Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[N:28]=[C:29](N2CCC(F)(F)C2)[C:30]2N=NNC=2N=1)(C)(C)C.Br.BrCC1C=CN=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:30]=[CH:29][N:28]=[CH:27][CH:23]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Br
Agent: BrCc1ccncc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccncc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(bromomethyl)pyridine hydrobromide and isolated as orange solid (4.1 mg, 27%). MS (m/e): 374.4 (MH+).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[CH3:3][CH:2]([O:18][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[CH:17]=[CH:16][CH:15]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: COc1cccc(O)c1
Reactant: CC(C)CCCC(C)Br
Product: COc1cccc(OC(C)CCCC(C)C)c1

Procedure:
2-bromo-6-methyl-heptane was reacted with m-methoxy-phenol to obtain m-[(1,5-dimethyl-hexyl)-oxy]-anisole (boiling point =210°-212° C/12 mmHg);
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C(=O)N(C)C.[H-].[Na+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:19]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C(=O)N(C)C
Product: O=C1CCCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
33.9 g (0.3 mol) of caprolactam are dissolved in 200 ml of absolute dimethylsulphoxide and 100 ml of absolute tetramethyl urea and 14.4 g (0.33 mol) of 55% sodium hydride/oil dispersion is added in batches. The resulting jelly-like precipitate is stirred for 2 hours at ambient temperature. Then 38 g=34.4 ml (0.3 mol) of benzyl chloride are added dropwize, the mixture is stirred for 2 hours at ambient temperature and then poured onto ice water. The aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, washed four times with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue remaining is distilled in vacuo. Yield: 49.9 g (81.8% of theory), Bp 0.27 mm Hg: 110°-114° C.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].Cl>>[P:1]([O:4][P:1]([OH:4])([OH:3])=[O:2])([OH:3])([OH:2])=[O:5]
Reactant: O=P(O)(O)O
Agent: Cl
Product: O=P(O)(O)OP(=O)(O)O

Procedure:
To do this, a concentrated orthophosphoric acid is entered into a cooled hydrochloric acid solution, while being mixed. In order to produce pyrophosphoric acid (H4P2O7) according to the reaction:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br-].[K+]>[Cu].O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2ccccn2)n1
Reactant: Brc1ccccn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: Cc1cccc(N(c2ccccn2)c2ccccn2)n1
Reaction time: 10 h

Procedure:
To a flask were added 3.7 g of 6-methyl-N-pyridin-2-ylpyridin-2-amine, 9.4 g of 2-bromopyridine, 2.0 g of sodium carbonate, 0.05 g of copper bronze, 0.01 g of potassium bromide, and 5 ml of mesytylene. After stirring under nitrogen at 160 C for 10 hours, the mixture was cooled to 22 C, and 35 ml of water was added and the product was extracted with 75 ml ethyl acetate. After washing twice with 30 ml of water, the solvent was removed, and the product was purified by silica gel chromatography using 75% ethyl acetate, 25% hexane, and 0.01% triethylamine resulting in 3.2 g of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O.[H][H]>ClCCl.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CC(C)Cn1c(CO)nc2c(N)nc3ccccc3c21
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cn1c(CO)nc2c(N)nc3c(c21)CCCC3

Procedure:
A mixture of [4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol (15.2 g, 56.2 mmol, U.S. Pat. No. 5,389,640 Example 9), platinum(IV) oxide (7.6 g), and trifluoroacetic acid (75 mL) was hydrogenated at 50 psi (3.5×105 Pa) of hydrogen on a Parr apparatus for 2 days. The mixture was diluted with dichloromethane and filtered through CELITE filter agent, which was rinsed afterwards with dichloromethane and methanol. The filtrate was concentrated under reduced pressure and the residue was partitioned between dichloromethane (250 mL) and 1:1 saturated aqueous sodium bicarbonate/water (250 mL). Some solid formed that was isolated by filtration. The aqueous layer was extracted with dichloromethane (2×200 mL). The solid was dissolved in methanol and the resulting solution was combined with the organic layers, concentrated under reduced pressure, and purified by chromatography using a HORIZON HPFC system (silica gel, elution with 10% 1 M NH3 in methanol/dichloromethane) to afford 4.98 g of [4-amino-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methanol as a grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH2:36][CH3:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH3:34])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:33]([O:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([NH:35][CH2:36][CH3:37])[C:22]([CH2:21][C:6]1[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18])=[CH:31]2)[CH3:34]
Reactant: CCNc1nc2ccc(OCC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OCC)ccc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (149 mg, 0.60 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-ethoxy-N-ethylquinolin-2-amine hydrochloride SLA 41042 (181 mg, 0.68 mmol) at RT followed by a 2 N aq. LiOH solution (0.60 mL, 1.20 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided 35 mg of 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 49 as a yellow solid (14 mg, 4% yield).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[Cl-].[Ca+2:24].[Cl-]>C(O)C>[CH:1]1([O:7][C:8]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[Ca:24]
Reactant: [Ca+2]
Agent: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OC1CCCCC1
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: [Ca]

Procedure:
To 2 ml of an ethanol solution containing 0.2 g of sodium N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide obtained in Example 16 was added 0.6 ml of 1N calcium chloride at room temperature with stirring. The solvent was evaporated, and the resulting residue was recrystallized from water to give 0.17 g of calcium N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH:17]=[O:18])[C:12]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:11]=2[O:10][C@@H:9]1[CH3:24])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(OC(=O)C)C.CCCCCCC>O1CCCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][OH:18])[C:12]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:11]=2[O:10][C@@H:9]1[CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC=O)C(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H]1Oc2ccc(F)cc2N(CCO)C(=O)[C@H]1NC(=O)OC(C)(C)C
Yield: 60.5 %

Procedure:
0.10 g (0.28 mmol) [(6R,7S)-2-Fluoro-6-methyl-8-oxo-9-(2-oxo-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester in 4 ml tetrahydrofurane were reduced with 0.02 g (0.34 mmol) sodium borohydride. Chromatography on silicagel with ethylacetate/heptane 8:2 yielded 0.06 g (56%) [(6R,7S)-2-fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester, MS m/e (%): 377.3 (M+Na+, 86), 355.2 (M+H+, 14), 255.3 (100).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:15])[CH2:12][C:13]#[CH:14])([CH3:3])[CH3:2].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=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.[Cu]I.C(N(CC)CC)C>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:15])[CH2:12][C:13]#[C:14][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)([CH3:3])[CH3:2]
Reactant: Brc1ccccn1
Reactant: C#CCC(O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(O)CC#Cc1ccccn1
Temperature: 60 °C
Yield: 43.6 %

Procedure:
To a round bottom flask were added 1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)but-3-yn-1-ol (0.47 g, 2.3 mmol), triethylamine (10 mL), 2-bromopyridine (0.28 mL, 2.7 mmol), bis(triphenylphosphine)palladium(II) dichloride (16 mg, 0.023 mmol) and copper(I) iodide (9 mg, 0.045 mmol). After this mixture was stirred with heating overnight at 60° C., it was allowed to cool to room temperature. The reaction was mixed directly with silica, concentrated and purified by silica chromatography to give the desired coupling product (286 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([C:23]#[CH:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.C1COCC1>C([O-])(O)=O.[Na+].CCOC(C)=O.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.[Cu]I>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:24]#[C:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)nc1
Reactant: C#CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C#CC2CCCCC2)nc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
Under a nitrogen atmosphere, add 3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine (1 g, 4.12 mmol), cyclohexylacetylene (0.446 g, 4.12 mmol), dichlorobis(triphenylphosphine)-palladium (578 mg, 0.824 mmol), copper(I) iodide (157 mg, 0.824 mmol) and triethylamine (8.6 mL, 6.18 mmol) to THF (20 mL). Heat the mixture to reflux overnight. Cool the mixture to room temperature, and dilute with saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL). Separate the layers and extract the aqueous layer with EtOAc (4×30 mL). Wash the combined organic extracts with brine (20 mL), dry over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 6:1 gradient over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (0.71 g, 55%). MS (APCI+) m/z: 215 (M-Boc+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][N:13]=[CH:12][C:11]=3[C:15](OCC)=[O:16])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][N:13]=[CH:12][C:11]=3[CH2:15][OH:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)c1cnoc1-c1ccc2c(c1)OCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of ethyl 5-(1,3-benzodioxol-5-yl)isoxazole-4-carboxylate (8.56 g) in tetrahydrofuran (70 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 70 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(1,3-benzodioxol-5-yl)-4-isoxazolylmethanol (6.97 g, yield 97%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 92–93° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][OH:16])[NH:13][C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]1[C:23]([O:25][CH3:26])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O>COCCOC.CCOC(C)=O>[CH2:33]([O:32][C:30]([N:13]1[C@H:14]([CH2:15][OH:16])[C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:11]([C:23]([O:25][CH3:26])=[O:24])[C@@H:12]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](CO)N[C@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](CO)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Reaction time: 8 h
Yield: 112 %

Procedure:
To a stirred and ice-cooled suspension of (2R*,3S*,4S*,5S*)-4-benzyloxymethyl-5-hydroxymethyl-3-methoxycarbonyl-2-phenylpyrrolidine semifumarate (12.0 g, 29.0 mmol) in 1M NaOH aqueous solution (70.0 ml, 70.0 mmol) and DME (40 ml) was added benzyl chloroformate (Cbz-Cl, 4.97 ml, d1.195, 34.8 mmol) rapidly. After the heterogeneous white reaction mixture was stirred with ice-cooling for an hour, H2O (40 ml) and AcOEt(40 ml) was added to dissolve the white solids, and then a further amount of Cbz-Cl (1.0 ml, d1.195, 7.0 mmol) was added to the mixture at room temperature; on the addition, the reaction mixture became neutral. After stirring at room temperature for 30 minutes, the reaction went to almost completion. The stirring was continued at room temperature overnight, and then the layers were separated. The aqueous layer was extracted with AcOEt (50 ml×4). The combined organic layer and AcOEt extracts were washed with 0.5M NaOH aq. solution (×2), half sat. NaCl aq. solution (×1), 0.5M HCl aq. solution (×1), sat. NaCl aq. solution (×1), sat. NaHCO3 aq. solution (×1) and sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give crude title compound (15.9 g, quant.) as an almost colorless viscous oil: IRmax (film): 3420(s), 1738(vs), 1698(vs), 1680(vs), 1605(w), 1595(w), 1492(s), 1280(s), 1210(s), 1075(s), 758(s), 699(vs) cm-1 ; 1H-NMR δ: 7.53-7.10(m, 14H), 6.94(br.s, 1H), 5.30(d, J=9.5 Hz, 1H), 5.02(br.s, 2H), 4.53(d, J=12.1 Hz, 1H), 4.47(d, J=12.1 Hz, 1H), 4.13-3.90(m, 3H), 3.62(dd, J=9.7, 3.5 Hz, 1H), 3.58-3.41(m, 1H), 3.53(dd, J=9.7, 4.6 Hz, 1H), 3.29(s, 3H), 2.73(br.s, 1H), 1.61(br.s, OH, 1H) ppm. This was employed in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[NH:29][CH:30]=[N:31][C:27]=3[CH:26]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][CH3:23])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34].C(Cl)(=O)C.[O:39]1[CH2:44][CH2:43]OCC1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Cl:34])=[CH:4][C:5]([S:9]([NH:12][CH:13]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[NH:29][CH:30]=[N:31][C:27]=3[CH:26]=2)[C:14]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]([CH3:23])[C:44](=[O:39])[CH3:43])[CH2:20][CH2:21]2)=[O:15])(=[O:10])=[O:11])=[CH:6][C:7]=1[Cl:8]
Reactant: C1COCCO1
Reactant: CNC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)N(C)C1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1

Procedure:
Prepared from 4-amino-N-[1-(1H-benzimidazol-5-yl-methyl)-2-(4-methylamino-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and acetylchloride in dioxane and triethylamine analogously to Example 2.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42][CH:43]1[O:47][C:44]1([CH3:46])[CH3:45].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:42][CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC1(C)OC1CBr
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](OCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 100.1 %

Procedure:
After a mixed solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (97 mg, 0.175mmol), sodium hydride (50 mg, 2.08 mmol) and 4-bromo-2,3-epoxy-2-methylbutane (145 mg, 0.877 mmol) in tetrahydrofuran (2ml) was heated under reflux for 12 hours, 1M lithium tri-s-butylborohydride solution in tetrahydrofuran (1.8 ml, 1.80 mmol) was added and the mixed solution was heated under reflux for 45 minutes. The reaction solution was stirred with 3N aqueous sodium hydroxide solution and 30% aqueous hydrogen peroxide at room temperature for 30 minutes, then diluted with ethyl acetate, washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography (hexane:ethyl acetate=10:1) to give the title compound as a colorless oil (113 mg, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:7]=1.[OH:17][CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH:14]1([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:20]3[CH2:21][CH2:22][CH:18]([OH:17])[CH2:19]3)=[CH:7][CH:8]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(c1ccc(OCCCCl)cc1)C1CC1
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(OCCCN2CCC(O)C2)cc1)C1CC1
Yield: 68 %

Procedure:
The product from Example 151B (200 mg, 0.83 mmol), 3-hydroxypyrrolidine (72 mg, 0.83 mmol), potassium carbonate (121 mg) and potassium iodide (146 mg) in 10 mL of 2-butanone were heated at 110° C. for 72 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (68 % yield).
Reaction SMILES: [C:1]([C:5]1[N:10]2[C:11](=[S:15])[C@H:12]([O:13][CH3:14])[C@H:9]2[S:8](=[O:17])(=[O:16])[CH:7]([CH2:18][C:19]([O:21]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:20])[C:6]=1[CH3:35])([CH3:4])([CH3:3])[CH3:2]>ClCCl.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:1]([C:5]1[N:10]2[C:11](=[S:15])[C@H:12]([O:13][CH3:14])[C@H:9]2[S:8](=[O:16])(=[O:17])[CH:7]([CH2:18][C:19]([OH:21])=[O:20])[C:6]=1[CH3:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H]1C(=S)N2C(C(C)(C)C)=C(C)C(CC(=O)OC(c3ccccc3)c3ccccc3)S(=O)(=O)[C@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CO[C@H]1C(=S)N2C(C(C)(C)C)=C(C)C(CC(=O)O)S(=O)(=O)[C@H]12

Procedure:
To a solution of 4-tert-butyl-7α-methoxy-3-methyl-2-(benzhydryloxycarbonylmethyl)thio-3-cephem 1,1-dioxide (see Example 16) (20 mg) in dichloromethane (0.5 ml), anisole (60 ml) and trifluoroacetic acid (0.3 ml) were added sequentially. The mixture was let stand for 3 hours at room temperature then concentrated in vacuo. Diisopropylether (10 ml) was added under stirring. The light yellow powder thus obtained was filtered and dried in vacuo (12 mg).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH3:19][NH2:20].C1COCC1>C1COCC1>[CH3:19][NH:20][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CN
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
A mixture of 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (750 mg, 3.06 mmol), 2.0M Methylamine/THF (2.3 mL, 4.60 mmol) in 50 mL of THF was stirred at room temperature for 6 hr. Then the traction mixture was concentrated to give 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (760 mg, 90% yield). Rt=2.21 min; 277 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1([CH3:14])[CH2:13][O:12]1.B(F)(F)F>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH:11]([CH3:14])[CH:13]=[O:12]
Reactant: CC1(c2cc([N+](=O)[O-])ccc2F)CO1
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C=O)c1cc([N+](=O)[O-])ccc1F
Reaction time: 1 h

Procedure:
2-(2-fluoro-5-nitrophenyl)-2-methyloxirane (1 eq) was dissolved in ethyl ether (1 mL) under nitrogen. BF3-etherate (0.87 eq) was added dropwise at room temperature and after complete addition solution was allowed to stir for 1 h. Solution was then quenched with water, extracted with ethyl ether. Organics washed with brine, dried with sodium sulfate and concentrated. Crude product was purified using flash chromatography (85% Hex:15% EtOAc) on silica to afford 2-(2-fluoro-5-nitrophenyl) propanal.