cc1csc(C=O)c1
Yield: 69 %

Procedure:
To a solution of 4-[(trimethylsilyl)ethynyl]thiophene-2-carboxaldehyde (3.3 g, 16 mmol) that was obtained in Example 9 (9a) in methanol (160 ml) was added potassium carbonate (4.3 g, 31 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, insoluble materials were removed by filtration, and the filtrate was evaporated in vacuo. The residue thus obtained was diluted with ethyl acetate, poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:1 to 1:19) as the eluent to afford the title compound (1.5 g) in a yield of 69% as a brown solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1(O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]1=O)C.C(OCC)(=O)C.O>C1COCC1>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC1(O)C(=O)Nc2ccc(F)cc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The aldol product 34 (10 mmol) was dissolved in absolute THF (20 ml) under an argon atmosphere. BH3xTHF (40 ml, 1 M solution, 40 mmol) was then added to the mixture, and the mixture was stirred at room temperature for 14 hours. The course of the reaction was monitored of TLC. When the reaction had ended, the reaction solution was added to a mixture of ethyl acetate (50 ml) and H2O (50 ml). After separation of the phases, the aqueous phase was extracted twice with 30 ml portions of ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was filtered over silica gel with ethyl acetate. After removal of the solvent, the product was obtained in the form of a sufficiently pure oil and crystallized spontaneously.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.C1COCC1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CO>[CH:27]1([NH:31][C:2]2[C:3]3[N:4]([C:9]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[F:21])=[O:13])=[CH:10][N:11]=3)[N:5]=[C:6]([NH:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:7]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: NC1CCC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccncc1F)c1cnc2c(NC3CCC3)cc(NC3CCCCC3)nn12
Temperature: 80 °C
Reaction time: 4 h
Yield: 18.4 %

Procedure:
A 1 dram vial was charged with 8A (25 mg, 0.077 mmol) and THF (1 mL). Cyclobutylamine (8.54 μL, 0.100 mmol) was added and the reaction was heated to 80° C. After 4 hours at 80° C., the reaction was cooled to room temperature and the solvent was removed under a stream of nitrogen. Cyclohexylamine (500 μL, 4.37 mmol) was added and the reaction was heated to 140° C. for 12 hours. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 50 min gradient, monitored at 220 nm). The product (retention time=35.6 minutes) was isolated and lyophilized to dryness to afford 8-(cyclobutylamino)-6-(cyclohexylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (6 mg, 14.56%). 1H NMR (400 MHz, DMSO-D6) δ ppm 11.33-11.47 (1H, m), 8.71-8.82 (1H, m), 8.51-8.62 (1H, m), 8.41-8.51 (1H, m), 8.01-8.09 (1H, m), 7.42-7.56 (1H, m), 6.69-6.86 (1H, m), 5.65-5.74 (1H, m), 3.89-4.02 (1H, m), 3.78-3.89 (1H, m), 2.28-2.42 (2H, m), 2.05-2.21 (2H, m), 1.87-2.01 (2H, m), 1.64-1.85 (4H, m), 1.53-1.64 (1H, m), 1.13-1.46 (5H, m). HPLC tR=4.775 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=424.32.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:14])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[N:7]2.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C.C(#N)C>C(O)CCC>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:14][CH:12]([C:10]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[C:8]3[C:3]([CH:4]=[CH:5][N:6]=[N:7]3)=[C:2]([Cl:1])[CH:11]=2)[CH3:13])[N:26]=[CH:25][N:24]=1
Reactant: CC(N)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1ncnc(N)c1C#N)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Yield: 45.8 %

Procedure:
A solution of the single enantiomer of 1-[5-chloro-8-(3-fluorophenyl)cinnolin-7-yl]ethanamine (400 mg, 1.3 mmol) from step O, 4-amino-6-chloropyrimidine-5-carbonitrile (250 mg, 1.6 mmol), and N,N-diisopropylethylamine (0.69 mL, 4 mmol) in 1-butanol (13 mL) was heated at 120° C. for 3 hours. The reaction mixture was concentrated and the residue was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min). The pure fractions were concentrated to remove all of the acetonitrile and the remaining aqueous solution was saturated with sodium bicarbonate. The aqueous solution was extracted with ethyl acetate (300 mL). The organic layer was separated, washed with brine, dried with sodium sulfate, filtered, and concentrated to give a solid. This solid was treated with acetonitrile and concentrated (2×) to give the desired product (0.25 g, 44%). LCMS for C21H16ClFN7 (M+H)+: m/z=420.1; Found: 420.1. 1H NMR (300 MHz, DMSO-d6): δ 9.48 (d, J=6.0 Hz, 1 H), 8.44 (d, J=7.8 Hz, 1 H), 8.28 (d, J=6.0 Hz, 1 H), 7.87 - 7.81 (m, 2 H), 7.61 - 7.44 (m, 2 H), 7.34 - 7.17 (m, 4 H), 5.24-5.11 (m, 1 H), 1.43 (d, J=7.0 Hz, 3 H).
Reaction SMILES: C(OCC)C.[OH:6][CH:7]([CH2:19][C:20]([CH2:23][Si](C)(C)C)=[C:21]=[CH2:22])[CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.O>C(OCC)(=O)C>[CH2:22]=[C:21]1[C:20](=[CH2:23])[CH2:19][CH:7]2[O:6][C:11]1([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: C=C=C(CC(O)CCC(=O)Cc1ccccc1)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C1CC2CCCC(c3ccccc3)(O2)C1=C
Temperature: -78 °C
Yield: 97.9 %

Procedure:
1.50 mL of diethyl ether was added to 5-hydroxy-1-phenyl-7-trimethylsilanylmethyl-nona-7,8-diene-2-one (117 mg, 0.37 mmol) under nitrogen atmosphere. While stirring at −78° C., trimethylsilyl trifluoromethanesulfonate (TMSOTf; 67 μL, 0.37 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with ethyl acetate (EtOAc) and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous magnesium sulfate (MgSO4). The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane={fraction (1/7)}) to obtain 82 mg of the product (98%). 1H NMR(300 MHz, CDCl3) δ 7.43 (d, 2H, J=1.5 Hz), 7.21 (m, 3H), 5.17 (s, 1H), 5.07 (s, 1H), 4.72 (s, 1H), 4.33 (s, 1H), 4.13 (s, 1H), 3.00 (m, 1H), 2.40 (d, 1H, J=14.8 Hz), 2.19 (m, 2H), 1.94 (m, 2H), 1.60 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 152.5, 147.0, 146.0, 128.2, 127.4, 126.4, 111.7, 109.4, 77.7, 69.5, 38.7, 36.7, 30.6, 17.8 ppm.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[NH2:15][C:16]1[N:17]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]([CH3:21])[CH:20]=1>C1COCC1>[CH3:21][N:19]1[CH:20]=[C:16]([NH:15][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)=[O:12])[N:17]=[C:18]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1nc(N)cn1C
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1C

Procedure:
Under argon, 1.46 g (7.21 mmol) of 4-(trifluoromethoxy)phenyl isocyanate are added to 1.22 g (3.61 mmol) of ethyl 4-amino-1-methyl-1H-imidazole-2-carboxylate (synthesis in analogy to Example 4A step 3, or also according to Tetrahedron Lett. 2003, 44, 1607 and the literature cited therein) in 50 ml of THF, and the mixture is stirred at room temperature overnight. The reaction mixture is filtered and the filtrate is concentrated in vacuo and purified chromatographically.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([C:21]([F:20])([F:29])[F:30])[CH:23]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCOCC
Product: O=C(Nc1cccc(C(F)(F)F)c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidine-1-yl]-oxo-acetic acid (Example 1b) and 3-(trifluoromethyl)-aniline (Aldrich) according to the method described in Example 94. Melting Point: 113-115° C. (diethylether
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.[CH:18]1([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:28][C:27]2[CH:29]=[CH:30][C:24]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:25][CH:26]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
3-(4-Formylbenzoylamino)propionic acid methyl ester (10 g, 42.5 mmol) was dissolved in methanol (100 ml). With mechanical stirring 4-cyclohexylaniline (7.4 g, 42.5 mmol) was added in portions. Methanol (100 ml) was added and the resulting suspension was stirred under nitrogen at room temperature for 3 hours. Sodium cyano borohydride (4.01 g, 63.8 mmol) was added in portions and the resulting solution was stirred at room temperature for 4 days. Filtration and drying in vacuo of the formed crystals afforded 6.40 g (38%) of 3-{4-[(4-cyclohexylphenylamino)methyl]benzoylamino}propionic acid methyl ester as a solid. From the mother liquor a second crop of 2.49 g (15%) could be isolated by concentration in vacuo followed by washing with methanol.
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]#N)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[OH-:13].[Na+].Cl.CCO.[OH2:19]>>[S:1]1[C:5]([CH2:6][C:7]([OH:19])=[O:13])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: N#CCc1cc2ccccc2s1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1cc2ccccc2s1
Temperature: 80 °C

Procedure:
To a solution of benzo[b]thiophen-2-yl-acetonitrile (1 eq.) in EtOH/water (1/1) was added NaOH pellets (12 eq.). The reaction was heated at 80° C. for 4 h and then allowed to cooled down to 20° C., at which point concentrated HCl was added carefully until pH=7 was reached. The reaction mixture was partially concentrated under reduced pressure then partitioned between water and EtOAc. The aqueous layer was extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford benzo[b]thiophen-2-yl-acetic acid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]>Cl>[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]([OH:10])=[O:15])=[O:9])=[CH:20][CH:19]=1)[CH3:17]
Reactant: CCc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
aluminum chloride (270 g) was added in portions to a stirred mixture of phthalic anhydride (270 g) and ethyl benzene (1125 ml). After 4 hours the mixture was poured onto ice and concentrated hydrochloric acid (450 ml) was added. Excess ethylbenzene was removed by steam distillation, and the residual solution was cooled and filtered so as to afford 2-(4-ethylbenzoyl)benzoic acid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])(=O)=O.CN(C=O)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O.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>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2F)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
To a stirred solution of dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate T4.1 (1.60 g, 4.7 mmol) in DMF (9.4 mL, 4.7 mmol) at 23° C. was added 2-fluorophenylboronic acid (0.98 g, 7.0 mmol, commercially available from Sigma-Aldrich, St. Louis, Mo., USA), potassium carbonate (1.9 g, 14 mmol), and then tetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol). The reaction mixture was heated to 90° C. and the reaction was stirred for 22 hours. The reaction was then cooled to room temperature, diluted with water, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield T28.1 as a colorless oil (1.10 g, 82% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)([O-])=O.C([OH:22])C>O=[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]1([O-:22])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1
Reactant: O=[N+]([O-])c1ccncc1N1CCc2ccccc2C1
Reactant: CCO
Agent: O=[Pt]=O
Product: Nc1ccncc1[N+]1([O-])CCc2ccccc2C1
Reaction time: 24 h

Procedure:
To a slurry of PtO2 (0.3 g) in 10 ml of ethanolwas added 2-(4-nitro-3-pyridinyl)-1,2,3,4-tetrahydroisoquinoline, N-oxide (5.0 g) in 240 ml of ethanol and this was hydrogenated with a Parr apparatus at room temperature for 24 hours. The mixture was filtered and the filtrate concentrated to yield an oil (5.1 g), which was eluted with 20% methanol/DCM on a silica gel column via HPLC. The desired fractions were concentrated to a solid (2.0 g), m.p. 216°-219° C. (decomp). This solid was recrystallized from acetonitrile to yield a solid, 1.0 g, m.p. 217°-219° C.
Reaction SMILES: [NH:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[Cl:31])[NH2:27]>>[ClH:15].[NH:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]=[C:12]2[NH:27][C:26]2[CH:28]=[CH:29][C:30]([Cl:31])=[C:24]([Cl:23])[CH:25]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Product: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Nc3ccc(Cl)c(Cl)c3)c2c1
Product: Cl

Procedure:
The preparation is carried out in the manner described under Example 25, starting from 7-acetamino-1-chloro-4-(4-pyridylmethyl)phthalazine and 3,4-dichloroaniline.