Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[NH:11][NH2:12].[CH3:13][CH2:14][C:15](=O)[CH2:16][C:17](=O)[CH2:18][CH3:19].C(N(CC)CC)C>C(O)C>[CH2:14]([C:15]1[CH:16]=[C:17]([CH2:18][CH3:19])[N:11]([C:4]2[C:3]([CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=2[CH3:10])[N:12]=1)[CH3:13]
Reactant: CCC(=O)CC(=O)CC
Reactant: Cc1cc(C)c(NN)c(C)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cc(CC)n(-c2c(C)cc(C)cc2C)n1
Yield: 95 %

Procedure:
A solution of 7.46 g (0.04 mol) of 2,4,6-trimethylphenylhydrazine hydrochloride, 5.12 g (0.40 mol) of 3,5-heptanedione and 4.18 mL (0.60 mol) of triethylamine in 100 mL of absolute ethanol was refluxed overnight. The solvent was evaporated from the cooled reaction mixture and the residues were partitioned between water and ethyl acetate. The organic extracts were dried with brine and magnesium sulfate, and the solvent was evaporated to give the desired product in 95% yield. This compound was used in the subsequent reaction without further purification 1H-NMR (CDCl3): 0.11 (3H, t, J=7), 1.24 (3H, t, J=7), 1.90 (6H, s), 2.22 (2H, q, J-7), 2.28 (3H, s), 2.65 ) (2H, q, J=7), 5.96 (1H, s), 6.86 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:31]1[CH2:35][CH2:34][C@@H:33]([OH:36])[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)Cl.CO.O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([C@@H:24]3[CH2:29][CH2:28][C@H:27]([N:31]4[CH2:35][CH2:34][C@@H:33]([OH:36])[CH2:32]4)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O[C@@H]1CCNC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@H]1CC[C@@H](N2CC[C@@H](O)C2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (1.00 g, 2.51 mmol) and (R)-(+)-3-pyrrolidinol (0.62 mL, 7.5 mmol) in 1,2-dichloroethane (50 mL) was stirred at ambient temperature under an atmosphere of nitrogen for 1.5 hours. Sodium triacetoxyborohydride (0.691 g, 3.26 mmol) was added and the mixture stirred at ambient temperature for 22 hours. Water (50 mL) and sodium bicarbonate (1.34 g, 16.1 mmol) were added and the mixture was stirred for 2 hours. The reaction mixture was transferred to a separatory funnel and the organic layer was separated, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield a yellow-brown solid. The cis isomer was purified by flash chromatography on silica gel (1 L 5% MeOH in CH2Cl2, then 2 L 10% MeOH in CH2Cl2, 1 L 20% MeOH in CH2Cl2, and 1 L 40% MeOH in CH2Cl2) to yield cis-(3R)-1-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}tetrahydro-1H-3-pyrrolol as a pale yellow oil (0.529 g, 1.12 mmol). The cis-(3R)-1-{4-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}tetrahydro-1H-3-pyrrolol (0.464 g, 0.988 mmol) was dissolved in warm ethanol (5 mL) and added to a solution of maleic acid (0.344 g, 2.96 mmol) in ethanol (5 mL). The mixture was cooled to ambient temperature then the solid was collected by filtration and dried to give cis-(3R)-1-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}tetrahydro-1H-3-pyrrolol dimaleate salt (0.549 g) as a pale yellow solid: 1H NMR (d6 DMSO, 400 MHz): δ H 8.22(1H, s), 7.41-7.50 (5H, m), 7.08-7.19(5H, m), 6.49(2H, bs), 6.13(4H, s), 4.85(1H, bs), 4.49(1H, bs), 3.37-3.68(5H, m), 1.92-2.18(11H, m); HPLC: (Hypersil HS C18, 5 μm, 254 nm, 250×4.6 mm; 25-100% acetonitrile-0.1N ammonium acetate over 10 min, 1 ml/min) tr=7.167 min.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@@:16]([OH:48])([CH2:42][N:43]1[CH:47]=[N:46][CH:45]=[N:44]1)[C@H:17]([S:19][C@@H:20]1[CH2:25][O:24][C@@H:23]([C:26]2[CH:41]=[CH:40][C:29]([C:30]([NH:32][C:33]3[CH:38]=CC(O)=[CH:35][CH:34]=3)=[O:31])=[CH:28][CH:27]=2)[O:22][CH2:21]1)[CH3:18].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:5]([O:4][C:1]1[CH:35]=[CH:34][C:33]([NH:32][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([C@H:23]3[O:22][CH2:21][C@H:20]([S:19][C@H:17]([CH3:18])[C@:16]([C:10]4[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=4[F:8])([OH:48])[CH2:42][N:43]4[CH:47]=[N:46][CH:45]=[N:44]4)[CH2:25][O:24]3)=[CH:41][CH:40]=2)=[CH:38][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(O)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(NC(=O)c2ccc([C@H]3OC[C@H](S[C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)CO3)cc2)cc1
Temperature: 0 °C

Procedure:
Acetic anhydride (1.5 ml) was added dropwise to a solution of 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-4′-hydroxybenzanilide (40 mg, 0.07 mmol), obtained in Example 23(2), in anhydrous pyridine (3 ml) cooled to 0° C. with stirring. The resulting mixture was stirred at room temperature overnight. At the end of this time, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution at 0° C. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (43 mg, yield 100%) as a colorless oil. The oil was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[N:10]=[C:11]([N:20]([CH:28]2[CH2:30][CH2:29]2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:12]2[N:13]([C:15]([CH:18]=[O:19])=[CH:16][N:17]=2)[CH:14]=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>CN(C=O)C.CCOC(C)=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.[Cu]I>[CH:28]1([N:20]([C:11]2[C:12]3[N:13]([C:15]([CH:18]=[O:19])=[CH:16][N:17]=3)[CH:14]=[C:9]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[N:10]=2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N(c1nc(Br)cn2c(C=O)cnc12)C1CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1nc(C#C[Si](C)(C)C)cn2c(C=O)cnc12)C1CC1
Temperature: 65 °C
Yield: 70.7 %

Procedure:
Triethylamine (912 μL, 6.56 mmol) was added to tert-butyl 6-bromo-3-formylimidazo[1,2-a]pyrazine-8-yl(cyclopropyl)carbamate (250 mg, 0.66 mmol) dissolved in anhydrous DMF (2.2 mL) in a 15 mL pressure tube. The solution was degassed with a stream of N2 for 10 min. Trimethylsilylacetylene (927 μL, 6.56 mmol), Pd(PPh3)4 (76 mg, 0.07 mmol), and copper(I) iodide (25 mg, 0.13 mmol) were added and the reaction was sealed and heated to 65° C. for 24 h. The reaction was diluted with EtOAc (50 mL) and then washed with 10% brine (4×50 mL) and brine (50 mL). The organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (30% EtOAc/hexanes) to give tert-butyl cyclopropyl(3-formyl-6-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazin-8-yl)carbamate (186 mg, 71%) as a brown foamy solid. LCMS (ES): >95% pure, m/z 400 [M+1]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH2:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Br:22])[CH2:12][C:13]#[CH:14]>CN(C=O)C.C(N(C(C)C)CC)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][CH2:11][CH2:12][C:13]#[C:14][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: C#CCCOCCCCCCBr
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(C#CCCOCCCCCCBr)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
A mixture of 1-iodo-3-nitrobenzene (3 g), 6-bromohexyl but-3-ynyl ether (3 g), bis(triphenylphosphine)palladium (II) chloride (0.421 g), copper (I) iodide (0.114 g) in DMF (10 ml) and diisopropylethylamine (4 ml) was stirred under nitrogen at 20° C. for 5 h. The mixture was concentrated under reduced pressure and the residue was diluted in EtOAc and washed with 2M HCl, NaHCO3, brine and dried (MgSO4). The solvent was removed by evaporation and the residue was chromatographed on a Biotage column eluting with ether:petroleum ether(40–60° C.) (1:9) to give the title compound (4.12 g). LCMS RT=4.14 min
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:25]([O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:34]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 88 %

Procedure:
In a manner similar to the procedure described for step 7 of Example 330 and using tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate and (3-benzyloxyphenyl)boronic acid as starting material, 300 mg (88%) of the desired product was isolated. LC-MS m/z [M+H]+500.2, RT 3.47 min.
Reaction SMILES: CC1C=C(P(C2C=C(C)C=C(C)C=2)C2C=C[C:16]3[C:11](=CC=CC=3)[C:10]=2[C:19]2C3C(=CC=CC=3)C=[CH:21][C:20]=2[P:29]([C:38]2[CH:43]=[C:42](C)[CH:41]=[C:40](C)[CH:39]=2)C2C=C(C)C=C(C)C=2)C=C(C)C=1>CCN(CC)CC>[C:38]1([P:29]([C:20]2[CH:21]=[CH:16][CH:11]=[CH:10][CH:19]=2)[C@H:11]([CH2:10][C@@H:19]([P:29]([C:20]2[CH:19]=[CH:10][CH:11]=[CH:16][CH:21]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH3:20])[CH3:16])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2ccc3ccccc3c2-c2c(P(c3cc(C)cc(C)c3)c3cc(C)cc(C)c3)ccc3ccccc23)c1
Solvent: CCN(CC)CC
Product: C[C@@H](C[C@H](C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1

Procedure:
Among these transition metal complexes, preferable ones include [Ru2 Cl4 (DM-BINAP)2 ]NEt3, [Ru2Cl4(OcH-BINAP)2 ]NEt3, [Ru2Cl4 (OcH-DM-BINAP)2 ]NEt3, [RuI(p-cymene)(DM-BINAP)]I, [RuCl(p-cymene)(DM-BINAP)]Cl, [RuBr(p-cymene)(DM-BINAP)]Br, [RuI(benzene)(DM-BINAP)]I, [RuCl(benzene)(DM-BINAP)]Cl, [RuBr(benzene)(DM-BINAP)]Br, [RuI(p-cymene)(OcH-BINAP)]I, [RuCl(p-cymene)(OcH-BINAP)]Cl, [RuBr(p-cymene)(OcH-BINAP)]Br, [RuI(benzene)(OcH-BINAP)]I, [RuCl(benzene)(OcH-BINAP)]Cl, [RuBr(benzene)(OcH-BINAP)]Br, [RuI(p-cymene)(OcH-DM-BINAP)]I, [RuCl(p-cymene)(OcH-DM-BINAP)]Cl, [RuBr(p-cymene)(OcH-DM-BINAP)]Br, [RuI(benzene)(OcH-DM-BINAP)]I, [RuCl(benzene)(OcH-DM-BINAP)]Cl and [RuBr(benzene)(OcH-DM-BINAP)]Br, and still preferable ones include [RU2Cl4 (DM-BINAP )2 ]NEt3, [Ru2Cl4 (OcH-BINAP)2 ]NEt3 and [Ru2 Cl4 (OcH-DM-BINAP)2 ]NEt3.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](=[O:29])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:33]=[CH:34][C:35]=1[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1Cl
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(3-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH2:9][C:10]1[C:11]([O:23][CH3:24])=[N:12][S:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.O1CCCC1.[Li+].[OH-]>O>[F:25][C:6]1[CH:5]=[C:4]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:3]=[C:2]([F:1])[C:7]=1[O:8][CH2:9][C:10]1[C:11]([O:23][CH3:24])=[N:12][S:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(OC)nsc2-c2ccc(OC)cc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2snc(OC)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(3,5-difluoro-4-[[3-methoxy-5-(4-methoxyphenyl)-1,2-thiazol-4-yl]methoxy]phenyl)propanoate (50 mg, 0.11 mmol, 1.00 equiv), tetrahydrofuran (3 mL), water (1 mL), LiOH (50 mg, 2.09 mmol, 19.30 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5 with hydrogen chloride (2 mol/L). The solids were collected by filtration, washed with n-hexane, dried. This resulted in 8.2 mg (17%) of 3-(3,5-difluoro-4-[[3-methoxy-5-(4-methoxyphenyl)-1,2-thiazol-4-yl]methoxy]phenyl) propanoic acid as a white solid. 1H NMR (300 MHz, CD3OD) δ7.53 (d, J=11.6 Hz, 2H), 7.05 (d, J=11.6 Hz, 2H), 6.81 (d, J=11.6 Hz, 2H), 5.16 (s, 2H), 4.06 (s, 3H), 3.92 (s, 3H), 2.88 (m, 2H), 2.71 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H19F2NO5S, 436.1 (M+H). found 436.0.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4].CCN(C(C)C)C(C)C.[CH:21]1([CH2:26][C:27]2[N:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:30]3[CH:37]=[CH:38][C:39]([C:41](Cl)=[O:42])=[CH:40][C:29]=3[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[CH:6]1([CH2:5][C@H:2]([NH:1][C:41]([C:39]2[CH:38]=[CH:37][C:30]3[N:31]([CH:32]([CH2:33][CH3:34])[CH2:35][CH3:36])[C:27]([CH2:26][CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:28][C:29]=3[CH:40]=2)=[O:42])[CH2:3][OH:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: N[C@H](CO)CC1CCCCC1
Reactant: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)Cl)ccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)N[C@H](CO)CC3CCCCC3)ccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 26.3 %

Procedure:
47 mg of (S)-2-amino-3-cyclohexyl-propan-1-ol and 0.14 ml DIPEA were dissolved in 2 ml dry THF. The mixture was cooled to −10° C. and 67 mg of 2-cyclopentylmethyl-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carbonyl chloride in 1 ml of dry THF were added. The mixture was stirred under exclusion of moisture for 15 min at −10° C. and then at RT over night. It was then filtered, the filter was washed with 10 ml ethyl acetate. The filtrate was evaporated, the residue was taken up in 20 ml ethyl acetate and extracted with 20 ml 5% NaHCO3. The organic phase was dried and evaporated and the residue was purified by HPLC to yield 24 mg (27%) of 2-cyclopentylmethyl-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carboxylic acid ((S)-1-cyclohexylmethyl-2-hydroxy-ethyl)-amide.
Reaction SMILES: C([O:3][C:4](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH2:5][F:6])C.Cl.O>C(OCC)C>[F:6][CH2:5][C:4](=[O:3])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CCOC(=Cc1ccc(OC)cc1)CF
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COc1ccc(CC(=O)CF)cc1
Reaction time: 3 h
Yield: 96.1 %

Procedure:
2-Ethoxy-1-fluoro-3-(4-methoxyphenyl)prop-2-ene (5 g, 0.024 mol) is stirred with a saturated solution of hydrogen chloride in diethyl ether (40 ml) overnight. Water (18 ml) is added and the stirring is continued for another 3 hours. The ether layer is separated, washed with water, dried (MgSO4), and filtered. Concentration of the solvent affords 1-fluoro-3-(4-methoxyphenyl)-2-propanone (4.2 g); NMR (CDCl3): 6.7-7.3 ppm (4H, m), 4.8 ppm (2H, J=48 Hz), 3.7-3.9 ppm (5H, m).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([NH:23][S:20]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]([O:9][CH3:10])=[C:3]([CH:1]=[O:2])[CH:4]=1)(=[O:22])=[O:21])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and benzoyl chloride, gave N-benzoyl-5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>C(O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[NH:6][C:5]3=[O:12])=[CH:22][CH:21]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1NC(=O)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1NC(=O)c2cc(OCc3ccc(F)cc3)ccc21
Temperature: 80 °C
Yield: 46.8 %

Procedure:
A mixture of 5-hydroxy-isoindole-1,3-dione (200 mg, 1.0 mmol), potassium carbonate (178 mg, 1.05 mmol), 4-fluorobenzylbromide (204 mg, 1.05 mmol) in ethanol (5 mL) was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was filtered and evaporated. The residue was purified by chromatography (SiO2, heptane-CH2Cl2 2:3 then CH2Cl2— 2N NH3-MeOH 99:1: to 95:5) to afford the title compound (127 mg, 38%) as an off-white solid. MS: m/e=271.1 (M+).
Reaction SMILES: N[C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.N([O-])=O.[Na+].[OH-].[Na+].S(OC)([O:26][CH3:27])(=O)=O>O.CO>[CH3:27][O:26][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: COS(=O)(=O)OC
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Ground 3-amino-2-methylbenzoic acid (17 g, 0.11 mole) was mixed with methanol (120 mL) in a 1-13-neck round bottom flask provided with a mechanical stirrer and a thermometer. To this mixture, concentrated sulfuric acid, 15.5 mL, was added dropwise with stirring. Upon the addition, the temperature of the mixture went up to 50° C. The addition time was 2 minutes. Following the addition, the flask was placed on a pre-heated oil bath and the temperature of 50°-55° C. inside the flask was maintained. Thereafter, a dropwise addition of sodium nitrite solution (8.1 g in 17 mL of water) was started. When the temperature reached 62° C., the heating under the oil bath was turned off. After additional 10 min on the oil bath (the heater still turned off), the temperature dropped to 55° C., at which point sodium hydroxide (50% aqueous, 55 g) diluted water (55 mL) was added dropwise over 30 minutes, followed by water (55 mL) in one portion, and dimethyl sulfate (25 mL) dropwise in two portions (15 mL plus 10 mL) over 30 minutes with 20 minutes apart. The reaction mixture was allowed to cool to room temperature whereupon it was poured over concentrated sulfuric acid, 40 mL, diluted with water (360 mL), the product collected by filtration, and dried in vacuo over 24 hours to give 3-methoxy-2-methylbenzoic acid (12 g). 1H-NMR (CDCl3) δppm 2.50 (s, 3H), 3.85 (s, 3H), 7.03 (d 1H, Ar), 7.22 (dd, 1H, C-5), 7.59 (d, 1H, Ar).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:14](Br)[CH3:15])[CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].[N-:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Na+].[H-].[Na+].N1C=CN=C1.[I-].[K+]>CN(C)C=O>[C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:14]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH3:15])[CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: c1c[n-]cn1
Reactant: CC(=O)c1ccc2cc(C(C)Br)ccc2c1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2cc(C(C)n3ccnc3)ccc2c1
Yield: 69.3 %

Procedure:
9.82 g (35.4 mmol) of 2-acetyl-6-(1-bromoethyl)naphthalene, 6.38 g (70.9 mmol) of sodium imidazolide (from 3.1 g (70.9 mmol) of sodium hydride dispersion (55%) and 4.83 g (70.9 mmol) of imidazole) and 0.588 g (3.54 mmol) of potassium iodide in 100 ml of absolute N,N-dimethylformamide are stirred at 100° C. (24 hours). The mixture is then evaporated in vacuo, the residue is taken up in 4N HCl, the solution is extracted with ethyl acetate, and the aqueous phase is neutralized with sodium carbonate solution. It is then extracted 4× with dichloromethane, and the dichloromethane phase is dried and evaporated in vacuo. The residue is filtered through silica gel using ethyl acetate/methanol 8:1. 6.48 g (70%) of 2-acetyl-6-[1-(1-imidazolyl)ethyl]naphthalene are obtained as an oil. RF (ethyl acetate/methanol 8:1): 0.15.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[O:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])[CH3:9])[N:7]=1.[BrH:14].BrBr>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[O:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])[CH2:9][Br:14])[N:7]=1
Reactant: CC(=O)c1nc(C(F)(F)F)oc1C
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1oc(C(F)(F)F)nc1C(=O)CBr
Temperature: 80 °C

Procedure:
3.8 g (0.02 mol) of 2-Trifluoromethyl-5-methyl-4-acetyl-oxazole are dissolved in 30 ml of glacial acetic acid, and 3 ml of a 33% strength solution of hydrogen bromide in glacial acetic acid are added. The mixture is heated to 80° C. and, over the course of 1 hour, a solution of 3.2 g (0.02 mol) of bromine in 10 ml of glacial acetic acid is added. After a further 30 minutes the glacial acetic acid is removed. The residue which remains is a dark oil which is reacted further as the crude product.