Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][C:6]1[CH:13]=[CH:12][C:9](C=O)=[CH:8][C:7]=1[Br:14].Cl.[N-:16]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>C1COCC1.O.CCOC(C)=O>[Br:14][C:7]1[CH:8]=[C:9]([NH2:16])[CH:12]=[CH:13][C:6]=1[F:5]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(Br)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 47 %

Procedure:
Sodium chlorite (6.78 g, 75 mmol) and 4-fluoro-3-bromobenzaldehyde (24.63 mmol) were dissolved in 1:1 THF/water (100 mL) and stirred vigorously at 50° C. for 5 h. EtOAc (250 mL) and 1N HCl (50 mL) was added and the layers were separated. The organic layer was washed with water (3×50 mL), then was extracted with 0.5M Na2CO3 (10×50 mL). The combined basic aqueous layers were slowly acidified with concentrated HCl while stirring, to precipitate the carboxylic acid product. The solid was collected via filtration and dried under high vacuum overnight (4.93 g, 91%). A portion of the solid carboxylic acid was dissolved in chloroform (30 mL) and concentrated sulfuric acid was added. A reflux condenser was attached to the flask and the solution was heated to 55° C. Sodium azide (2.36 g, 36.45 mmol) was added in 3 portions over 1 h. After 4 h, additional sulfuric acid (10 mL) and sodium azide (1 g) were added and the reaction was stirred at 55° C. for 16 h. The mixture was transferred to a large cooled flask and the sulfuric acid was slowly quenched with 5N sodium hydroxide. The solution was adjusted to pH˜8 and the aqueous solution was extracted with DCM (5×30 mL). The organic extracts were dried over sodium sulfate and concentrated in vacuo to yield a dark brown oil (2.2 g, 95%) that solidified upon standing. 1H-NMR (CDCl3): δ 6.94 (t, 8.4 Hz), 6.88 (dd, 1H, J=2.8, 5.6 Hz), 6.58 (m, 1H), 3.62 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.Cl.[O:17]1[CH2:22][CH2:21][NH:20][C@@H:19]2[CH2:23][CH2:24][C:25]3[C:30]([C@H:18]12)=[CH:29][CH:28]=[CH:27][CH:26]=3.C(N(CC)CC)C>O1CCCC1>[O:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[N:3]=2)[C@@H:19]2[CH2:23][CH2:24][C:25]3[C:30]([C@H:18]12)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: c1ccc2c(c1)CC[C@H]1NCCO[C@@H]21
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCO[C@H]3c4ccccc4CC[C@H]32)nc(-c2ccncn2)cc1=O
Yield: 84.2 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.26 g, 1.17 mmol), (4aRS,10bSR)-cis-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine hydrochloride (0.4 g, 1.77 mmol) and triethylamine (1.2 g, 11.4 mmol) in tetrahydrofuran (20 ml) was stirred for 48 hours at 100° C. The solution was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-((4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (0.37 g, 85%) as white crystals.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.CC([O-])(C)C.[K+]>CC(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1CN2CCC1CC2
Temperature: 30 °C
Reaction time: 6 h

Procedure:
To a 100 mL autoclave with a stirrer, 3-quinuclidinone (1.0 g, 8.0 mmol) and trans-RuCl2[(R)-dm-segphos][(R)-daipen] (0.5 mg, 0.40 μmol, 1/20,000 molar fold of 3-quinuclidinone) were added. After purging with nitrogen, 2-propanol (6 mL) and 2-propanol solution of t-BuOK (0.1 mol/L, 0.4 mL, 0.04 mmol) were added. Subsequently, the autoclave was purged with hydrogen, the mixture was stirred at 30° C. for 6 hours under hydrogen pressure of 3 MPa. As a result of analysis of the reaction solution, it was found that the conversion rate is 26.7% and the optical purity is 89.7% ee.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[F:44][C:45]1[C:53]([N:54]2[CH2:58][CH2:57][CH2:56][C:55]2=[O:59])=[CH:52][CH:51]=[CH:50][C:46]=1[C:47]([OH:49])=O.[CH:60]12[CH2:66][CH:63]([CH2:64][CH2:65]1)[CH2:62][CH:61]2[NH:67][C:68](=[O:83])[C@H:69]([CH3:82])[CH2:70][C@H:71]([OH:81])[C@@H:72]([NH2:80])[CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>>[CH2:73]([C@H:72]([NH:80][C:47](=[O:49])[C:46]1[CH:50]=[CH:51][CH:52]=[C:53]([N:54]2[CH2:58][CH2:57][CH2:56][C:55]2=[O:59])[C:45]=1[F:44])[C@@H:71]([OH:81])[CH2:70][C@H:69]([C:68](=[O:83])[NH:67][CH:61]1[CH2:62][CH:63]2[CH2:66][CH:60]1[CH2:65][CH2:64]2)[CH3:82])[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1
Reactant: O=C(O)c1cccc(N2CCCC2=O)c1F
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(N2CCCC2=O)c1F)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 2-fluoro-3-(2-oxopyrrolidin-1-yl)benzoic acid (D27) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]([O:12][CH3:13])=[O:11])=[C:5]1[CH2:14][C:15]([O:17][CH3:18])=[O:16].S(OCCN1C=C(C)C(C(OC)=O)=C1CC(OC)=O)(C)(=O)=O.[H-].[Na+]>CN(C)C=O>[CH3:9][C:7]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[C:5]2[CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:2][CH2:3][N:4]2[CH:8]=1
Reactant: COC(=O)Cc1c(C(=O)OC)c(C)cn1CCO
Agent: COC(=O)Cc1c(C(=O)OC)c(C)cn1CCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cn2c1C(C(=O)OC)CC2

Procedure:
By following the method of Example 2, methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = CH3) is converted into methyl N-(2-mesyloxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate and then cyclized with sodium hydride in dimethylformamide, in accordance with the method of Example 8, to afford dimethyl 1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([NH2:9])=[CH:7][N:6]=[CH:5][N:4]=1.[CH2:10]([O:13][C:14]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17])[CH2:11][CH3:12]>>[NH2:2][C:3]1[C:8]([NH:9][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:14]=2[O:13][CH2:10][CH2:11][CH3:12])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: Nc1cncnc1N
Reactant: CCCOc1cc(OC)ccc1C(=O)Cl
Agent: Cl
Product: CCCOc1cc(OC)ccc1C(=O)Nc1cncnc1N

Procedure:
The above compound was prepared from 4.4 g of 4,5-diaminopyrimidine hydrochloride and 7.6 g of 2-n-propyloxy-4-methoxy-benzoylchloride using a procedure analogous to that of Example 11(a). The crude product obtained was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[CH:20][CH:19]=3)=[O:17])[C:8]=2[CH:29]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[CH:22][CH:23]=3)=[O:17])[C:8]=2[CH:29]=1
Reactant: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OCCC#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCC#N)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1 g of (5-nitro-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VII) is dissolved in 15 ml of methanol and 0,1 g of 10 w/w % wet Pd/C catalyst is added and the reaction mixture is heated to 50° C. with a stirring of 800 round/min. Hydrogen pressure of 5 bar is set in the reactor and the mixture is stirred at this temperature for 2 hours. After cooling to room temperature the catalyst is, filtered off and the solvent is evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]2[CH3:21])=[N:6][CH:7]=1.[Br:22][C:23]1[C:31]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[Cl:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:22][C:23]1[C:31]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][C:26]([C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]3[CH3:21])=[N:6][CH:7]=2)=[O:28])=[CH:25][C:24]=1[Cl:37]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cn1
Reactant: O=C(O)c1cc(Cl)c(Br)c(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(NC(=O)c2cc(Cl)c(Br)c(OC(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (R)-tert-butyl 4-(5-aminopyridin-2-yl)-3-methylpiperazine-1-carboxylate (59.9 mg, 0.21 mmol) and 4-bromo-3-chloro-5-(trifluoromethoxy)benzoic acid (65.5 mg, 0.21 mmol; Preparation 50) in DMA (0.5 mL) at RT was added HATU (86 mg, 0.23 mmol) followed by DIPEA (0.11 mL, 0.62 mmol). The reaction mixture was stirred at RT for 1 h, partitioned between EtOAc (10 mL) and water (2 mL). The organic layer was washed with water (2 mL), dried over sodium sulfate, filtered and concentrated to give the title intermediate as a dark purplish oil. (m/z): [M+H]+ calcd for C23H25BrClF3N4O4 593.07; 595.07. found 595.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Sn](Cl)Cl>C(O)C>[NH2:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([Br:1])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc(Br)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of ethyl 3-bromo-5-nitrobenzoate (4.4 g, 16 mmol) and tin(II) chloride (40 g, 170 mmol) in ethanol (125 ml) was heated at 80° C. for 2 hours. The mixture was cooled to room temperature and the solvent evaporated. The residue was suspended in ethyl acetate (250 ml) and washed with 2M NaOH (2×250 ml). The organic phase was washed with water, dried and evaporated to give the title compound as a yellow solid (3.6 g, 92%)
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].[Al].Cl.[OH-].[Na+]>>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: Cl
Agent: [Al]
Agent: [Na+]
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a scintillation vial was placed 180mgs of BSA (2.6 × 10-6Moles) (Pentex, crystallized) dissolved in 6mls H2O containing 180mgs K2CO3. To this was added 18.3mgs fluorescein isothiocyanate (FITC) (4.85 × 10-5Moles) and the mixture was stoppered, covered with aluminum foil then placed in the center hole of a vortex mixer and shaken gently overnight at room temperature. The following morning the reaction mixture was acidified to pH 4 with 1N HCl (heavy preciptate), then made basic to pH 8 with 0.1N NaOH, applied to a 2.5 × 30cm column of Sephadex G-10 and eluted with 0.05M PO4, pH 8.0 at 5.4 mls/hr, 0.9 ml/fraction. Fractions 43-72 were pooled. Hapten number was calculated from the UV absorption of the conjugate at 493mμ and the extinction coefficient for protein-bound fluorescein of 7.2 × 104. Hapten number was thus calculated to be 14.5.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=1)[CH2:2]2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]([F:61])([F:60])[C:51]1[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=1>CN(C=O)C>[N:12]1[C:11]2[NH:15][CH:16]=[CH:17][C:10]=2[C:9]([N:3]2[CH2:2][CH:1]3[N:8]([C:55]([C:54]4[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:60])[F:61])=[CH:59][CH:58]=4)=[O:56])[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)=[N:14][CH:13]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: c1nc(N2CC3CCC(C2)N3)c2cc[nH]c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(C(F)(F)F)cc1)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reaction time: 16 h

Procedure:
4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 4) (0.05 mmol) was dissolved in dry DMF (0.3 mL). Triethylamine (0.18 mmol) and HATU (0.09 mmol) was added followed by 4-trifluoromethylbenzoic acid (0.07 mmol). The reaction mixture was left at it for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([C:36]([O:38][CH3:39])=[O:37])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH:28]=1>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:27]1[CH:28]=[C:23]([CH2:22][N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:24]=[C:25]([C:36]([O:38][CH3:39])=[O:37])[CH:26]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: COC(=O)c1cc(CBr)cc(-c2ccccc2Cl)c1
Product: COC(=O)c1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc(-c2ccccc2Cl)c1

Procedure:
Analogously to the preparation of Example 139, 248 mg (0.81 mmol) of the compound from Example 5A were reacted with 274 mg (0.81 mmol) of the compound from Example 112A. This gave 271 mg (59% of theory) of the target compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1>>[C:18]([N:13]1[C:12]([C:32]2[CH:33]=[CH:34][O:30][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccoc1
Product: CC(C)(C)n1nc2c(c1-c1ccoc1)CCNCC2
Yield: 50.3 %

Procedure:
The title compound (60 mg) was prepared according to Example 215 using 203 mg of 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 215, Step A) and 154 mg of 3-furanboronic acid. MS (ESI): exact mass calculated for C15H21N3O, 259.17; found, m/z 260.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.69-7.68 (m, 1H), 7.61 (br s, 1H), 6.50-6.49 (m, 1H), 3.38-3.36 (m, 2H), 3.27-3.25 (m, 2H), 3.13-3.11 (m, 2H), 2.63-2.61 (m, 2H), 1.50 (s, 9H).
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.[C:16]1([CH3:24])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1.Cl>ClCCCl>[CH3:24][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([OH:10])=[O:15])=[O:9]
Reactant: Cc1cc(C)cc(C)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cc(C)c(C(=O)c2ccccc2C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (60 g, 0.45 mol) was added in portions to a solution of phthalic anhydride (30 g, 0.20 mol) and mesitylene (40 mL) in 150 mL of 1,2-dichloroethane at 0° C. the reaction mixture was stirred at room temperature for 2 hours, then poured into ice-water. The mixture was acidified with 37% hydrochloric acid and extracted with ether. The ether extract was washed with 1 N hydrochloric acid, water, dried and concentrated to give 59 g of the title compound as white solids which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.O.[CH3:40]COC(C)=O>CO.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[N:15]\[NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:40])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)/[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2cccc(N/N=C3\C(=O)N(c4ccc(C)c(C)c4)N=C3C)c2O)c1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
Pure 3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid (Eltrombopag) (20 g, 0.045 mol) was suspended in a mixture of MeOH/THF=1/1 (400 mL). The suspension was heated to reflux and sulfuric acid (5 mL) was added drop wise. The reaction mixture was refluxed overnight, cooled to room temperature and evaporated to obtain an oily residue. Water (200 ml) was added to the and a thick suspension was formed. EtOAc (200 ml) was added to form a 2-phase system and the layers were separated. The organic layer was left for half an hour at room temperature resulting in formation of orange crystals. The crystals were filtered, washed with 2×20 mL EtOAc and dried in a vacuum oven at 35° C./0 bar for 2 hours, giving 17.17 g of (Z)-methyl 3′-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-2′-hydroxybiphenyl-3-carboxylate (Yield: 83.3%); (HPLC: >95%)
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:11])[CH2:6][CH:7]1[CH2:10][NH2+:9][CH2:8]1)[CH3:3].[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:32][CH:31]=2)=[C:21]([CH:25]=1)[C:22](O)=[O:23])=[O:16])[CH3:13]>>[CH2:2]([O:4][C:5](=[O:11])[CH2:6][CH:7]1[CH2:10][N:9]([C:22]([C:21]2[CH:25]=[C:17]([CH:18]=[CH:19][C:20]=2[O:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:32][CH:31]=2)[C:15]([O:14][CH2:12][CH3:13])=[O:16])=[O:23])[CH2:8]1)[CH3:3]
Reactant: CCOC(=O)CC1C[NH2+]C1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)O)c1
Agent: [Cl-]
Product: CCOC(=O)CC1CN(C(=O)c2cc(C(=O)OCC)ccc2OCCCc2ccc(OCCCCOc3ccccc3)cc2)C1

Procedure:
Preparation takes place in analogy to Example IX, method 3, from 3-(2-ethoxy-2-oxoethyl)azetidinium chloride and 5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)-phenyl]propoxy}benzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:20]([NH:28][C:29]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:20]([NH:28][C:29]1[CH:38]=[C:37]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[CH:6]=[CH:5]3)[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: Cn1ccc2cc(O)ccc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Oc2ccc3c(ccn3C)c2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
26 mg of 5-hydroxy-1-methyl-1H-indole, 64 mg of tripotassium phosphate, 3.8 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl and 5.5 mg of tris(dibenzylideneacetone) dipalladium (0) were added to 1.0 mL of toluene solution containing 50 mg of methyl 2-(benzamido)-4-bromobenzoate at zoom temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia chemical Ltd., eluent; hexane:ethyl acetate=5:1] to obtain 53 mg of methyl 2-(benzamido)-4-(1-methyl-1H-indol-5-yloxy)benzoate as pale yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:41]=[CH:40][C:9]2[N:10]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:33])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])C>C1COCC1.CCO.[OH-].[Na+]>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:23]([C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:11]4[N:10]([CH:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)[C:9]5[CH:40]=[CH:41][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=5[N:12]=4)[CH:14]=3)[N:19]=2)=[O:33])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NCc4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NCc4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Reaction time: 8 h
Yield: 10.1 %

Procedure:
A solution of 63 mg (0.11 mmol) of Compound 546c in 0.55 mL THF, 0.44 mL of EtOH and 0.11 mL of 2 N aq. NaOH was allowed to stand at room temperature overnight. The reaction was quenched with 0.22 mL 1 M aq. HCl. The solvents were removed and the residue was purified by HPLC to yield 6 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([Cl:12])(=[O:11])=[O:10])#[N:2].[NH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.NCC1C=CC=CC=1S(N(C(C)(C)C)C)(=O)=O>>[ClH:12].[N:13]1([S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][NH2:2])(=[O:11])=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCCNCC1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: CN(C(C)(C)C)S(=O)(=O)c1ccccc1CN
Agent: Cl
Product: NCc1ccccc1S(=O)(=O)N1CCCCCC1

Procedure:
A (125 mg) was prepared in two steps from 2-cyanobenzene-1-sulfonyl chloride (100 mg) and azepane in 82% overall yield following procedures analogous to those used in the preparation of 2-(aminomethyl)-N-tert-butyl-N-methylbenzenesulfonamide hydrochloride salt. LC-MS: 269.25 (M+H)+.