Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][CH:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:30][Si:31]([CH3:48])([CH3:47])[CH2:32][CH2:33][O:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[CH:45]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22][CH2:21]2)[CH2:45][C:37]2[N:36]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:30])([CH3:47])[CH3:48])[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(NCc1ccccn1)c1ccc(CNC2CCCc3cccnc32)cc1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1c(CN(Cc2ccc(S(=O)(=O)NCc3ccccn3)cc2)C2CCCc3cccnc32)nc2ccccc21
Yield: 39.2 %

Procedure:
Using general procedure B: Reaction of N-pyridin-2-ylmethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzenesulfonamide (97 mg, 0.24 mmol), 1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-2-carbaldehyde (72 mg, 0.26 mmol), and NaBH(OAc)3 (151 mg, 0.71 mmol) for 1 h at room temperature followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) gave the title compound (63 mg, 50%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.77 (dd, 2H, J=7.5, 7.5 Hz), 1.73-1.74 (m, 1H), 1.95-2.06 (m, 2H), 2.20-2.25 (m, 1H), 2.66-2.86 (m, 2H), 3.29-3.35 (m, 2H), 3.78 (d, 1H, J=14.7 Hz), 3.98 (d, 1H, J=14.7 Hz), 4.05 (dd, 1H, J=9.3, 6.3 Hz), 4.13 (d, 2H, J=6.0 Hz), 4.18 (brs, 2H), 5.70 (d, 1H, J=12.0 Hz), 5.98 (d, 1H, J=12.0 Hz), 7.06-7.10 (m, 2H), 7.13-7.18 (m, 3H), 7.31-7.36 (m, 2H), 7.43 (d, 2H, J=8.1 Hz), 7.52-7.66 (m, 4H), 8.42 (d, 1H, J=4.8 Hz), 8.52 (d, 1H, J=4.5 Hz).
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:24]=[CH:23][C:22](C(=O)C)=[CH:21][C:20]=1[F:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=[C:32](C=CC=1)[C:33]([O:35]O)=[O:34]>C(Cl)(Cl)Cl.ClCCl>[C:33]([O:35][C:22]1[CH:23]=[CH:24][C:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:20]([F:28])[CH:21]=1)(=[O:34])[CH3:32]
Reactant: CC(=O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c1

Procedure:
1-(4-{[t-Butyl(diphenyl)silyl]oxy}-3-fluorophenyl)-1-ethanone (8.27 g, 21.07 mmol) was dissolved in chloroform (300 mL). 3-Chloroperoxybenzoic acid (4.0 g, 23.18 mmol) was added and the solution heated to reflux for 72 hours. The solution was diluted with dichloromethane, washed with saturated sodium hydrogen sulfate, saturated sodium hydrogen carbonate, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to yield the title compound which was used without further purification (5.28 g, 12.92 mmol).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[CH:4]1[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5]1.[CH:13]1([C:16](=O)[CH2:17][C:18]([O:20]C)=[O:19])[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[O:1][N:2]=[C:3]([CH:4]3[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5]3)[C:17]=2[C:18]([OH:20])=[O:19])[CH2:15][CH2:14]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: CC1(C)CCC(C(Cl)=NO)CC1
Product: CC1(C)CCC(c2noc(C3CC3)c2C(=O)O)CC1

Procedure:
5-cyclopropyl-3-(4,4-dimethylcyclohexyl)isoxazole-4-carboxylic acid (I-9E) Was prepared by reaction of N-hydroxy-4,4-dimethylcyclohexanecarbimidoyl chloride and methyl 3-cyclopropyl-3-oxopropanoate following the same protocol as described for I-6E. MS m/z 264.1 (M+1).
Reaction SMILES: C(OC([C:6](=[C:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH:19]([CH3:21])[CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O)C.Cl.C(=O)=O>[Pt].[H][H].[OH-].[Na+]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]([CH3:21])[CH3:20])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(=C1CCCN1C(C)C)c1ccc(Cl)cc1
Agent: [Pt]
Agent: Cl
Agent: O=C=O
Product: CC(C)N1CCCC1Cc1ccc(Cl)cc1

Procedure:
Boil 40.6 g of 2-(α-ethoxycarbonyl-4-chlorobenzylidene)-1-isopropylpyrrolidine and 115 ml of conc. hydrochloric acid under reflux until evolution of carbon dioxide ceases. Alkalize the resulting reaction mixture with 250 ml of 6 N sodium hydroxide solution before extracting with 400 ml of diethyl ether, dry the ether phase over sodium sulfate and concentrate it. Dissolve thus-obtained residue in 250 ml of ethanol, and hydrogenate the resulting solution with platinum/hydrogen. Then filter off the catalyst and distil off the solvent before distilling the product under a high vacuum to obtain a yield [21.8 g (70% of theory)] of title compound and having a b.p. of 75° at 7·10-3 mm of Hg.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:27]1(B(O)O)[CH2:29][CH2:28]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C.O>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([CH:27]3[CH2:29][CH2:28]3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)C1CC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(C3CC3)cc2)C(=O)O1
Temperature: 100 °C
Yield: 45.4 %

Procedure:
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (15 mg, 0.036 mmol), cyclopropylboronic acid (5.5 mg, 1.78 equiv.), Pd(OAc)2 (2 mg, 25% mol), tricyclohexylphosphine (5 mg, 50% mol), K3PO4 (20 mg, excess), water (1 mL) and DMF (1 mL) were heated in a microwave oven for 45 min at 100° C. The mixture was diluted with EtOAc (10 mL), washed with water (4 mL) and brine (5 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC to afford (R)-6-allyl-3-((S)-1-(4-cyclopropylphenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (6.2 mg, 45%). LC-MS Method 1, tR=2.02 min, m/z=380. 1H NMR (CDCl3) 7.24 (m, 2H), 7.02 (t, 2H), 6.76 (q, 4H), 5.75-5.56 (m, 2H), 5.10-4.98 (dd, 2H), 2.57 (m, 2H), 1.48 (d, 3H), 0.92 (m, 2H), 0.60 (m, 2H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:9]2[C@H:8]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:6]12[CH3:7])[C@:20]1([CH3:21])[C@@:15]2([O:34][C@@H:14]2[C@H:13]3Cl)[CH2:16][C@@H:17]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:19]1)(=[O:3])[CH3:2].CC(O)C>C(O)(=O)C.[Zn]>[C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:9]2[C@H:8]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:6]12[CH3:7])[C@:20]1([CH3:21])[C@@:15]([OH:34])([CH2:16][C@@H:17]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:19]1)[CH:14]=[CH:13]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H]2C[C@H]2[C@H]2[C@@H]3[C@H](Cl)[C@H]4O[C@]45C[C@@H](OC(=O)c4ccccc4)CC[C@]5(C)[C@H]3CC[C@@]21C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)O[C@H]1[C@H]2C[C@H]2[C@H]2[C@@H]3C=C[C@]4(O)C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 72.5 %

Procedure:
200 mg of 17β-acetoxy-3β-benzoyloxy-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β-androstane is stirred in 4 ml of acetic acid and 4 ml of propan-2-ol with 800 mg of zinc dust for 1 hour at 80° C. The mixture is filtered off from the zinc, washed with diethyl ether, and worked up analogously to Example 1. After chromatography and recrystallization from diisopropyl ether-acetone, 135 mg of 17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5β-androst-6-en-5-ol is obtained, mp 212°-212.5° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[Si:11]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH:23]([OH:24])[CH:1]=[CH2:2])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCOCCO
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(O)COCCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (8.38 mL) in dichloromethane (470 mL) was cooled to −78° C. in a nitrogen atmosphere. A solution of dimethyl sulfoxide (8.01 mL) in dichloromethane (10 mL) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred at the same temperature for 10 minutes. A solution of 2-[2-(tert-butyldimethylsilanyloxy)ethoxy]ethanol (25.9 g) in dichloromethane (20 mL) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred at the same temperature for 30 minutes. Triethylamine (52.1 mL) was added to the reaction solution at the same temperature. The reaction solution was stirred for one hour while gradually returning to room temperature. Aqueous ammonium chloride was added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was filtered through a silica pad and the filtrate was concentrated. Tetrahydrofuran (500 mL) was added to the residue. The reaction solution was cooled to −78° C. in a nitrogen atmosphere. Vinylmagnesium chloride (148 mL, 1.38 M solution in tetrahydrofuran) was added dropwise to the reaction solution at the same temperature. The reaction solution was heated to room temperature with stirring over six hours. Aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (10.03 g).
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]1[C@H:14]2[C@H:9]([CH2:10][CH2:11][C:12]3[CH:18]=[CH:17][C:16](N)=[CH:15][C:13]=32)[NH:8][CH2:7][CH2:6]1.[NH2:20][C:21](N)=O.[C-]#N.[Na+].[Cu]C#N>O.S(=O)(=O)(O)O>[CH2:5]1[C@H:14]2[C@H:9]([CH2:10][CH2:11][C:12]3[CH:18]=[CH:17][C:16]([C:21]#[N:20])=[CH:15][C:13]=32)[NH:8][CH2:7][CH2:6]1
Reactant: Nc1ccc2c(c1)[C@H]1CCCN[C@H]1CC2
Reactant: NC(N)=O
Agent: N#C[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1ccc2c(c1)[C@H]1CCCN[C@H]1CC2
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
Sodium nitrite (0.12 g) dissolved in water (0.7 mL) is added dropwise to a solution of cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-9-ylamine (0.36 g) in half-concentrated sulfuric acid (0.6 ml) cooled to ca. −5° C. The solution is stirred for 15 min in the cooling bath prior to the addition of urea (30 mg). The resulting solution is added to a vigorously stirred solution of sodium cyanide (0.32 g) and copper(I) cyanide (0.19 g) in water (1.4 mL) cooled to ca. −5° C. The mixture is stirred in the cooling bath for another 10 min and then the cooling bath is removed. After stirring at room temperature for 10 min, the mixture is heated to 70° C. and stirred at this temperature for 1 h. The mixture is cooled to room temperature, basified with 4 M NaOH solution (1.5 mL), and extracted with dichloromethane. The combined extracts are dried (Na2SO4) and the solvent is evaporated. The residue is chromatographed on silica gel [dichloromethane/(dichloromethane/methanol/NH4OH 50:48:2) 80:20→40:60] to give the title compound as a resin-like solid. Yield: 0.12 g (31% of theory); Mass spectrum (ESI+): m/z=213 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:12][N:13]([CH3:24])[S:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.Cl[O-:26].[Na+].[OH-].[Na+].Cl[O-]>O>[CH3:12][N:13]([CH3:24])[S:14]([C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)=[O:26]
Reactant: [O-]Cl
Reactant: CN(C)Sc1nc2ccccc2s1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)S(=O)c1nc2ccccc2s1
Yield: 90 %

Procedure:
10 parts of sodium carbonate and 4 parts of sodium bicarbonate are added to a well stirred suspension of 63 parts 2-N,N-dimethylbenzothiazole-sulphenamide in 130 parts of water. 170 parts by volume of a solution of sodium hypochlorite titrating 177 g. of NaClO and 3 g. of free caustic soda per liter are then slowly introduced, in about 5 hours and keeping the temperature within the range from 25° C. to below 30° C. The excess of hypochlorite is controlled by starchiodide paper. After introduction, the mixture is stirred for a further hour. The creamy white precipitate obtained is filtered off, washed until the washings are neutral and dried at 60° C. The 2-N,N-dimethyl-benzothiazole-sulphinamide melting at 121°-122° C., free from dibenzothiazyl disulphide, is obtained with a yield of 90%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([C:26]#[N:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[NH2:27][CH2:26][C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:19][N:14]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:15][CH2:16]1
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
A suspension of 2.8 g of lithium aluminum hydride in 50 ml of THF is cooled to 0° C. and a solution of 20 g of 1-benzyl-4-cyano-4-phenylpiperidine in 50 ml of THF is added dropwise. The reaction mixture is stirred for 1 hour at RT and then heated for 1 hour at 40° C. It is cooled in an ice bath and 3 ml of water, 3 ml of 4 N NaOH solution and 12 ml of water are added successively. The mineral salts are filtered off and the filtrate is evaporated under vacuum. The residue is chromatographed on silica H using a gradient of a DCM/MeOH mixture (from 100/3; v/v to 100/10; v/v) as the eluent to give 11 g of the expected product.
Reaction SMILES: [F:1][CH2:2][C:3]([CH:7]([F:9])[F:8])=[C:4]([F:6])[F:5].S(=O)(=O)(O)[OH:11]>O>[F:1][CH2:2][C:3]([OH:11])([CH:7]([F:9])[F:8])[CH:4]([F:6])[F:5]
Reactant: O=S(=O)(O)O
Reactant: FCC(=C(F)F)C(F)F
Solvent: O
Product: OC(CF)(C(F)F)C(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,3,3-tetrafluoro-2-propanol may be prepared by fluorinating commercially available 1,1,3-trichloro-2-propanone to form 1,1,3-trifluoro-2-propanone which may then be reacted with CF2 carbene to form 2-fluoromethyl-1,1,3,3-tetrafluoro-1-propene. The 2-fluoromethyl-1,1,3,3-tetrafluoro-1-propene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,3,3-tetrafluoro-2-propanol.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(C([Cl:18])=O)=O>C1COCC1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Oc1ccccc1C(=O)Cl

Procedure:
To a solution of compound 2-acetoxybenzoic acid (1.0 g, 5.5 mmol) in THF (30 mL) was added (COCl)2 (0.8 mL, 9.1 mmol) at 0° C. The mixture was heated (reflux, 1.5 h) and concentrated under reduced pressure to afford 2-(chlorocarbonyl)-phenyl acetate.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCl>[CH3:7][O:6][C:4]([C:3]1[C:2]([CH2:1][Cl:12])=[N:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)c1cccnc1C
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: COC(=O)c1cccnc1CCl
Yield: 45.7 %

Procedure:
A solution of methyl 2-methylnicotinate (20.0 g, 0.132 mol) and trichloroisocyanuric acid (46.0 g, 0.198 mol) in dichloromethane (100 mL) was stirred at room temperature overnight. The reaction mixture was then washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated in vacuo to provide the title compound as a yellow liquid (11.2 g), which was used as such in the next step.
Reaction SMILES: N1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][NH:17]3)=[CH:9][CH:8]=1.Cl.CN(C)CCCN=C=NCC.[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([O-])=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Na+]>CN(C)C=O>[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48](=[O:49])[N:17]3[C:18]4[C:14](=[C:13]([C:10]5[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=5)[CH:21]=[CH:20][CH:19]=4)[CH2:15][CH2:16]3)[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: c1cc2c(c(-c3ccncc3)c1)CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3ccncc3)cccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
0.2 ml of pyridine, 25 mg of 4-pyridin-4-yl-2,3-dihydro-1H-indole and 23 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 26.7 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) in 0.8 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 24 hours, and then concentrated under reduced pressure. The residue is taken up in 10 ml of water and then filtered through sintered glass, and the precipitate is washed with water (2×1 ml) and oven-dried. 27.6 mg of 6-(morpholin-4-yl)-2-{2-oxo-2-[4-(pyridin-4-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one are obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34]Br)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CC#N>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:34][CH2:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)c1ccc(OCCBr)cc1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OCCn2c(C(F)F)cc3c(Cl)c(C#N)ccc32)cc1
Temperature: 100 °C
Yield: 61.6 %

Procedure:
To a solution of 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile (0.019 g, 0.084 mmol) in MeCN (2 mL), under N2, was added Cs2CO3 (0.055 g, 0.17 mmol) and 4-[(2-bromoethyl)oxy]phenyl methyl sulfone (0.047 g, 0.17 mmol). The mixture was heated in a sealed tube at 100° C. for 1 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-70% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.022 g, 61% yield): MS (ES) m/z 425 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[C:14]#[N:15]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=2[C:14]#[N:15])=[O:7])=[CH:9][CH:10]=1
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: N#Cc1cc(Cl)ccc1NC(=O)c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2-amino-5-chlorobenzonitrile as a white solid as described in Example 1. 1H NMR (CDCl3): 8.96 (d, J=2.7, 1H), 8.53-8.50 (M, 1H), 8.24 (s, 1H), 8.19-8.15 (m, 1H), 7.67-7.63 (m, 2H), 7.54-7.51 (m, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:40])[CH2:4][C:5]([NH:7][CH:8]1[C:38](=[O:39])[N:10]2[C:11]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:12](/[CH:15]=[CH:16]\[C:17]3[N:18]=[N:19][S:20][CH:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[N:41]([O-])=[O:42].[Na+].NC(N)=O>C(Cl)Cl.C(O)(=O)C>[Br:1][CH2:2][C:3](=[O:40])[C:4](=[N:41][OH:42])[C:5]([NH:7][CH:8]1[C:38](=[O:39])[N:10]2[C:11]([C:22]([O:24][CH:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:12](/[CH:15]=[CH:16]\[C:17]3[N:18]=[N:19][S:20][CH:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=N[O-]
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\c3csnn3)CS[C@H]12
Agent: NC(N)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\c3csnn3)CS[C@H]12
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A methylene chloride-acetic acid (20 ml-10 ml) solution of diphenylmethyl 7-(4-bromoacetoacetamido)-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (2.22 g, 3.4 mmol) was cooled from -7° C. to -5° C. and an aqueous solution (2 ml) of sodium nitrite (0.32 g, 4.6 mmol) was added in portions. After its dropwise addition the mixture was stirred for 30 minutes, then urea (0.3 g) was added and the temperature of the reaction solution was returned to toom temperature. The reaction mixture was extracted with methylene chloride, then washed with water (40 ml×2) and then dried over magnesium sulfate. When the solvent was distilled off, diphenylmethyl 7-(4-bromo-2-hydroxyiminoacetoacetamido)-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (1.85 g) was obtained as a light yellow powder compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=O)[CH2:16][O:17][CH3:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:39][C:40]([O:42][CH3:43])=[O:41])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH2:16][O:17][CH3:18])=[CH:39][C:40]([O:42][CH3:43])=[O:41])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(=O)c1cccc(OCc2ccccc2)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COCC(=CC(=O)OC)c1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 53.4 %

Procedure:
To a solution of 102.A (0.17 g, 0.66 mmol) in benzene (7 mL) was added methyl (triphenylphosphoranylidene)acetate (available from Aldrich) (2.2 g, 6.6 mmol) at room temperature. The mixture was stirred for 72 hours at reflux (100° C.), cooled to room temperature, filtered through silica gel (EtOAc), and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 102.B (mixture of geometric isomers) (0.11 g, 53% yield) as a pale yellow oil.