Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][CH:42]([C@@H:66]1[CH2:70][C@H:69]([SH:71])[CH2:68][N:67]1[C:72]([O:74][CH2:75][C:76]1[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=1)=[O:73])[CH2:43][C:44]([N:46]1[CH2:50][CH2:49][C@H:48]([CH2:51][NH:52][C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])[CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:71][C@@H:69]3[CH2:68][N:67]([C:72]([O:74][CH2:75][C:76]4[CH:77]=[CH:78][C:79]([N+:82]([O-:84])=[O:83])=[CH:80][CH:81]=4)=[O:73])[C@H:66]([CH:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:50][CH2:49][C@H:48]([CH2:51][NH:52][C:53]([O:55][CH2:56][C:57]5[CH:58]=[CH:59][C:60]([N+:63]([O-:65])=[O:64])=[CH:61][CH:62]=5)=[O:54])[CH2:47]4)=[O:45])[CH2:70]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(NC[C@H]1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
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)CC(=O)N4CC[C@H](CNC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 75.9 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (199.5 mg) and (2S,4S)-2-[1-hydroxy-2-[(3R)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (202.3 mg), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[1-hydroxy-2-[(3R)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (237.1 mg) was obtained.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([NH:18][CH:19]=[N:20]2)=[C:16]([Cl:23])[N:15]=1.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:29]=CC=C[CH:25]=1.C(O)(C)C>C1COCC1>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:24]([CH3:29])[CH3:25])=[C:16]([Cl:23])[N:15]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Add DEAD (4.7 g, 27.09 mmol) slowly to a solution of 2,6-dichloropurine (1, 5 g, 26.5 mmol), triphenylphosphine (11.75 g, 44.5 mmol) and isopropyl alcohol (2b, 10 ml) in THF (100 ml), and stir at room temperature for 24 hours. Concentrate the reaction mixture, dissolve the residue in DCM (20 ml) and filter to remove the unwanted solids. Load the filtrate onto a 90 gram silica gel column (Biotage), and elute with DCM/acetone (95:5). Concentrate the desired fractions to give 3.0 grams of 2,6-dichloro-9-isopropyl-9H-purine (3b).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:10].[NH4+].N[C@H:13]([C:18]([O-])=[O:19])[CH2:14][C:15]([O-])=[O:16].[Na+:21].[Na+]>>[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Na+:21].[Na+:21].[C:18]1(=[O:19])[NH:10][C:15](=[O:16])[CH2:14][CH2:13]1
Reactant: [NH4+]
Agent: N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Product: O=C1CCC(=O)N1

Procedure:
The reactions and procedures of this Example were repeated, except that the monomer ratios of ammonium aspartate and sodium aspartate were adjusted (in part A) to produce a 1:2 copolymer of sodium aspartate and succinimide. A solution of this copolymer was titrated to pH 4.0 and ring-closed as above. The resulting terpolymer of sodium aspartate, asparagine, and succinimide had a residue ratio of 0.53:10.97 (asp:asn:suc). This terpolymer also was water-soluble.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][CH:14]([CH3:17])[C:15]#[CH:16]>CCN(CC)CC.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][CH:14]([CH3:17])[CH3:13])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C#CC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-iodo-4-methoxy-2-nitrobenzene (Aldrich, 10 g, 35.8 mmol) in Et3N (60 ml) and DMF (6 ml) was added CuI (34 mg, 0.18 mmol), Pd(PPh3)2Cl2 (126 mg, 0.18 mmol), and 3-methyl-1-butyne (5.0 ml, 73.5 mmol). The mixture was stirred at room temperature for 16 h and was concentrated. The resulting mixture was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→15% EtOAc-hexanes) to yield the title compound as a brown oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:49][O:50][CH2:51][CH2:52][NH2:53]>C(Cl)Cl>[CH3:49][O:50][CH2:51][CH2:52][NH:53][C:13](=[O:15])[C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1)([CH3:17])[CH3:16]
Reactant: COCCN
Reactant: CC(C)(C(=O)O)c1ccc(-c2ccco2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNC(=O)C(C)(C)c1ccc(-c2ccco2)cc1
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic Acid (reference example 28) (344 mg, 1.5 mmol) in CH2Cl2 (4 mL) is added TBTU (528 mg, 1.65 mmol) followed by diisopropylethylamine (280 mL, 1.6 mmol). The resulting mixture is stirred for 2 h then a further portion of DIEA added (280 mL) along with 2-methoxy-ethylamine (225 mL, 2.6 mmol). The resulting solution is stirred for 90 minutes then concentrated. The residue is purified by flash chromatography (eluting with 10% CH2Cl2/50% ethyl acetate in hexanes) to give 380 mg of product as a white solid. 1H NMR (CD3OD) d 1.58 (s, 6H), 3.24 (s, 3H), 3.36 (m, 4H), 5.58 (bs, 1H), 6.47 (dd, J=3, 2 Hz, 1H), 6.65 (d, J=3 Hz, 1H), 7.41 (m, 2H), 7.49 (d, J=2 Hz, 1H), 7.65 (m, 2H). MS (EI) m/z 287 (M+).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH:13]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]1.Br[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:21]>C1COCC1>[Cl:28][C:24]1[CH:23]=[C:22]([CH:20]([C:13]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]2)[CH3:21])[CH:27]=[CH:26][CH:25]=1
Reactant: N#CC1CCC1
Reactant: CC(Br)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(c1cccc(Cl)c1)C1(C#N)CCC1
Reaction time: 0.08 h

Procedure:
n-BuLi (4.7 mL, 11.8 mmol, 2.5 M in hexane) was added to a solution of diisopropylamine (1.13 g, 11.2 mmol) in THF (20 mL) at −78° C. After stirring for 5 min, neat cyclobutanecarbonitrile (0.8 g, 9.87 mmol) was added and the mixture was stirred at −78° C. for 1 hour. Then a solution of Example 44A (2.6 g, 11.8 mmol) in THF (10 mL) was added and the mixture was stirred at −78° C. for 1 h. The mixture was quenched with water and extracted with EtOAc (40 mL). The solvent was evaporated and the residue was used directly in the next step without further purification. LC-MS: m/z 220 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:18])([F:17])[CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.CCN(C(C)C)C(C)C>CC#N>[Cl:8][C:6]1[CH:5]=[C:4]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[C:11]([F:18])([F:17])[F:10])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: FC(F)(F)C1CCCN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCCC2C(F)(F)F)n1
Yield: 36.6 %

Procedure:
2-Amino-4,6-dichloropyrimidine (143 mg, 0.870 mmol) was added to a stirring mixture of 2-trifluoromethylpyrrolidine (121 mg, 0.870 mmol) and Hunig's base (0.23 mL, 1.31 mmol) in CH3CN (2.5 mL) in a microwave vessel. The reaction was capped and heated in a microwave reactor for 1 hour. Silica gel chromatography (Analogix RS-12 g cartridge) eluting with 5-10% EtOAc—CHCl3 gave the title compound (85 mg) as a white solid. 1H NMR (400 MHz, CDCl3, * denotes minor rotamer): δ 1.96-2.15 (m, 2H), 2.15-2.32 (m, 2H), 3.37-3.52 (m, 1H), 3.54-3.65 (m, 1H), 4.82, 5.60* (bs, 1H), 5.00 (bs, 2H), 5.94, 6.72* (s, 1H).
Reaction SMILES: [C:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@:12]4([CH3:21])[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)#[CH:2].O1CCO[CH2:25][CH2:24]1.C(OC(O)O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.N1C=CC=CC=1>[C:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@:12]4([CH3:21])[C:17](=[CH:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH:16]=[C:15]([O:20][CH2:24][CH3:25])[CH2:14][CH2:13]4)#[CH:2]
Reactant: C1COCCO1
Reactant: C#C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CCC2=O
Agent: CCOC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccncc1
Product: C#C[C@]12CC[C@H]3[C@@H](CC=C4C=C(OCC)CC[C@@]43C)[C@@H]1CCC2=O
Temperature: 25 °C

Procedure:
A mixture of 1.2 g of 13-ethinyl-10-methyl-gon-4-ene-3,17-dione, 20 ml of dioxane, 2 ml of orthoformic acid ethyl ester and 60 mg of p-toluenesulphonic acid is stirred at room temperature for 3 3/4 hours with exclusion of light. The reaction mixture is poured into 150 ml of water containing 5 drops of pyridine and extracted twice with ethyl acetate and the organic layer is washed with water and saturated sodium chloride solution until neutral, dried and evaporated in a water pump vacuum. The crystalline crude 13-ethinyl-3-ethoxy-10-methyl-gona-3,5-dien-17-one, which is obtained, is then dissolved in 20 ml of dioxane and the solution is added dropwise, in the course of 30 minutes, to a solution, which is saturated with acetylene, of 6 g of a lithium acetylide/ethylenediamine complex in 60 ml of dioxane, whilst passing acetylene through the mixture at the same time. The reaction mixtue is then stirred for a further 15 minutes at room temperature and treated, whilst cooling, with saturated ammonium chloride solution and with ethyl acetate and the organic phase is washed successively with 1 N hydrochloric acid and saturated sodium chloride solution, dried and evaporated in a water pump vacuum.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:29]2[C:34](=O)[CH2:33][CH2:32][CH2:31][C:30]=2[O:36]CC)[NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[O:17])=[C:10]([O:39][CH3:40])[CH:9]=1.O>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:29]3[C:30](=[O:36])[CH2:31][CH2:32][CH2:33][C:34]=3[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)[C:16](=[O:17])[NH:15]2)=[C:10]([O:39][CH3:40])[CH:9]=1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(Br)cc2OC)C(=O)CCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reaction time: 0.33 h

Procedure:
Sodium tert-butoxide (175 mg, 1.82 mmol) is added to a solution of 1-((4-bromo-2-methoxyphenyl)(2-ethoxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)-urea (intermediate 49, 760 mg, 1.40 mmol) in acetonitrile (4 mL), and the mixture is shaked in an ultrasound bath for 20 min Water is added, and the mixture is extracted with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 41 mg; ESI mass spectrum [(79Br)-M+H]+=495, [(81Br)-M+H]+=497; Retention time HPLC: 0.96 min (Z011_S03).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCO[C:17](OCC)(OCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Cl:1][C:2]1[C:11]2[N:10]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: NNc1nc2ccccc2nc1Cl
Solvent: CCO
Product: Clc1nc2ccccc2n2c(-c3ccccc3)nnc12
Temperature: 25 °C

Procedure:
2-Chloro-3-hydrazinoquinoxaline (2.2 g., 0.011 mole) was mixed with 6 ml. of triethyl orthobenzoate and heated at 100° C. for 30 minutes. After cooling the orange mixture to room temperature, ethanol was added. Filtration of the resultant precipitate afforded 2.1 g. of crude product which was further purified by means of trituration with warm methanol, followed by filtration and air drying to ultimately yield 1.58 g. (51%) of pure 4-chloro-1-phenyl-[1,2,4]triazolo[4,3-a]quinoxaline as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].ClCCCl.[CH3:14][O:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(OCC)C>[CH3:28][O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:16]([O:15][CH3:14])[C:17]=1[C:18]([NH:20][C:21]([NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[O:22])=[O:19]
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Reactant: Nc1c(Cl)cccc1Cl
Solvent: CCOCC
Solvent: ClCCCl
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1c(Cl)cccc1Cl

Procedure:
A 16.2 g. portion of 2,6-dichloroaniline (Aldrich Chemical Co., Milwaukee, Wis.) was dissolved in 200 ml. 1,2-dichloroethane in a flask under a nitrogen atmosphere at about 25° C. To this was added 25 g. of 2,6-dimethoxybenzoylisocyanate in 25 ml. 1,2-dichloroethane and the solution was warmed to 40° C. for two hours after the addition was complete. Thin layer chromatography on silica gel developed in diethyl ether indicated that no 2,6-dichloroaniline remained. The solvent was removed in vacuo and the residue slurried in methanol. The solids were collected and washed with methanol. Yield 26.5 g. (72%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:18]2[O:20][CH2:19]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
25 g of p-benzyloxyphenol, 165 ml of epichlorohydrin, and 34.5 g of potassium carbonate were refluxed while stirring for 4 hours. The mixture was cooled down to room temperature and filtered, whereupon it was evaporated to dryness. The product was recrystallized from the smallest possible amount of diisopropyl ether. M.p. 68° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[N+:12]([O-])([OH:14])=[O:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1sc(C)cc1C
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1sc(C)c([N+](=O)[O-])c1C
Temperature: 0 °C

Procedure:
To a well stirred, chilled (0°) solution of 51.4 g (0.3 mol) of methyl 3,5-dimethylthiophene-2-carboxylate in 200 ml of glacial acetic acid are added dropwise over a period of 40 minutes, a mixture of 30 ml of fuming nitric acid (specific gravity=1.5) and 120 ml of acetic anhydride. After the addition is completed the resulting brown solution is stirred a further two hours at 5° and then poured into 3000 ml of ice water.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>O1CCOCC1.ClCCl>[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([O:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:1][CH2:2][CH2:3]2)[N:14]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OC1CCOc2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1cncc(OC2CCOc3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
K-t-BuO (1.28 g, 11.42 mmol) was added to a stirred solution of 4-chromanol (1.81 g, 12.0 mmol) in dioxane (30 mL) at 0° C. (ice-bath). After being stirred for 5 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (1.49 g, 10.0 mmol) was added. The reaction mixture was stirred at room temperature for 15 min and diluted with dichloromethane. Filtration and concentration in vacuo furnished an orange thick oil which was purified by chromatography on silica gel (15×4 cm) using n-hexane/ethyl acetate (8:2) as eluent. This furnished 1.87 g (71%) of the title compound as a colorless oil. HRMS m/z calcd for C13H11ClN2O2 (M)+ 262.0509, found 262.0520. Anal. (C13H11ClN2O2) C, H, N.
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>>[F:12][C:2]([F:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1)=[O:5]
Reactant: O=C(O)C(F)(F)c1ccccc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(F)(F)c2ccccc2)CC1

Procedure:
Example 124 was prepared from 2,2-difluoro-2-phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 2H), 7.68–7.63 (m, 3H), 7.49–7.39 (m, 3H), 7.23 (d, 1H, J=1.8 Hz), 7.07 (d, 1H, J=8.3Hz), 3.45 (q, 2H, J=4.9 Hz), 3.11 (d, 2H, J=10.2 Hz), 2.76–2.66 (m, 1H), 2.56 (t, 2H, J=5.0 Hz), 2.44 (septet, 1H, J=6.9 Hz), 2.28 (s, 3H), 2.13–2.05 (m, 2H), 1.82–1.71 (m, 6H), 1.15 (d, 6H, J=6.9 Hz); ESMS m/e: 472.4 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4ccc(F)cc4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (25 mg, 0.074 mmol) (from Example 5 supra) and Et3N (21 μL , 0.148 mmol) in 3 mL of chloroform was treated with 4-fluorobenzoyl chloride (10.5 μL , 0.088 mmol) (Aldrich). The resulting reaction mixture was stirred at room temperature for 8 h and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate-hexanes elution) to provide pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-4-fluorobenzamide (yield: 26 mg, 83%) as a yellow solid (mp 130-131° C.).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:28]=1[O:40][CH3:41]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:37]1([CH2:36][O:35][C:29]2[C:28]([O:40][CH3:41])=[C:27]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[C:14](=[O:18])[O:13][CH2:12]4)[CH:32]=[CH:31][C:30]=2[O:33][CH3:34])[CH2:38][CH2:39]1
Reactant: COc1ccc(Br)c(OC)c1OCC1CC1
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCC1CC1
Temperature: 85 °C
Yield: 42.4 %

Procedure:
A solution of 5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (325 mg, 1.25 mmol) in dioxane (25 mL) was purged with argon for 1 h, to this was added cesium carbonate (1 g, 3.12 mmol), Pd(PPh3)4 (36 mg, 0.031 mmol) and 1-bromo-3-(cyclopropylmethoxy)-2,4-dimethoxybenzene (300 mg, 1.04 mmol) and the resultant reaction mixture was heated to 80-90° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded a solid (150 mg, 42.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([Cl:24])[CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[Cl:24][C:4]1[CH:3]=[C:2]([N:27]2[CH2:28][CH2:29][O:25][C:26]2=[O:30])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[CH3:23])[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3Cl)CC2)c(C)c1
Yield: 52.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-chlorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (814 mg) described in Preparation Example 11 and oxazolidin-2-one (174 mg), the title compound (437 mg) was obtained.
Reaction SMILES: Cl[CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)C=CCl
Reactant: CNC
Product: CCCCCC(=O)C=CN(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of dimethylamine (560 ml, 40% aqueous) is cooled to 5° C. 1-Chloro-1-octen-3-one (192 g) is added and the mixture stirred at room temperature for 20 min. The solution is then saturated with potassium carbonate and extracted with ether. The organic layer is washed 3 × with sat. sodium chloride solution, dried over sodium sulfate, concentrated and distilled to give the title compound, b.p. 94°-96° C/0.2mm.