Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38](=[O:42])([OH:41])([OH:40])[OH:39]>C(O)(C)C>[CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38]([O-:42])([O-:41])([O-:40])=[O:39]
Reactant: O=P(O)(O)O
Agent: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Solvent: CC(C)O
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Maraviroc (10 gm) was dissolved in isopropyl alcohol (100 ml) and stirred for 30 minutes at room temperature. To the solution was added phosphoric acid (2 gm) and stirred for 11 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 10.5 gm of crystalline form 3 of maraviroc phosphate.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14](P(OCC)(OCC)=O)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=O>C1COCC1>[CH2:3]([O:10][C:11]([NH:13]/[C:14](=[CH:27]\[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[NH:35][C:36]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:42])/[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOP(=O)(OCC)C(NC(=O)OCc1ccccc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.5 %

Procedure:
To a slurry of 60% of sodium hydride (224 mg, 5.6 mmol) in THF (10 mL) at 0° C. was added 1A (1.72 g, 4.8 mmol) in several portions over 10 min. The reaction mixture was then brought to RT for 20 min, then cooled again at 0° C. A suspension of tert-butyl 3-formylpyridin-4-ylcarbamate (889 mg, 4 mmol) in THF (10 mL) was added over 10 min at 0° C., then the reaction was warmed up to RT. After stirring for 20 min, the reaction was quenched with water (40 mL). The aqueous layer was extracted with EtOAc (50 mL×3). The combined EtOAc extracts were dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (20-100%) in hexane to give the title compound as an white foam (1 g, 58%). LC/MS (method A): retention time=2.65 min, (M+H)+=428.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12](Cl)=[O:13])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[BH4-].[Na+].Cl.O>O1CCCC1.C(OCC)C>[OH:13][CH2:12][C:11]1[N:2]([CH3:1])[C:3](=[O:21])[C:4]2[C:9]([C:10]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cn1c(C(=O)Cl)c(-c2ccccc2)c2ccccc2c1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cn1c(CO)c(-c2ccccc2)c2ccccc2c1=O
Reaction time: 0.5 h

Procedure:
A stirred suspension of 2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride (5.96 g; prepared according to the method of F. Duro et al., Il. Farmaco Ed. Sci., 36,400) in dry tetrahydrofuran (120 ml) was treated, portionwise, with sodium borohydride (1.68 g) and the mixture was stirred at room temperature for 4 hours. A further portion of sodium borohydride (0.4 g) was then added and the mixture was stirred for a further period of 30 minutes. The reaction mixture was then treated, dropwise, with dilute hydrochloric acid (60 ml; 2N) and then with water (80 ml). The mixture was diluted with diethyl ether (200 ml) and the organic phase was separated, washed with water (2×80 ml), dried over magnesium sulphate and evaporated. The resulting residue was crystallised from ethyl acetate, to give 3-hydroxymethyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline (3.5 g) in the form of white crystals, m.p.159°-161° C. [Elemental analysis: C,77.2; H,5.76; N,5.37%; calculated: C,77.0; H,5.70; N,5.28%].
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>ClCCl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=2)(=[O:39])=[O:38])[CH2:3]1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccc(F)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg, 0.47 mmol) and pyridine (148 mg, 1.44 mmol) in anhydrous dichloromethane (5 mL) was added a solution of 3-fluorobenzene-1-sulfonyl chloride (92 mg, 0.36 mmol) at ice-bath. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with dichloromethane. The combined organic layer was dried over anhydrous Sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-3-fluoro-benzenesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 478.90.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2ccc(Br)cn2)cc1
Reaction time: 8 h

Procedure:
5-Bromo-pyridin-2-ylamine (9, 4.0 g, 23 mmol) was dissolved in 100 mL of acetonitrile and 4-chloro-benzaldehyde (10, 3.2 g, 23 mmol) was added. Triethylsilane (11.0 mL, 69 mmol) was added followed by trifluoroacetic acid (5.0 mL, 65 mmol). The reaction was heated to reflux and stirred overnight. The solvent was removed under vacuum and the residue was poured into a solution of 1 M potassium carbonate. This was extracted with ethyl acetate and the organic portion was isolated and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting solid was washed with ether to give the desired compound. The remaining material was purified with silica gel chromatography eluting with a gradient of 0-25% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide additional compound (11, 6.36 g, 92%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH:2]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:6][N:5]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:4]1)=[O:1]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To a solution of tert-butyl (3R,5S)-3-(hydroxymethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (1.0 g) in acetonitrile (20 ml) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.98 g), and the mixture was stirred at room temperature for 3 hr. 10% Aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 30 min. After partitioning, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object product (1.0 g).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].CS[C:8](=[NH:10])[NH2:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:8]([NH2:10])=[NH:9])[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: CN1CCN(C(=N)N)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of S-methylisothiourea sulfate (2.78 g, 10.0 mmol) in distilled water (20 mL) was added 1-methylpiperazine (2.22 mL, 20 mmol). After stirring for 48 h at room temperature, the solution was concentrated to approximately 5 mL and treated with EtOH (10 mL). The resulting solid was collected by filtration, washed with EtOH, and dried to yield 4-methyl-piperazine-1-carboxamidine sulfate as a colorless solid. Further concentration of the mother liquor yielded a second crop or the material.
Reaction SMILES: C(N1CC(=C([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:24]=2)S(C)(=O)=O)C1)(C1C=CC=CC=1)C1C=CC=CC=1.BrCCCCBr.C(=O)([O-])[O-].[K+].[K+].[CH:47]([N:60]1[CH2:63][C:62](=[C:64](C2C=CC=C(O)C=2)[S:65]([CH3:68])(=[O:67])=[O:66])[CH2:61]1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC(CC)=O>[CH:47]([N:60]1[CH2:61][C:62](=[CH:64][S:65]([CH2:68][C:27]2[CH:28]=[CH:23][CH:24]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:26]=2)(=[O:67])=[O:66])[CH2:63]1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(OCCCCBr)c1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: BrCCCCBr
Product: O=S(=O)(C=C1CN(C(c2ccccc2)c2ccccc2)C1)Cc1cccc(OCCCCBr)c1

Procedure:
1-Benzhydryl-3-{[3-(4-bromobutoxy)phenyl]-methanesulfonylmethylene}azetidine may be prepared in the following manner: 0.586 cm3 of 1,4-dibromobutane and 255 mg of potassium carbonate are successively added at a temperature close to 20° C., under an inert atmosphere of argon, to a solution of 500 mg of 1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine in 10 cm3 of methylethyl ketone. The reaction mixture is heated at the reflux temperature of the solvent, under an inert atomosphere of argon, for 7 hours and then left at a temperature close to 20° C. for about 4 days. The reaction mixtue is filtered on sintered glass covered with celite. The solid residue is rinsed with ethyl acetate and then the filtrate is concentrated to dryness under reduced pressure (10 kPa) at a temperature close to 40° C. The brown oil obtained is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.200 mm) contained in a column 3 cm in diameter, eluting with a methanol-dichloromethane mixture (0.5-99.5 by volume). The fractions (10 cm3) containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40° C. for 2 hours, 408.4 mg of 1-benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidine are thus obtained in the form of a brown foam.
Reaction SMILES: [OH-:1].[K+].OO.[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>O>[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:1])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)n1ncc(C#N)c1N
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Product: CC(C)(C)n1ncc(C(N)=O)c1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
To a mixture of water (500 ml) and 85% KOH (37.91 g) at 0° C. was added 30% H2O2 (49.4 ml, 483 mmol), followed by 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile (15.83 g, 96.5 mmol). The reaction mixture was stirred for four hours at 0° C. and then at room temperature for 1 hour. A yellow precipitate had formed which was collected by filtration and air dried to afford 13.2 g (75%) of 1-tert-butyl-5-amino-1H-pyrazole-4-carboxamide, m.p. 193-195° C.
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:8]=[C:7](Cl)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1)[NH2:24].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]1([C:5]2[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:8]=[C:7]([NH:24][C:23]3[CH:25]=[CH:26][C:27]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:21]([O:20][CH3:19])[CH:22]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)COCc1cc(N2CCC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(N3CCC3)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C

Procedure:
A mixture of 4-(azetidin-1-yl)-2-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (31 mg, 0.11 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (22.37 mg, 0.11 mmol), cesium carbonate (71.7 mg, 0.22 mmol), palladium(II) acetate (3.71 mg, 0.02 mmol) and 2-(dicyclohexylphosphino)biphenyl (5.79 mg, 0.02 mmol) in dioxane (2 mL) was heated under argon at 120° C. for 90 minutes in microwave reactor. The mixture was filtered through a short silica plug which was washed with 10% methanol in ethyl acetate and the mixture was concentrated in vacuum. The residue was purified by preparative HPLC give the title compound as a dry film (41 mg, 83%).
Reaction SMILES: [CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:38])[CH2:32]OS(C)(=O)=O)[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:39])[CH2:7]1)=[O:5])=[CH2:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-:57].[F-].[K+]>C1COCC1>[CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:38])[CH2:32][F:57])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:39])[CH2:7]1)=[O:5])=[CH2:2]
Reactant: [F-]
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)COS(C)(=O)=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Solvent: C1CCOC1
Product: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CF)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A mixture of 165 (774 mg, 1.359 mmol), TBAF 1M in THF (2038 μl, 2.038 mmol) and potassium fluoride (79 mg, 1.359 mmol) in dry THF (25 ml) is stirred under nitrogen at r.t. for 2 hours, then at reflux for 1 hour 30 minutes. The mixture is partitioned between AcOEt and water, then the aqueous phase is extracted with AcOEt; the combined organic layers are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give an orange oil which is purified by silica gel chromatography (eluent: DCM/MeOH 98/2) to give the title compound (185 mg, 27.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:22])[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[OH:10].[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30])([O-:25])=[O:24].C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:21][C:6]1[CH:5]=[N+:4]([O-:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:10][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
To a stirred solution of (1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (0.500 g, 1.45 mmol) and 3-nitrobenzoic acid (0.242 g, 1.45 mmol) in dichloromethane (15.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.560 g, 2.91 mmol) and N,N-dimethylpyridin-4-amine (0.089 g, 0.73 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (25.0 mL) and extracted with dichloromethane (×2). The combined organic extracts were dried on magnesium sulphate, filtered and the solvent removed in vacuo to afford a yellow oil. The crude material was purified by silica gel chromatography eluting sequentially with iso-hexane, ethyl acetate and 10% methanol in ethyl acetate to afford the title compound as a yellow solid (0.642 g, 90% yield).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12](O)=[O:13])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[CH:25]1([S:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])[CH2:27][CH2:26]1.C1(S(Cl)(=O)=O)CC1.N1(C(OC(C)(C)C)=O)CCNCC1>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([N:34]3[CH2:35][CH2:36][N:31]([S:28]([CH:25]4[CH2:27][CH2:26]4)(=[O:30])=[O:29])[CH2:32][CH2:33]3)=[O:13])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1
Reactant: O=S(=O)(C1CC1)N1CCNCC1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=S(=O)(Cl)C1CC1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)C5CC5)CC4)[nH]c3cc2Br)CC1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 1, from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate a) and cyclopropylsulfonyl-piperazine (prepared in analogy to International Patent Application Publ. No. WO 2003/064413 by using cyclopropylsulfonyl chloride and tert-butyl 1-piperazinecarboxylate) to afford the title compound as a light-yellow solid (62%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[ClH:12].Cl.[F:14][C:15]([F:31])([F:30])[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25])=[CH:19][CH:18]=1>C(O)C>[ClH:12].[NH2:25][C:24]1[N:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][C:15]([F:14])([F:30])[F:31])=[CH:22][CH:21]=2)[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[N:28]=[C:27]([NH2:29])[N:26]=1
Reactant: CCCCCCCCCC=O
Reactant: N=C(N)NC(=N)Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCC1N=C(N)N=C(N)N1c1ccc(OC(F)(F)F)cc1

Procedure:
100 ml of ethanol, 4.7 ml (25.1 mmol) of 1-decanal and 0.7 ml of concentrated hydrochloric acid were added to 5.0 g (16.8 mmol) of N1-(4-trifluoromethoxyphenyl)-biguanide hydrochloride, and the mixture was refluxed for 16 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (8:1.5)), and recrystallized from 80% ethanol to obtain 1.1 g of colorless crystals having a melting point of 213 to 215° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:19][CH2:18]3)[CH2:10][CH2:9]1)(C)(C)C.[ClH:33]>O1CCOCC1.C(OCC)C>[ClH:33].[C:26]1([CH3:31])[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][C@H:11]3[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]3)[CH:16]=2)[O:21]1
Reactant: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)ccc2O1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@H](N)CC3)ccc2O1
Temperature: 0 °C

Procedure:
6 g (13.7 mmol) of [trans-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester were dissolved in 50 ml of 1,4-dioxane and 25 ml of 2N hydrogen chloride in diethyl ether. The diethyl ether was removed by evaporation and the remaining solution was refluxed until no starting material could be detected by RP-HPLC. The resulting suspension was cooled to 0° C. and the crystals were collected by filtration, washed once with cold methyl tert-butyl ether and dried in vacuum at 25° C. to yield 3.6 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:12][O:13][CH3:14])=[C:6](Br)[CH:5]=1.[CH2:17](OB(C=C)OCCCC)[CH2:18]CC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([CH:17]=[CH2:18])[C:7]([O:11][CH2:12][O:13][CH3:14])=[C:8]([F:10])[CH:9]=1
Reactant: COCOc1c(F)cc(C(=O)OC)cc1Br
Reactant: C=CB(OCCCC)OCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=Cc1cc(C(=O)OC)cc(F)c1OCOC
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of 3-bromo-5-fluoro-4-methoxymethoxybenzoic acid methyl ester (300 mg) and vinylboronic acid dibutyl ester (226 mg) in toluene (4 mL)-ethanol (2 mL) were added dichlorobis(triphenylphosphine)palladium (II) (36 mg) and an aqueous solution (1 mL) of sodium carbonate (217 mg). The mixture was stirred at 100° C. for 8 hours, and then allowed to stand for cooling down to room temperature. The resulting insoluble materials were filtered through a Celite pad, and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=30:1, v/v) to give the title compound (190 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[S:27])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[S:27])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3COC(C)(C)O3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3COC(C)(C)O3)CS[C@H]12)c1csc(N)n1
Yield: 66.2 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2,2-dimethyl-1,3-dioxolan-4-yl)methylthio-3-cephem-4-carboxylate (58 mg) was reacted with iodomethyl pivalate (51 mg), followed by purifying the reaction product in the same manner as in Example 2, yielding the titled compound (45 mg; 66%) as pale yellow powder.