Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][CH:11]=1.C1(C(F)(F)F)C=CC=CC=1>C(Cl)Cl>[N+:1]([C:7]1[C:6]([CH3:5])=[CH:11][CH:10]=[CH:9][C:8]=1[C:12]([F:13])([F:15])[F:14])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C(F)(F)F)c1
Solvent: FC(F)(F)c1ccccc1
Solvent: ClCCl
Product: Cc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: -18 °C
Reaction time: 0.25 h

Procedure:
The nitration vessel is charged with 250 gms (3.97 moles) of 98% HNO3 and cooled to about -18° C. Then 100 gms (0.62 moles) of 3-methyl benzotrifluoride is added dropwise with stirring and the temperature is maintained within the range of about -16° C. to about -22° C. The addition of the benzotrifluoride takes about 2 hours and 15 minutes. After it has been added, stirring is continued for about another 15 minutes. The reaction mixture is poured into ice water and methylene chloride is added to phase separate the nitration products. The organic layer is washed with sodium carbonate solution. The solvent is then stripped on a rotary evaporator. Yield is 127.5 gms of oil comprising 43% 2-nitro isomer; 31% 4-nitro isomer, 24% 6-nitro isomer and about 1% of the 5-nitro isomer as determined by glc and 19F NMR.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([NH:28][C:29]([NH2:31])=[O:30])=[C:12]([CH2:26][CH3:27])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([C:12]1[N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Br:25])[C:14]2[C:10]([C:11]=1[NH:28][C:29]([NH2:31])=[O:30])=[C:9]([O:8][CH2:7][C:6]([OH:32])=[O:5])[CH:17]=[CH:16][CH:15]=2)[CH3:27]
Reactant: CCc1c(NC(N)=O)c2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1c(NC(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1Br
Reaction time: 4 h

Procedure:
[[2-Ethyl-1-(2-bromo-phenylmethyl)-3-ureido-1H-indol-4-yl]oxy]acetic acid tert-butyl ester (0.7 g) was dissolved in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid was added. After stirring for 4 hours the reaction mixture was concentrated to dryness, the residue dissolved in ethyl acetate and extracted with 1 N sodium hydroxide. This solution was acidified and extracted with ethyl acetate, the solvent removed by flash evaporation, and the residue slurried in 1 N hydrochloric acid. The resulting greenish solid was isolated by filtration and vacuum dried. This material was flash chromatographed on silica eluting with 19:1 ethyl acetate/methanol containing 2.5% acetic acid to provide [[2-ethyl-1-(2-bromo-phenylmethyl)-3-ureido-1H-indol-4-yl]oxy]acetic acid.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O1C=CC=C1>C(Cl)Cl>[O:5]1[CH:6]=[CH:7][CH:2]=[C:3]1[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14])=[O:22]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)CCCCCCBr
Solvent: ClCCl
Solvent: c1ccoc1
Product: O=C(CCCCCCBr)c1ccco1
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A solution of 135 mmol of trifluoroacetic anhydride in 50 ml of dry methylene chloride was added to a stirred solution of 130 mmol of 7-bromoheptanoic acid in 200 ml of dry methylene chloride. After 15 minutes, a solution of 390 mmol of furan in 25 ml of dry methylene chloride was added in a steady stream to the reaction mixture, and the resultant mixture stirred at 25° C. for 2.0 hrs. The methylene chloride and trifluoroacetic acid were removed by evaporation in vacuo. The residue was dissolved in ether, washed with water and distilled in vacuo to afford the title compound, bp 114° (0.01 mm Hg), 89.7% yield.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C@H:22]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:23]([O:25]C)=[O:24])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C@H:22]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:23]([OH:25])=[O:24])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
1.6 ml (1.6 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1N are added to a solution of 450 mg (1.1 mmol) of methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-piperidin-1-ylpropanoate in 15 ml of tetrahydrofuran and 0.5 ml of water. After stirring at ambient temperature for 18 h, the tetrahydrofuran is evaporated off under vacuum and then 1.8 ml of an aqueous solution of acetic acid having a concentration of 1N and 15 ml of water are added. The product precipitates and is filtered off. 420 mg (98%) of (S)-3-(4-benzyloxybenzenesulfonylamino)-2-piperidin-1-ylpropanoic acid are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[C:12](=O)[CH2:11]CC2=O)=[O:7])=[CH:4][CH:3]=1.NCC[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:12][CH2:11][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:7])=[CH:15][CH:16]=1
Reactant: NCCN1CCOCC1
Reactant: O=C1CCC(=O)N1C(=O)c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
2.4 G. of N-(p-chlorobenzoyl)-succinimide are added to a solution of 1.3 g. of N-(2-aminoethyl)-morpholine in 100 ml. of dioxane and the mixture is stirred overnight at room temperature. The mixture is then evaporated to dryness. 50 Ml. of ice-water are added to the oily residue and the mixture which crystallizes is allowed to stand overnight in a refrigerator. The product is removed by filtration, washed with cold water, dried and recrystallized from isopropanol, and 0.65 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:19])=[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:19])=[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:32]3[CH2:31][CH2:30][CH:29]([C:26]4[C:25]5[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=5[O:28][N:27]=4)[CH2:34][CH2:33]3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2sc(C)c(C(=O)CCCCl)c2C1
Agent: Cl
Product: CC(=O)N1CCc2sc(C)c(C(=O)CCCN3CCC(c4noc5cc(F)ccc45)CC3)c2C1
Yield: 23.2 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.6 g of 5-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine and 1.4 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.6 g of 5-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:20]([NH-])([CH3:22])[CH3:21].O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:20]([CH3:22])[CH3:21])=[C:7]([OH:12])[CH:6]=1)[CH3:2]
Reactant: CC(C)[NH-]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OC(C)C)c(O)c1
Yield: 25 %

Procedure:
To a solution of 3,4-dihydroxybenzoic acid ethyl ester (2.0 g, 11 mmol) in acetone (450 l) were added potassium carbonate (2.28 g, 16.5 mmol) and isopropylamide (1.03 ml, 11 mmol), and the resultant mixture was stirred at room temperature for 2 days. The reaction mixture was poured into chilled water and extracted with ethyl acetate under acidic conditions. The organic layer was concentrated, and the residue was chromatographed On a silica gel column to give a mixture (617 mg) of 3-hydroxy-4-isopropyloxybenzoic acid ethyl ester and its position isomer, 4-hydroxy-3-isopropyloxybenzoic acid ethyl ester (6:1). There was observed NOE of protons at 1'-position of the isopropyl group and 5-position. The reaction was effected using this mixture (617 mg) in the same manner as in Reference Example 18, and the resultant product was recrystallized from hexane to give the titled compound (370 mg, yield 12%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-ethynyl]piperidine-1-carboxylate (0.157 g, 0.423 mmol) synthesized in Example B55, Step 1 in ethyl acetate/ethanol (1:1, 3 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.0500 g), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)vinyl]piperidine-1-carboxylate (0.0610 g, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O:27]1CCCC1.B.[OH-].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]([OH:27])[CH2:22]3)[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1C1C=CCC1
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Product: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1C1CCC(O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)piperidin-2-one (Example 106, Step A) (394 mg, 1.020 mmol) in THF (10 mL) was added borane tetrahydrofuran complex (1.0 m in THF) (1020 μL, 1.020 mmol). Evolution of gas was observed. The reaction was stirred at room temperature for 30 min. before adding aq. NaOH (6 M) (1.25 mL) and 30% H2O2(1.25 mL). The reaction mixture became cloudy and was stirred at room temperature for 1 h. The reaction mixture was extracted with EtOAc. The organic layers were washed with sat. aq. NaCl solution and dried over Na2SO4. The residue was purified by flash chromatography on silica gel (eluent: 40 to 100% EtOAc in hexanes) to give the title compound as a mixture of diastereomers.
Reaction SMILES: C([NH:3][CH:4]([CH3:17])[CH2:5][C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)=O.Cl.O>CCOCC>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:6]2([CH2:5][CH:4]([NH2:3])[CH3:17])[CH2:9][CH2:8][CH2:7]2)=[CH:15][CH:14]=1
Reactant: CC(CC1(c2ccc(Cl)cc2)CCC1)NC=O
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(N)CC1(c2ccc(Cl)cc2)CCC1

Procedure:
N-formyl-2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine (11.06 g) prepared as described above was heated under reflux for six hours with a mixture of concentrated hydrochloric acid (34 ml), water (34 ml) and diethyleneglycoldimethyl ether (40 ml). The mixture was cooled, washed with ether and basified with aqueous sodium hydroxide. The basified solution was extracted into ether, washed with water, dried, evaporated and distilled to give 2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine (b.p. 119°-121° C. at 0.8 mm Hg). The amine (2.65 g) was dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid added to pH 2. Ether (110 ml) was added and crystals of 2-[1-(4-chlorophenyl) cyclobutyl]-1-methylethylamine hydrochloride (m.p. 184°-185° C.) were collected. (Formula I R1, R2 =H; R3, R4 =H; R5 =4-Cl; R6 =H; R7 =Me and R8 =H.)
Reaction SMILES: [Cl-].[CH3:2][NH+:3]1[CH2:8][CH2:7][C:6]([C:9](=O)[NH2:10])=[CH:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.C(N(CC)CC)C>[OH-].[Na+].C(Cl)Cl>[CH3:2][N:3]1[CH2:8][CH2:7][C:6]([C:9]#[N:10])=[CH:5][CH2:4]1
Reactant: C[NH+]1CC=C(C(N)=O)CC1
Agent: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CC=C(C#N)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-methyl-4-carbamoyl-1,2,5,6-tetrahydropyridinium chloride (3.6 g;20.4 mmol) in sodium hydroxide (4N)(30 ml) was extracted with methylene chloride (3×50 ml). The combined extracts were dried, filtered, and evaporated to 50 ml. To the extract a solution of triphenylphosphine (15.7 g; 60 mmol), bromine (3.3 ml; 65 mmol) and triethylamine (11 ml) in methylenechlorid (150 ml) was added. The reaction was stirred at room temperature for 20 hours and evaporated in vacuo. The residue was dissolved in water (50 ml) and washed with methylene chloride (3×75 ml). To the water-phase sodium hydroxide (4N) (30 ml) was added and the mixture was extracted with methylene chloride. The combined extracts were dried, filtered, and evaporated in vacuo to give the title compound.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[O:33][N:32]=[C:31]([CH2:34][CH3:35])[N:30]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:26][CH2:25][N:24]([C:55]([C:54]6[CH:58]=[CH:59][C:51]([C:45]7[C:46]8[CH:47]=[C:48]([O:49][CH3:50])[C:39]([O:38][CH2:36][CH3:37])=[CH:40][C:41]=8[C@H:42]8[CH2:63][S:62][CH2:61][CH2:60][C@H:43]8[N:44]=7)=[CH:52][CH:53]=6)=[O:56])[CH2:23][CH2:22]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[O:33][N:32]=[C:31]([CH2:34][CH3:35])[N:30]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc7c(c6)OCO7)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6-(1,3-benzodioxol-5-yl)-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (232 mg; compound B86) and 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (191 mg; compound C10) in DMF (10 ml) is added HOBt (74 mg) and EDCI (92 mg) and the reaction mixture is stirred at RT for 48 h. One additional equivalent of EDCI (92 mg) is added in order to complete the reaction. The reaction mixture is extracted for three times with DCM/H2O/saturated sodium chloride solution (150 ml/100 ml/35 ml). The organic phase is separated and dried with Na2SO4. After filtration and evaporation of all volatiles the resulting residue is purified by flash column chromatography [amino phase silica gel, eluation gradient: DCM/ethanol, 100/0/to 95/5 (v/v)] and by preparative HPLC to give the title compound as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH2:18]([C:22]1([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21].FC(F)(F)S(O)(=O)=O>ClCCl>[CH2:18]([C:22]1([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Reactant: CCCCC1(N2CCCC2)CCC(=O)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC1(N2CCCC2)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
3-(2-pyridin-4-ylethyl)-1H-indole (667 mg, 3 mmol, synthesis cf. WO2008009415, indole unit Ind-14) together with 4-butyl-4-(pyrrolidin-1-yl)cyclohexanone (671 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-14) was dissolved in abs. dichloromethane (45 ml) and mixed with trifluoromethane sulphonic acid (0.613 ml, 6.9 mmol). The batch was stirred for 64 h at RT, and a brown oil separated out. For work up the reaction solution was mixed with 1N NaOH (30 ml) and methanol (10 ml). The mixture was stirred a further 60 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.35 g) was purified by column chromatography [silica gel 60 (90 g); ethyl acetate/methanol (1:1 (2400 ml)].
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.CS(O)(=O)=O.O>C1(C)C(C)=CC=CC=1>[N:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:4](=[O:5])[CH2:3][CH2:2][C:1]2=[O:7])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccncc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CCC(=O)N1c1ccncc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The starting material is prepared as follows: The mixture of 500 g of succinic acid anhydride, 471 g of 4-aminopyridine and 5,200 ml of xylene is heated to reflux while stirring and separating the water formed. After 30 minutes 15 ml of methane sulfonic acid are added and refluxing is continued until 5 moles of water are collected, requiring about 4 days. The mixture is cooled to room temperature, the supernatant is decanted off and the suspension combined with 1000 ml of isopropanol. It is stirred for 5 minutes, filtered, the residue washed with 250 ml of isopropanol and dried for 3 days under reduced pressure at room temperature and shortly at 50°, to yield the 1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 232°-235°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:30][CH3:31])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([CH3:26])=[C:24]([CH:27]=O)[NH:23][C:22]=1[CH3:29])=[O:20])[CH3:13]>>[CH2:30]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([CH3:26])=[C:24]([CH:27]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:23][C:22]=1[CH3:29])=[O:20])[CH3:31]
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C
Yield: 97.2 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.5 g, 2.36 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (0.51 g) to give 0.84 g of the title compound as a red-orange solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CC=CC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/C=C\C1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 75.3 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-propenyl)-3-cephem-4-carboxylic acid (Ia, R2 =CH3, R3 =H) (E/Z=1/17, 90 mg, 0.21 mmole) and potassium carbonate (44 mg, 0.32 mmole) in DMF (3 ml) was added at 0° C. pivaloyloxymethyl iodide (77 mg, 0.32 mmole). The mixture was stirred at 0° C. for 40 minutes, diluted with ethyl acetate (20 ml), washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in CHCl3 and chromatographed on a silica gel column (silica gel: 3 g) by eluting with 1% methanol in CHCl3 to yield 85 mg (75%) of the title compound. Mp. 100°-104° C. Estimated purity 90% (by HPLC).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[N:7]=[N+:8]([O-:19])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH2:16]3)=[CH:12][C:10]=2[N:11]=1>COCCOC>[O-:19][N+:8]1[C:9]2[CH:18]=[C:17]3[C:13](=[CH:12][C:10]=2[N:11]=[C:6]([NH:1][CH2:2][CH2:3][OH:4])[N:7]=1)[CH2:14][CH2:15][CH2:16]3
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: NCCO
Solvent: COCCOC
Product: [O-][n+]1nc(NCCO)nc2cc3c(cc21)CCC3
Yield: 99.1 %

Procedure:
2-Aminoethanol (1.80 mL, 30.0 mmol) was added to a stirred solution of chloride 21 (2.21 g, 10.0 mmol) in DME (100 mL) and the solution stirred at reflux temperature for 90 min. The solvent was evaporated and the residue stirred with water (150 mL) at 20° C. for 30 min. The solid was filtered, washed with water several times and dried to give alcohol 24 (2.44 g, 99%) as an orange solid: mp (DME/water) 222-224° C.; 1H NMR [(CD3)2SO] δ 7.92 (s, 1H, H-9), 7.54 (br t, J=6.0 Hz, 1H, NH), 7.36 (s, 1H, H-5), 4.68 (t, J=6.0 Hz, 1H, OH)), 3.56 (q, J=6.0 Hz, 2H, CH2O), 3.40 (q, J=6.0 Hz, 2H, CH2N), 2.89-3.00 (m, 4H, H-6, H-8), 2.00-2.08 (m, 2H, H-7); 13C NMR [(CD3)2SO] δ 158.7, 154.0 148.0, 142.3, 128.8, 120.0, 113.9, 59.3, 43.2, 32.4, 31.6, 25.2. Anal. calcd for C12H14N4O2: C, 58.5; H, 5.7; N, 22.8. Found: C, 58.8; H, 5.9; N, 22.9%.