Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8].Cl.[NH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][CH:30]2[S:34][C:33](=[O:35])[NH:32][C:31]2=[O:36])=[CH:27][CH:26]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[N:20][O:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:37][CH:38]=2)[CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(S(=O)(=O)c2ccccn2)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(S(=O)(=O)c2ccccn2)cc1
Yield: 61.3 %

Procedure:
Following a procedure similar to that described in Example 40(f), 150 mg of 4'-(2-pyridylsulfonyl)-acetophenone were reacted with 183 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:98 by volume mixture of methanol and methylene chloride as the eluent, to give 185 mg of the title compound as a gum.
Reaction SMILES: [F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH:20]=[O:21])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.[CH3:24][Mg+].[Br-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH:20]([OH:21])[CH3:24])[C:3]=1[O:22][CH3:23]
Reactant: C[Mg+]
Reactant: COc1c(F)cc2c(ccn2S(=O)(=O)c2ccccc2)c1C=O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1c(F)cc2c(ccn2S(=O)(=O)c2ccccc2)c1C(C)O
Reaction time: 0.33 h

Procedure:
A solution of crude 6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (72.3 mg, 217 μmol) in THF (2 mL) was treated with MeMgBr (310 μL of a 1.4 M solution in Toluene/THF, 2 eq) at rt and stirred for 20 min (50% conversion). After 20 min another 2 eq Grignard solution were added and stirring continued for 15 min. The reaction mixture was quenched with sat. NH4Cl, extracted with EtOAc (3×), the combined org. phases were washed with brine, dried and the solvent removed in vacuo to give a yellow-brownish foam (81.9 mg), 56% pure according to LC/MS. This material was purified by prep. HPLC (25-55% MeCN/50 mM NH4HCO3) to yield the title compound as an off-white solid (26.5 mg, 9% over 4 steps). MS (ESI+) for C17H16FNO4S m/z 332 (M-OH)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:19]1[C:20]([F:32])=[C:21]2[O:25][C:24]([CH3:26])=[N:23][C:22]2=[C:27]([C:30]#[N:31])[C:28]=1[CH3:29]>O1CCOCC1>[F:32][C:20]1[C:19]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:28]([CH3:29])[C:27]([C:30]#[N:31])=[C:22]2[C:21]=1[O:25][C:24]([CH3:26])=[N:23]2
Reactant: OB(O)c1ccccc1
Reactant: Cc1nc2c(C#N)c(C)c(Br)c(F)c2o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Yield: 45.2 %

Procedure:
Phenylboronic acid (1.30 g, 10.63 mmol), tetrakistriphenylphosphine palladium(0) (473 mg, 0.41 mmol) and tripotassium phosphate (4.51 g, 21.2 mmol) were added to a 1,4-dioxane (80 ml) solution of 6-bromo-7-fluoro-2,5-dimethyl-1,3-benzoxazole-4-carbonitrile (I-101) (2.2 g, 8.18 mmol), followed by heating under reflux for 3 hours under nitrogen atmosphere. After cooling, the reaction liquid was filtered, the solvent was evaporated away from the filtrate under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and eluted with n-hexane/ethyl acetate (5:1, v/v→4:1, v/v) to obtain a main product. This was washed with isopropyl ether and then collected by filtration to obtain the entitled compound (985 mg, 45%) as a colorless solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[N:17]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClC(Cl)C>[NH2:15][C:16]1[C:21]([NH:22][CH:35]2[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]2)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(N)c(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)n1
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (3.39 g, 16.0 mmol) was added to a solution of 2,3-diamino-6-methoxypyridine (2.23 g, 16.0 mmol) and N-(t-butoxycarbonyl)-4-piperidone (7.66 g, 38.4 mmol) in dichloroethane (50 mL) at room temperature. The reaction was quenched with water (50 mL) and stirred overnight, then extracted with chloroform and washed with 5% aqueous sodium hydroxide, water and saturated sodium chloride solution. After drying over sodium sulfate, the solution was filtered and evaporated to give the crude product. This was purified by chromatography, where the more polar product was isolated (silica gel, 50% ethyl acetate hexane, Rf=0.36), to give the title compound. MS 323 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=8 Hz, 1H), 6.05 (d, J=8 Hz, 1H), 4.45 (br s), 4.03 (br s), 3.83 (s, 3H), 3.15 (m, 1H), 2.86 (m, 2H), 1.91 (d, J=12 Hz, 2H), 1.5 (br s, 11H), 1.26 (br s, 2H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[SH:51][C@@H:52]1[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[C@H:54]([C:70]([N:72]2[CH2:76][CH2:75][C@H:74]([N:77]3[CH:81]=[N:80][CH:79]=[N:78]3)[CH2:73]2)=[O:71])[CH2:53]1>C(#N)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([S:51][C@@H:52]3[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=4)=[O:58])[C@H:54]([C:70]([N:72]4[CH2:76][CH2:75][C@H:74]([N:77]5[CH:81]=[N:80][CH:79]=[N:78]5)[CH2:73]4)=[O:71])[CH2:53]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](n2cncn2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](n5cncn5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 70.1 %

Procedure:
486 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate were dissolved in 5 ml of dry acetonitrile, and 379 mg of diphenylphosphoryl chloride and 182 mg of diisopropylethylamine were added dropwise, with ice-cooling, to the resulting solution. The mixture was then stirred at the same temperature for 1 hour. At the end of this time, a solution of 173 mg of diisoproylethylamine and 690 mg of (2S,4S)-4-mercapto-2-[(3S)-3-(1-1,2,4-triazolyl)-1-pyrrolidinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 119) in 4 ml of dry acetonitrile was added dropwise with ice-cooling, to the resulting mixture, and the mixture was stirred at the same temperature for 6 hours. The solvent was then removed by distillation under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The resulting solution was then washed with water, with an aqueous solution of sodium hydrogencarbonate, again with water and finally with a saturated aqueous solution of sodium chloride. The aqueous layer was extracted with methylene chloride, and the aqueous layer was combined with the washings and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography, using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent, to obtain 744 mg of the title compound, as a powder.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10].[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]1[CH2:44][C:43]2[CH:42]=[C:41]([OH:45])[CH:40]=[CH:39][C:38]=2[C@@H:37]2[C@@H:28]1[C@H:29]1[C@@:33]([CH2:35][CH2:36]2)([CH3:34])[C@@H:32]([OH:46])[CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:45][C:41]1[CH:40]=[CH:39][C:38]2[C@@H:37]3[C@H:28]([C@H:29]4[C@@:33]([CH2:35][CH2:36]3)([CH3:34])[C@@H:32]([OH:46])[CH2:31][CH2:30]4)[C@H:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:16])[C:9](=[O:10])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:44][C:43]=2[CH:42]=1
Reactant: CNCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)COC(=O)N(C)CCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 2.5 h

Procedure:
N-Methylmorpholine (0.028 ml.) and isobutyl chloroformate (0.038 ml.) were successively added to a stirred solution of 7α-(9-methylaminononyl)oestra-1,3,5(10)-trien-3,17β-diol (Example 28; 0.08 g.) in tetrahydrofuran (3 ml.) and the mixture was stirred at laboratory temperature for 150 minutes. Saturated aqueous sodium bicarbonate solution (2 ml.) was added and the mixture was extracted three times with methylene chloride (10 ml. each time). The combined extracts were washed with water (5 ml.), dried and evaporated to dryness and there was thus obtained as residual oil isobutyl N-[9-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)nonyl]-N-methylcarbamoate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:16][CH2:15][N:14]([C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[CH3:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH2:21]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[CH3:17])[C:6]3[CH:11]4[CH2:16][CH2:15][N:14]([C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4
Reactant: C=Cc1ccccc1C
Reactant: Cc1ccc2[nH]c3c(c2c1)N1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2C)C2CCN1CC2

Procedure:
The coupling of 8-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (80 mg, 0.38 mmol; Example 211) and 2-methylstyrene (85 mg, 0.72 mmol; Aldrich) was performed according to the procedure described in Example 106A to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 0.87-1.03 (m, 2H), 1.60-1.76 (m, 2H), 1.97 (s, 3H), 2.38-2.46 (m, 2H), 2.41 (s, 3H), 3.01 (quintet, J=2.9 Hz, 1H), 3.06-3.16 (m, 4H), 4.14-4.55 (m, 2H), 6.77 (d, J=7.3 Hz, 1H), 6.91-6.97 (m, 2H), 6.99-7.03 (m, 2H), 7.32 (d, J=8.2 Hz, 1H), 7.35 (s, 1H); MS (APCI) m/z 331 (M+H)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)([CH3:12])[C:10]#[N:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:8][C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)([CH3:12])[C:10]#[N:11]
Reactant: CC(C)(C#N)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C#N)c1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Yield: 71.4 %

Procedure:
A mixture of thiophenol (9.09 g 0.0826 m), 2-methyl-2-(3-nitro-4-bromophenyl)propionitrile (18.68 g, 0.0694 m), sodium carbonate (16.0 g, 0.151 m) and absolute ethanol (300 ml) was stirred and heated at reflux for 5 hours. The cooled mixture was then poured onto ice-water and the resultant yellow solid filtered off. The crude solid was slurried with water/SVM (1.1, 300 ml) and the solid filtered and mixed with water/SVM (1:1, 150 ml. The solid was crystallised from methanol to give yellow needles (14.78 g, 65%) mpt. 146°-147° C. Calcd., for C16H14N2SO2 : C, 64.4 H, 4.7 N, 9.4; S, 10.7 Found: C, 64.5; H, 4.6; N, 9.3; S, 10.8
Reaction SMILES: 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.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[CH:59]=[C:58]([CH3:60])[CH:57]=[CH:56][C:55]=1[O:61][CH3:62].[NH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>C1(C)C=CC=CC=1>[CH3:62][O:61][C:55]1[CH:56]=[CH:57][C:58]([CH3:60])=[CH:59][C:54]=1[N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1
Reactant: C1CNCCN1
Reactant: COc1ccc(C)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C)cc1N1CCNCC1
Yield: 67.1 %

Procedure:
15 mg (0.016 mmol, 0.027 eq) Tris(dibenzylidene-acetone)dipalladium (0) (Pd2dba3), 27 mg (0.043 mmol, 0.072 eq) racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl [(±)-BINAP] and 450 mg (1.38 mmol, 2.3 eq) cesium carbonate were combined in a microwave vial. 1.5 mL anhydrous toluene was added, followed by 121 mg (0.60 mmol, 1.0 eq) 2-bromo-4-methylanisole and 207 mg (2.40 mmol, 4.0 eq) piperazine. The vial was flushed with nitrogen prior to being microwaved at 140° C. for 30 minutes. The reaction mixture was diluted with 3.0 mL DMSO:methanol (1:1), filtered and purified by reverse-phase HPLC (2-99% CH3CN in 0.085% TFA (aq), 50 mL/min, 3×1.5 mL injected). Yield=83 mg (43%) of 1-(2-Methoxy-5-methyl-phenyl)-piperazine as a pale yellow oil (isolated as the mono-TFA salt);
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[N:33]([CH2:36][CH3:37])=[C:34]=[O:35]>O1CCCC1>[CH2:36]([NH:33][C:34]([NH:24][CH2:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:18]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:25])[N:7]=4)[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)=[O:35])[CH3:37]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)NCc1ccc2c(c1)OCCc1sc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine 532 (0.050 g, 0.00014 mol) in tetrahydrofuran (1.0 mL) was added triethylamine (0.0588 mL, 0.000422 mol) then isocyanatoethane (0.110 mL, 0.00141 mol). The reaction was stirred at room temperature overnight, quenched with a small amount of methanol and concentrated in vacuo. The crude was precipitated from MeOH/H2O to give 525. MS(ESI+) 427.1
Reaction SMILES: [Br:1]Br.[C:3]1([CH3:12])[C:4]([C:9]([OH:11])=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1>[Fe]>[Br:1][C:7]1[CH:8]=[C:3]([CH3:12])[C:4]([C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: Cc1ccccc1C(=O)O
Agent: [Fe]
Product: Cc1cc(Br)ccc1C(=O)O
Reaction time: 2 h

Procedure:
Chill a mixture of 140 gm. (0.875 mole) of bromine and 2.45 gm. of iron powder in an ice-bath and add portionwise during 15 minutes 93.31 gm. (0.7 mole) of o-toluic acid. Remove the reaction flask from the ice-bath and stir for 2 hours. Allow the resulting mushy solid to stand at room temperature overnight. Flush the reaction mixture with nitrogen. Finely grind the resulting solid cake, wash with water, aqueous sodium thiosulfate solution, water and dry to obtain the title compound together with the 3-bromo isomer (yield 144.7 gm., m.p. 112°-148° C.). The product is employed in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]([CH3:11])([C:8]([OH:10])=O)[CH2:4][O:3]1.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.[NH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:48]=1[C:59]([NH2:61])=[O:60]>C(Cl)Cl>[C:59]([C:48]1[C:47]([NH:46][C:8]([C:5]2([CH3:11])[CH2:4][O:3][C:2]([CH3:1])([CH3:12])[O:7][CH2:6]2)=[O:10])=[CH:52][CH:51]=[CH:50][C:49]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(=[O:60])[NH2:61]
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OCC(C)(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a solution of the commercially available 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid (0.6 g, 4 mmol) in DCM (30 mL) was added HATU (1.8 g, 4.7 mmol) and DIPEA (1.6 mL, 23.5 mmol). The reaction mixture was stirred at room temperature for 1 h. After this time, 3-aminobiphenyl-2-carboxamide (0.6 g, 2.35 mmol) was added and the resulting solution was stirred for 16 h. At the conclusion of this period, the reaction mixture was washed with water, dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (25% ethyl acetate in hexanes) to yield N-(2-carbamoylbiphenyl-3-yl)-2,2,5-trimethyl-1,3-dioxane-5-carboxamide (0.25 g, 24% yield) as a white solid. LCMS Method Y: retention time 1.69 min; [M+1]=367.2.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14])=[O:5].[F:22][CH2:23][C:24](Cl)=[O:25]>N1C=CC=CC=1>[F:22][CH2:23][C:24]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:25]
Reactant: Cc1cc(F)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)CF
Solvent: c1ccncc1
Product: Cc1cc(F)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 84.9 %

Procedure:
3.9 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-4-fluoroaniline, 1.6 g of pyridine and 1.96 g of fluoroacetyl chloride are treated in the same manner as described in Example 1-(1), whereby 4.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-fluoroaniline are obtained as colorless needles.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][CH:6]=1.S(Br)([Br:15])=O>O1CCOCC1.CCOCC>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][Br:15])=[CH:7][CH:6]=1
Reactant: OCc1ccc(OCCCl)cc1
Reactant: O=S(Br)Br
Solvent: CCOCC
Solvent: C1COCCO1
Product: ClCCOc1ccc(CBr)cc1
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To 4-(2-Chloroethoxy)benzylalcohol CAS No. [111728-87-1](6.4 g, 34.31 mmol) in dioxane (100 mL) at 0° C. was added slowly thionylbromide (7.13 g, 34.31 mmol). The reaction was run at 0° C. after 5 min. The reaction mixture was diluted with ether (200 mL) and washed with H2O (1×30 mL) then NaHCO3 (2×25 mL), and brine (30 mL). The organic extract was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (15% EtOAc/Hex) to yield 5.0 g (58%) of the desired product. Mp=64-66° C.; 1H NMR (DMSO) 7.37 (d, 2H, J=8.8 Hz), 6.93 (d, 2H, J=8.8 Hz), 4.68 (s, 2H), 4.24 (t, 2H, J=5.05 Hz), 3.93 (t, 2H, J=5.27 Hz); MS eI m/z 248 (M+).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCCCCCBr
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-Triphenylimidazol-2-one was treated with 7-bromo-heptanonitrile and potassium carbonate in butanone to give after chromatographic work-up 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptanonitrile, m.p. 100°-101° C., Found: C, 79.7; H, 6.6; N, 9.8%; C28H27N3O requires: C, 79.9; H, 6.4; N, 10.0%; and
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.[CH3:26][Mg]Br.[Cl-].[NH4+]>C1COCC1>[C:11]([C:10]1[S:9][C:8]([NH:17][C:18]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:19])=[N:7][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:16])[CH3:26]
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.9 %

Procedure:
Compound 98 (1.01 g, 2.82 mmol) was suspended in THF (20 mL), and a 0.93 mol/L solution of methylmagnesium bromide (12.0 mL, 11.2 mmol) in THF was added thereto under ice-cooling, followed by stirring at room temperature for 2.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the precipitated solid was collected by filtration to afford the entitled Compound 377 (609 mg, 69%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]([NH:15]C(=O)OC(C)(C)C)[CH2:10][C:11]([F:14])([F:13])[CH3:12])=[O:8])[CH2:5][CH2:4]1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:3]1([NH:6][C:7](=[O:8])[C@@H:9]([NH2:15])[CH2:10][C:11]([F:14])([F:13])[CH3:12])[CH2:4][CH2:5]1)#[N:2]
Reactant: CC(F)(F)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(C#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(F)(F)C[C@H](N)C(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To detach the Boc protecting group, the compound from example 17 (580 mg, 1.83 mmol) was admixed with 10 ml of 1:1 TFA/DCM and stirred at RT for 30 min. Subsequently, the mixture was concentrated by evaporation under reduced pressure and subjected to azeotropic distillation with dichloromethane and toluene, and solvent residues were removed under high vacuum. The product was present as the trifluoroaceate.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([CH3:8])[CH2:21][O:22]2)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)c(Cl)c2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(3,4-dichlorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]1([CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:28]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C(c4ccccc4)c4ccccc4)cc23)CC1
Yield: 66.1 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.0 mg (0.10 mMol) diphenylacetic acid, 14.0 mg (66%) of the title compound were recovered.