Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][N:18]4[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:35].[CH:36]1(B(O)O)[CH2:38][CH2:37]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH:36]1([C:2]2[C:7]3[N:8]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:9]([C@@H:11]([NH:13][C:14]4[N:22]=[CH:21][N:20]=[C:19]5[C:15]=4[N:16]=[CH:17][N:18]5[CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[CH3:12])=[N:10][C:6]=3[CH:5]=[CH:4][C:3]=2[F:35])[CH2:38][CH2:37]1
Reactant: OB(O)C1CC1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
A mixture of [(S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (50 mg, 0.09 mmol), cyclopropylboronic acid (10 mg, 0.12 mmol) and Cs2CO3 (46 mg, 0.14 mmol) in a 4:1 mixture dioxane:water (2.5 mL) was degassed with a stream of argon prior to addition of Pd(PPh3)4 (5 mg) and was heated at 100° C. for 18 h in a sealed vial. Additional cyclopropylboronic acid (10 mg, 0.12 mmol) and Pd(PPh3)4 (5 mg) in dioxane (0.25 mL) were added and stirring at 100° C. in a sealed vial was continued for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90%, 0.1% HCO2H in acetonitrile/water) to afford the title compound (20 mg, 43%). LCMS (Method C): RT 3.32 min [M+H]+ 498.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][C:13](=[O:14])[N:12]([CH3:11])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1cccc2[nH]ccc12)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxyindole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (48%, off-white solid). HPLC-MS: m/z=267.1 (M+1); Rt: 3.57 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][N:24]1[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(N(CCc1ccccc1)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](N(CCc2ccccc2)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 60.4 %

Procedure:
189 mg (0.992 mmol) of 3,5-dichlorobenzoic acid are reacted in analogy to Example 2a first with 0.108 ml (1.49 mmol) of thionyl chloride and subsequently with 155 mg (0.397 mmol) of (2R*,4S*)-2-benzyl-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine and 166 μl (1.19 mmol) of triethylamine to give the title compound (135 mg, 60%). TLC:methylene chloride/methanol/cone. ammonia (1000:50:1) Rf =0.70, FD-MS:M+ =562, 564.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8](=[O:13])[C:7]2([CH3:15])[CH3:14]>C(OC(=O)C)(=O)C>[C:10]([NH:9][C:3]1[CH:2]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[NH:9][C:10]2=[O:12])=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC1(C)C(=O)NC(=O)c2c(N)cccc21
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)C(=O)NC(=O)C2(C)C
Yield: 171.3 %

Procedure:
The above amine (1.5 g, 7.35 mmol) was stirred in acetic anhydride (9 mL) at room temperature for 3 h, then poured on to ice. The precipitate was filtered, washed with water and dried to give 7-acetamido-4,4-dimethyl-2H,4H-isoquinoline-1,3-dione (1.55 g, 86%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH:2]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11][C:12]2=[O:13])[CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCNCc1cccnc1
Solvent: C1CCOC1
Product: O=C1NCCN1Cc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of 1.6 g of N-(3-pyridylmethyl)-ethylenediamine dissolved in 30 ml of tetrahydrofuran, 1.49 g of carbonyldiimidazole was added at 0° C. The mixture was stirred at 0° C. for 30 minutes, then at room temperature for 4 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatorgraphy (solvent: chloroform-methanol=15:1) and recrystallized from a mixture of isopropanol and hexane to give 1.43 g of 1-(3-pyridylmethyl)-2-imidazolidinone.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:39])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)=[CH:8]2)=[O:4].[NH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:39])[C:5]([C:3]([NH:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:38])[F:37])[CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 40.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (29 mg, 0.055 mmol), β-alanine (487 mg, 5.5 mmol) and NaOMe solution (8.8 mL, 4.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 13 mg of the title compound. MS: (+) m/z 589.24 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[OH:14][C:11]1([CH3:15])[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -40 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of N-Boc-piperidin-4-one (1.0 g, 5.0 mmol) was dissolved in THF (20 mL) and then cooled to −40° C. MeMgBr (2.8 M, 7.2 mL, 20 mmol) was added slowly over 10 min. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was cooled to 0° C. and saturated aqueous NH4Cl (50 mL) was added. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1.0 g, 92% yield) as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][CH2:28][C:29]2[CH:30]=[N:31][C:32](Cl)=[CH:33][CH:34]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([NH:27][CH2:28][C:29]2[CH:30]=[N:31][C:32]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:33][CH:34]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)nc2)CC1
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in example-1 using 5-(methylsulfonyl)-1H-indole (intermediate 21) and tert-butyl-4-(((6-chloropyridin-3-yl)methyl)amino)piperidine-1-carboxylate (intermediate 79).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]3[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1.CCO>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]3[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)sc1nc(CO)cn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)sc1nc(C=O)cn12
Yield: 75 %

Procedure:
5.0 g (0.0225 mole) of the product of Step A and 10 g (0.115 mole) of manganese dioxide were stirred under reflux in 500 ml of chloroform for 2 hours. The mixture was filtered hot through celite and evaporated under reduced pressure to obtain 3.92 g (79% yield) of 7-methoxy-imidazo[2,1-b]benzothiazole-2-carboxaldehyde as colorless crystals melting at 214° to 215° C. (EtOH).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: NC1CCCCC1
Solvent: O
Product: C=CCNc1nc(NC2CCCCC2)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
A mixture of 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 867 mg (8.74 mmol) of cyclohexylamine was stirred at room temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 237 mg (yield: 76.6%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:65]=[CH:64][C:61]([C:62]#[N:63])=[CH:60][CH:59]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:65]=[CH:64][C:61]([C:62]#[N:63])=[CH:60][CH:59]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-isocyanatobenzonitrile as starting materials in 35% yield. LCMS for C32H31ClN9O2 (M+H)+: m/z=608.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:14])[C:11](O)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CSC.B.B>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH3:14])[CH2:11][OH:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@@H](C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@H](CO)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A 500 ml three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser and a continuous nitrogen purge is charged with (2R)-2-(4-nitrophenyl)propanoic acid (8.12 g, 41.6 mmol) and THF (120.0 mL). To this solution was added 10.0 M borane dimethylsulfide (10.56 ml, 105.66 mmol) over a period of 30.0 minutes at room temperature. Reaction is quite exothermic with evolution of gas (exotherm can be controlled by the rate of addition of borane solution). The reaction is then refluxed for 5.0 hours, brought to room temperature and then quenched very carefully with saturated potassium carbonate solution (100.0 mL). Foaming observed during the quench can be controlled by the rate of addition of the carbonate solution. After 3.0 hours of stirring, the top organic layer is separated and the aqueous layer back extracted with methylene chloride (130.0 mL). The combined organic layer is then washed with saturated brine (100.0 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure at 50° C. to afford (2R)-2-(4-nitrophenyl)propan-1-ol (7.24 g, 96%); 1H nmr (CDCl3, 300 MHz) δ 1.29 (d, 3H, J=7.02 Hz), 1.69 (b. triplet, OH), 3.05 (m, 1H), 3.72 (m, 2H), 7.39 (d, 2H), 8.15 (d, 2H); 13C nmr (CDCl3, 300 MHz) δ 17.61, 25.82, 42.61, 68.17, 123.92, 128.61, 146.90, 152.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].CS(O)(=O)=O>>[OH:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[C:12]([O:11][CH3:10])[CH:13]=1)=[O:16]
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cccc(O)c1
Agent: CS(=O)(=O)O
Product: COc1cccc(C(=O)c2ccc(OC)cc2O)c1

Procedure:
Substituted 2-hydroxybenzophenones may be prepared as illustrated by exemplary reaction in Scheme 8. Reaction of 3-methoxyphenol with 3-methoxybenzoic acid in the presence of Al2O3 and CH3SO3H produces 2-hydroxy-4-methoxy-3′-methoxy-benzophenone.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:15]=2)[N:13]=1>C(Cl)Cl>[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:27][CH:28]=2)[N:13]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2csc(N)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccc(OCC(=O)O)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 143.4 %

Procedure:
Trifluoroacetic acid (50 mL) was added to a solution of the product of example 2 (3.81 g, 12.4 mmol) in CH2Cl2 (50 mL). The resulting mixture was stirred at room temperature (20-22°) for 4 h, then concentrated under reduced pressure (coevaporated with CH2Cl2 and then Et2O). The residue was triturated with Et2O, then filtered and dried to afford 4.45 g (quantitative yield) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.96 (s, 1H), 4.72 (s, 2H). The product was used without further purification for the following reaction (example 4).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26](ON3C(=O)CCC3=O)=[O:27])=[C:24]([CH2:36][OH:37])[N:23]=[C:22]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl.[NH:43]1[CH2:51][CH2:50][CH2:49][C@H:44]1[C:45]([O:47][CH3:48])=[O:46].Cl>C(N(CC)CC)C>[CH2:38]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([N:43]2[CH2:51][CH2:50][CH2:49][C@H:44]2[C:45]([O:47][CH3:48])=[O:46])=[O:27])=[C:24]([CH2:36][OH:37])[N:23]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCc1nc(CO)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCc1nc(CO)c(C(=O)N2CCC[C@H]2C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 53, but using 529 mg of succinimido 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate [prepared as described in Example 52(a)], 180 mg of methyl (S)-prolinate hydrochloride and 0.2 ml of triethylamine, 0.39 g of the hydrochloride of the title compound was obtained as an amorphous powder, melting at above 120° C. (with softening).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[CH3:32][O-:33].[Na+].O>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[C:5]([C:16]#[N:17])=[C:6]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[C:7]([C:8]#[N:9])=[C:2]([O:33][CH3:32])[N:3]=3)[N:21]=2)=[CH:26][CH:27]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(N2CCCCC2)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100.0 mg (0.21 mmol) of the compound from Example 4A are initially charged in 2 ml of dry methanol. 12.2 mg (0.23 mmol) of sodium methoxide are added to this solution, and the mixture is stirred at +65° C. for 20 h. After cooling to RT the reaction mixture is stirred into 2 ml of water and stirred at RT for 1 h. The precipitate that is formed is filtered off with suction and washed with 1 ml of cold water. Purification is carried out by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1Br.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Oc1ccc(F)cc1F
Reactant: Cc1cc(Br)c(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
A mixture of 1,2-dibromo-4-methyl-5-nitrobenzene (84.3 g, 286 mmol), 2,4-difluorophenol (37.2 g, 286 mmol), and K2CO3 (43.5 g, 315 mmol) were heated to 100° C. for 45 hours. The reaction mixture was cooled to room temperature and then stored in a 5° C. refrigerator overnight. The reaction mixture was poured into 1200 mL of ice water all at once. The resulting damp solid was collected, partially ground up, and stirred in 900 mL H2O for 45 minutes. The solid was collected by filtration and rinsed with 700 mL of water portion-wise. The resulting solid was dried under high vacuum overnight to yield 93.5 g of a brown solid (95%yield). 1H NMR (400 mHz, CDCl3) δ 8.38 (s, 1H), 7.18 (m, 1H), 7.03 (m, 1H), 6.97 (m, 1H), 6.52 (s, 1H), 2.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11](Br)(Br)([Br:13])[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:12][C:11]([Br:13])=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1]
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(C=C(Br)Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Into a solution of 2,4-dichlorobenzaldehyde (8.7 g, 50 mmol) and carbon tetrabromide (18.3 g, 55 mmol) in dichloromethane (200 ml) was added portionwise triphenylphosphine (28.8 g, 10 mmol) at 0° C. The slightly yellow mixture was stirred at room temperature for 1 hour and diluted with hexanes (800 ml). This mixture was then filtrated through a short silica gel column with 1:10 ethyl acetate-hexanes and the filtrate was concentrated in vacuo to give a white solid (16.5 g, 100%). recrystallization from ether-hexanes gave a white crystalline product (14.2 g, 86% yield); 1H NMR (TMS/CDCl3):
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[N+]=[N-].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH:5]([OH:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: COc1ccc(CC(O)CN=[N+]=[N-])cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(O)CN)cc1

Procedure:
To a stirring solution of 1-azido-3-(4-methoxy-phenyl)-propan-2-ol (1.3 g, 6.3 mmol) in 50 mL methanol under a nitrogen atmosphere was added 10 mg of 10% Pd(OH)2/C. The mixture was stirred under a balloon atmosphere of hydrogen for 18 h. The reaction mixture was filtered through a bed of celite, and the filtrate reduced to a clear oil under reduced pressure. M+1=170.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[CH2:13]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])=[O:26])=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)NCC(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 2-amino-4′-bromoacetophenone hydrochloride (5.0 g), 4-heptyloxybenzoic acid (4.72 g) and 1-hydroxybenzotriazole (2.7 g) in dichloromethane (50 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSCD) (3.65 ml) and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was diluted with dichloromethane (200 ml), and washed with water, 1N hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in ethyl acetate and collected by filtration to give 2-(4-heptyloxybenzoylamino)-4′-bromoacetophenone (6.73 g).