Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[C:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)(=[O:30])[CH3:29].C(OCC)C>ClCCl>[C:28]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[O:22][C:21]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=4[O:19][CH2:18]3)[CH2:12][CH2:11]2)(=[O:40])=[O:39])=[CH:36][CH:37]=1)(=[O:30])[CH3:29]
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)NCC2CCN(C[C@H]3COc4ccc(Cl)cc4O3)CC2)cc1
Reaction time: 20 h
Yield: 46.4 %

Procedure:
Triethylamine (0.62 ml) was added to a cloudy solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 4-acetamidobenzenesulphonyl chloride (0.65 g) in dichloromethane (22 ml) under nitrogen. The resulting solution was stirred for 20 hours, diluted with dichloromethane (100 ml) and washed with water (100 ml) and brine (100 ml). After drying over anhydrous magnesium sulphate, the mixture was concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography on silica gel eluting with a 15:1 mixture of dichloromethane and methanol gave an orange gum. Trituration with diethyl ether (20 ml) yielded (S)-(-)-4-acetamido-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide as a pale orange solid (0.34 g); m.p. 173-176° C., [α]D22 -39.3° (c=0.37, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[CH:16]=[C:15](I)[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:20]([NH:27][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(I)cc1Nc1ccc(F)cc1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To toluene 3.0 mL solution of methyl 2-(4-fluoroanilino)-4-iodobenzoate 0.30 g were added benzylamine 0.13 mL, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 0.050 g, tris(dibenzylideneacetone)dipalladium(0) 0.022 g and sodium tert-butoxide 0.093 g at room temperature, and it was stirred under nitrogen atmosphere at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, acetic acid 1.0 mL was added to it, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to give methyl 4-(benzylamino)-2-(4-fluoroanilino)benzoate 0.24 g of brown oil.
Reaction SMILES: N1C(=O)[C@H](CC2N=CNC=2)NC(=O)[C@@H]1CC(C)C.[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:35]([OH:37])=O)[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:38][C@H:39]([C:46]([OH:48])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1.ClC(OCC(C)C)=O>>[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:35]([NH:38][C@H:39]([C:46]([OH:48])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[C@@H]1NC(=O)[C@H](Cc2c[nH]cn2)NC1=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
The cyclic dipeptide, cyclo-(Leu-His) is a known substance [F. Schneider, Hoppe-Seyler's Z. Phys. Chem. 338, 131 (1964)], which can be prepared according to the usual peptide synthesis. For example, condensation between N-benzyloxycarbonyl-(S)-leucine and methyl ester of (S)-histidine in the presence of isobutyl chloroformate is effected in accordance with the mixed acid anhydride process to obtain methyl ester of N-benzyloxycarbonyl-(S)-leucyl-(S)-histidine and then the ester is hydrogenolyzed in the presence of palladium-carbon, followed by cyclization under reflux in methanol.
Reaction SMILES: [OH:1][C:2]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH2:24][CH2:23]2)([CH:9]1[O:14][CH2:13][C:12](=O)[N:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[OH:1][C:2]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH2:24][CH2:23]2)([CH:9]1[O:14][CH2:13][CH2:12][N:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)N1CC(C(O)(Oc2ccc3c(c2)CCC3)c2ccccc2)OCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCOC(C(O)(Oc2ccc3c(c2)CCC3)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
After mixing 2.5 g. of 2-(1-hydroxy-1-phenyl-5-indanyloxymethyl)-4 -isopropyl-5-oxomorpholine, 100 ml. of tetrahydrofuran, and 1.0 g. of lithium aluminum hydride under ice-cooling, the mixture was stirred for 18 hours at room temperature and then 1 ml. of water, 1 ml. of aqueous 15% sodium hydroxide aqueous solution, and then 3 ml. of water were added to the mixture followed by stirring for 30 minutes. The mixture thus obtained was filtered and the filtrate was distilled and the residue formed was adsorbed on a silica gel column prepared from 50 ml. of silica gel in chloroform and eluted with ethyl acetate. After removing the first 5 ml. of the ethyl acetate eluate, 200 ml. of the subsequent ethyl acetate eluate was collected and dried to provide 2.05 g. (yield 85.3%) of 2-(1-hydroxy-1-phenyl-5-indanyloxymethyl)-4-isopropylmorpholine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])([N+:17]([O-])=O)[CH3:16])=[CH:8][CH:9]=2)[C:4]([C:21]2[N:26]=[C:25]3[C:27]([C:49]([O:51][CH3:52])=[O:50])=[CH:28][N:29]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:24]3=[N:23][CH:22]=2)=[N:3]1>CO.[Pd]>[NH2:17][C:15]([CH3:20])([CH3:16])[CH2:14][CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[C:21]1[N:26]=[C:25]2[C:27]([C:49]([O:51][CH3:52])=[O:50])=[CH:28][N:29]([C:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:24]2=[N:23][CH:22]=1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(C)c4ccc(OCCCC(C)(C)[N+](=O)[O-])cc34)nc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(C)c4ccc(OCCCC(C)(C)N)cc34)nc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To a solution of methyl 2-(1-methyl-5-(4-methyl-4-nitropentyloxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (500 mg, 0.72 mmol) in CH3OH (15 mL) was added Pd/C (0.1 g, cat.) and HCO2NH4 (226 mg, 3.6 mmol), after the addition, the reaction mixture was heated to 80° C. with stirring for 0.5 hour, then the mixture was filtered and filtrate evaporated, the residue was partitioned between H2O (25 mL) and EtOAc (100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 2-(5-(4-amino-4-methylpentyloxy)-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (400 mg, 85%) as yellow solid. LCMS: (M+H)+=665.
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][NH2:54])[CH:48]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([C:14]2[N:53]([C:49]3[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=3)[N:54]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Cl)cc(OC(F)(F)F)c1
Reactant: NNc1cccnc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1

Procedure:
500 mg (1.23 mmol) of the compound of Example 4A is reacted analogously to the synthesis of the compound of Example 20A with 197 mg (1.36 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 203 mg (43% of theory) of the title compound is obtained.
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].Br[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(#N)C.C1(C)C=CC=CC=1.O>[C:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:8][CH:3]([C:2](=[O:1])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[CH:12][CH:13]=1)#[N:19]
Reactant: N#CCc1ccc(Br)cc1
Reactant: C=C(C(=O)OC)C(C)O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(CC#N)cc1)C(C)=O
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A stirred mixture of methyl 3-hydroxy-2-methylenebutanoate (70.0 g), 2-(4-bromophenyl)acetonitrile (126.5 g), PdCl2[P(o-tol)3]2 (4.2 g) and triethylamine (108.9 g) in acetonitrile (280 mL) was heated under nitrogen at 70° C. for 6 hours. The mixture was cooled to room temperature, diluted with toluene (840 mL) and water (840 mL) and stirred for 10 minutes. The organic layer was separated, washed with water (840 mL) and concentrated under reduced pressure to give the subtitle compound as a red oil, 158.7 g. This product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:37]([Cl:38])=[CH:36][C:8]2[S:9][C:10]3[CH:15]=[C:14]([NH:16][C:17](=[O:31])[C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[C:21]=4[Cl:30])=[CH2:19])[C:13]([C:32]([O:34]C)=[O:33])=[CH:12][C:11]=3[C:7]=2[CH:6]=1)=[O:4].CC(C)([O-])C.[K+].Cl>CS(C)=O>[Cl:38][C:37]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]2[C:11]3[CH:12]=[C:13]([C:32]([OH:34])=[O:33])[C:14]([NH:16][C:17](=[O:31])[C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[C:21]=4[Cl:30])=[CH2:19])=[CH:15][C:10]=3[S:9][C:8]=2[CH:36]=1
Reactant: C=C(C(=O)Nc1cc2sc3cc(Cl)c(C(=O)OC)cc3c2cc1C(=O)OC)c1ccc(OC)c(OC)c1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: C=C(C(=O)Nc1cc2sc3cc(Cl)c(C(=O)O)cc3c2cc1C(=O)O)c1ccc(OC)c(OC)c1Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To 275 mg of the product of Example 13 was added 4 ml of freshly made 1M potassium t-butoxide in DMSO. The reaction was heated in a 40° C. oil bath and monitored by Mass Spectra for the appearance of product ion. The mixture was poured into 200 ml of cold 1N hydrochloric acid and stirred in the cold for 1 hour. The resulting precipitate was collected, washed with 1N hydrochloric acid and a little water, and dried in vacuo to give the desired product, 3-chloro-7-[2-(2-chloro-3,4-di-methoxyphenyl)-acryloylamino]dibenzothiophene-2,8-dicarboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@H:10]([CH3:11])[CH2:9][N:8]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=[O:14])=[O:13])[CH2:7][C@@H:6]1[CH3:25])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40]>C(#N)C.O>[CH3:25][C@H:6]1[CH2:7][N:8]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=[O:13])=[O:14])[CH2:9][C@@H:10]([CH3:11])[N:5]1[C:3](=[O:4])[CH2:2][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][CH3:32]
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc3ccccc3c2)C[C@H](C)N1C(=O)CCl
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1OCC(=O)N1[C@H](C)CN(S(=O)(=O)c2ccc3ccccc3c2)C[C@@H]1C
Reaction time: 4 h

Procedure:
2-Chloro-1-((2S,6R)-2,6-dimethyl-4-(naphthalene-2-ylsulfonyl)piperazin-1-yl)ethanone (200 mg, 0.52 moles) was dissolved in 20 mL of acetonitrile. Dry K2CO3 (106 mg, 0.79 moles) was added to the reaction mixture under nitrogen atmosphere and allowed to stir for about ten minutes. 2-methoxyphenol (97 mg, 0.78 moles) was slowly added to the reaction at room temperature and allowed the reaction to continue for another 4 h. The reaction was monitored by TLC and after product formation was observed, the reaction mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (25 mL×2). The combined organic layers were washed with bicarbonate followed by brine & then dried over sodium sulphate. The solvent was evaporated on reduced pressure to afford crude product which was purified by column chromatography to yield the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NC1C=CC=CC=1>CN(C=O)C.C(Cl)Cl.O>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and aniline (9.1 uL, 0.1 mmol). The mixture was stirred at rt overnight. To the mixture was added 5 mL dichloromethane and 2 mL water, stirred for 3 min. The organic layer was loaded onto the silica gel column. Chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (9 mg, 30%). LC-MS m/z 597 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[C:11]([N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)[CH:12]=[CH:13][CH:14]=1
Reactant: c1cn[nH]c1
Reactant: Fc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(-n2cccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a suspension of sodium hydride (3.52 g, 88 mmol) in DMF (40 ml), was added pyrazole (3.0 g, 44 mmol) in portions. After stirring at room temperature for 30 minutes, 1-bromo-3-fluorobenzene (9.3 g, 53 mmol) in DMF (20 ml) was added dropwise and the resulting mixture was stirred for 2 hours at 130° C. The mixture was cooled and quenched by the addition of a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using normal phase chromatography, eluting with petroleum ether containing 10% ethyl acetate to give 1-(3-bromophenyl)-1H-pyrazole (4.7 g) as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:18])([CH3:17])[CH3:10])[CH:9]=1)=[O:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Temperature: 80 °C
Reaction time: 10 h
Yield: 59.9 %

Procedure:
A flask charged with 1H-imidazole-4-carboxylic acid methyl ester (0.54 g, 4.3 mmol), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (1.0 mL, 5.6 mmol), K2CO3 (1.4 g, 10.4 mmol), and DMF (7 mL) was stirred for 10 h at 80° C. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4 and concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 50% EtOAc/hexane to give 0.66 g (60%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C11H20N2O3Si, 257.1 (M+H), found 257.0.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[CH3:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H][H]>[Ni].O1CCCC1>[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[CH3:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N)cc2C)cc1

Procedure:
30.6g (0.6 mole) of 4-(N-p-toluenesulfonyl)amino-3-methyl-nitrobenzene 1g of fresh-developed Raney nickel and 60ml of tetrahydrofuran were charged into an autoclave and the autoclave was pressurized to 60kg/cm2 with hydrogen. The reaction was carried out at 50° to 100° C while stirring. After completion of the reaction, the Raney nickel was removed from the reaction solution and the tetrahydrofuran was distilled out to obtain brown 4-(N-p-toluenesulfonyl)amino-3-methylaniline. The product was recrystallized from ethyl acetate to obtain 24g of yellow-brown crystals.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:10]1[C:2]([F:1])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1cccc(CBr)c1F
Yield: 17.5 %

Procedure:
A mixture of 2-fluoro-3-methylbenzoic acid (0.462 g, 3 mmol), N-bromosuccinimide (0.560 g, 3.15 mmol), azobisisobutyronitrile (AIBN) (0.024 g, 0.15 mmol) and CCl4 (10 ml) was heated at reflux for 18 h. The reaction mixture was then reduced in vacuo and partitioned between ethyl acetate and aqueous K2CO3. The aqueous layer was acidified (2M HCl) and cooled in ice. The precipitate obtained was collected by filtration and dried in vacuo to give 3-bromomethyl-2-fluoro-benzoic acid (0.1225 g, 13%) as a colourless solid. (LC/MS: Rt 3.18, [M−H]− 232.91).
Reaction SMILES: [O:1]([C:8]1[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O>[C:10]([C:9]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a mixture of dimethyl phenoxyterephthalate (10.4 g) in water. (50 mL) was added 50% aqueous NaOH (2.32 g) and water (4 mL) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and ether. The aqueous phase was acidified (a solid formed) and extracted with dichloromethane. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 4-carbomethoxy-3-phenoxybenzoic acid (6.6 g) as a 68:32 mixture of hydrolysis isomers.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH2:1]([O:9][C:10]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(C(=O)OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc(C(=O)OC)c1OCc1ccccc1
Yield: 90.1 %

Procedure:
Benzyl bromide (0.34 ml, 0.49 g, 2.89 mmol, 1.5 eq) was added to a stirred suspension of dimethyl 2-hydroxyisophthalate (0.4045 g, 1.92 mmol, 1 eq) and K2CO3 (0.5317 g, 3.85 mmol, 2 eq) in anhydrous DMF (2 ml) under Ar. After 48 h the reaction was diluted with Et2O. The mixture was washed with water (×4), brine (×1), and dried over Na2SO4. The inorganics were filtered off and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.5207 g (1.73 mmol, 90% yield) of dimethyl 2-(benzyloxy)isophthalate.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:37])[N:8]([CH2:31][C:32]([O:34]CC)=[O:33])[C:9](=[O:30])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][C:27](=[O:29])[O:26][N:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O1CCCC1.Cl>C(OCC)(=O)C.C(O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:37])[N:8]([CH2:31][C:32]([OH:34])=[O:33])[C:9](=[O:30])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][C:27](=[O:29])[O:26][N:25]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(CC(=O)OCC)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(=O)O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A mixture of ethyl [4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]acetate (0.25 g), 1 M aqueous sodium hydroxide solution (1.2 mL), tetrahydrofuran (3 mL) and ethanol (3 mL) was stirred at room temperature for 3 hr. 1 M hydrochloric acid (1.2 mL) was added to the reaction solution, and the mixture was stirred for 10 min. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as colorless crystals (0.22 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH:6]1[CH2:8][CH:9]=[CH2:10])=[O:4]>CCOC(C)=O.[Rh]>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:7][CH:6]1[CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: C=CCC1CC1(NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCCC1CC1(NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 0.75 h

Procedure:
A solution of 2-allyl-1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid methyl ester (0.27 mmol) in EtOAc (3 mL) was treated with 5% Rh/Al2O3 (0.014 mmol Rh). The atmosphere over the reaction was replaced with a H2 balloon and the reaction allowed to stir vigorously for 45 min. The H2 was removed and the catalyst removed by filtration through a pad of celite. Volatiles were removed in vacuo to afford 1-tert-butoxycarbonylamino-2-propyl-cyclopropanecarboxylic acid methyl ester as a colorless film that was used without further purification (0.069 g, quant). LCMS found 257.8 [M+H]+.