Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])=[C:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH3:2].FC(F)(F)C(O)=O.[CH:21]1([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][NH2:34])[CH:27]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([O:7][CH2:8][CH2:9][OH:10])=[N:34][N:33]([C:28]2[CH:27]=[C:26]([C:25](=[O:35])[NH:24][CH:21]3[CH2:23][CH2:22]3)[CH:31]=[CH:30][C:29]=2[CH3:32])[C:11]=1[NH2:12])=[O:13])[CH3:2]
Reactant: CCOC(=O)C(C#N)=C1OCCO1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(OCCO)nn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A stirred solution of cyano-[1,3]dioxolan-2-ylidene-acetic acid ethyl ester (prepared as described by Neidlein and Kikelj, Synthesis, 1988, 981, 266 mg, 1.45 mmol, 1.0 eq), N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetate (Example 6C, 463 mg, 1.45 mmol, 1.0 eq), and triethylamine (405 μL, 2.9 mmol, 2.0 eq) in 20 mL of ethanol was heated to 65° C. overnight. After cooling to room temperature, the mixture was concentrated and the residue purified by flash chromatography on silica gel (eluted with 1/1 hexanes/EtOAc followed by 100% EtOAc) to provide the desired compound as a tan solid (350 mg, 62%). HPLC (4 minute 10-95 gradient) tR1.59 min; MS ink 389.06 [M+H]+; 1H NMR (CD3OD), δ 7.87 (d, J=7.9 Hz, 1H), 7.78 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 4.29 (dd, J=14.9, 6.9 Hz, 2H), 4.19 (d, J=4.3 Hz, 2H), 3.84 (d, J=4.4 Hz, 2H), 2.84 (m, 1H), 2.22 (s, 3H), 1.35 (t, J=7.3 Hz, 3H), 0.81 (d, J=5.3 Hz, 2H), 0.63 (s, 2H) ppm.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([NH2:29])([CH3:28])[CH3:27].[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[N:36]=[C:35]2[C:42]1[N:43]=[C:44]2[C:50]([C:51](O)=[O:52])=[CH:49][N:48]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[C:45]2=[N:46][CH:47]=1>CN(C=O)C>[C:26]([NH:29][C:51]([C:50]1[C:44]2[C:45](=[N:46][CH:47]=[C:42]([C:35]3[C:34]4[C:38](=[CH:39][CH:40]=[C:32]([O:31][CH3:30])[CH:33]=4)[N:37]([CH3:41])[N:36]=3)[N:43]=2)[N:48]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:59])([CH3:61])[CH3:60])[CH:49]=1)=[O:52])([CH3:28])([CH3:27])[CH3:25]
Reactant: CC(C)(C)N
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)O)cn3COCC[Si](C)(C)C)nn2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (40.2 mg, 106 μmol.20) and 2-methylpropan-2-amine (25.8 mg, 353 μmol) then 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (40 mg, 88.2 mmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 30 min to yield N-tert-butyl-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 78.6 μmol, 89.2%) as an off-white solid. MS (M+H)+=509 (>90% purity); 1H NMR (CDCl3) δ: 9.11 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.40 (d, J=9.1 Hz, 1H), 7.20 (dd, J=9.1, 2.3 Hz, 1H), 5.72 (s, 2H), 4.18 (s, 3H), 3.92 (s, 3H), 3.54-3.64 (m, 2H), 1.58 (s, 9H), 0.90-1.01 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20][NH:21][CH2:22][CH3:23])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20][N:21]([C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH2:22][CH3:23])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(F)ccc1-c1cc(Cl)cc(CC(=O)OCC)c1
Reactant: O=C(Cl)C1CC1
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-chloro-2′-ethylaminomethyl-4′-fluoro-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7]([C:8]([CH3:20])([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=2[F:19])[CH3:9])=[N:6][N:5]=[C:4]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].O>CN(C=O)C>[ClH:1].[CH3:2][N:3]1[C:7]([C:8]([CH3:20])([O:10][C:11]2[C:12]([F:19])=[CH:13][C:14]([F:18])=[CH:15][C:16]=2[F:17])[CH3:9])=[N:6][N:5]=[C:4]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]
Reactant: Cn1c(-c2ccc(O)cc2C(F)(F)F)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(-c2nnc(C(C)(C)Oc3c(F)cc(F)cc3F)n2C)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}-3-(trifluoromethyl)phenol monohydrochloride (123 mg) was suspended in DMF (3 ml), and potassium carbonate (182 mg) and ethyl bromoacetate (0.060 ml) were added thereto, followed by stirring at 60° C. for one hour. The reaction solution was cooled to room temperature and water was added thereto followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine in this order and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added thereto and the solvent was evaporated under reduced pressure. The residue was washed with diisopropylether to obtain, as a white solid, ethyl [4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}-3-(trifluoromethyl)phenoxy}acetate monohydrochloride (68 mg).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)=[C:6]([NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH3:36])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:5]=1.[Li+].[OH-]>C1COCC1>[C:21]([O:20][C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([S:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:37])=[O:2])=[CH:5][C:6]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH3:36])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:16][CH:15]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.1 %

Procedure:
To a solution of 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid methyl ester (1.50 g, 2.9 mmol) in THF (15 mL) was added aqueous LiOH [prepared from LiOH monohydrate (0.39 g, 9.0 mmol) and H2O (3.9 mL)] dropwise at room temperature. The mixture was stirred at room temperature for 21 hours. Additional aqueous LiOH solution [prepared from LiOH monohydrate (0.25 g) and H2O (2.5 mL)] was added at room temperature. The mixture was mixture was stirred at room temperature for 24 hours, and then evaporated. The aqueous mixture was diluted with 50 mL of H2O, washed with AcOEt, and treated with active charcoal. The mixture was filtered and the filtrate was carefully acidified to pH 4-5 with 1N HCl under stirring. The mixture (including oily precipitate) was sonicated for 1 hour and stirred at room temperature for 1 hour to give pale yellow solid. The resulting solid was collected by filtration, washed with H2O, and dried at 60° C. overnight under reduced pressure to give the title compound as pale yellow crystal (1.36 g, 93%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.48 (s, 9H), 2.68 (s, 3H), 6.93 (d, J=8.5 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.5 Hz, 1H), 7.75 (br-d, J=8.5 Hz, 1H), 7.89 (br-s, 1H), 8.58 (s, 1H), 8.80 (d, J=8.5 Hz, 1H), 9.62 (s, 1H), 10.15 (s, 1H), 12.97 (br-s, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([B:16]([OH:21])[OH:17])[CH:3]=1)#[N:6]
Reactant: Cc1ccc(C#N)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C#N)cc1B(O)O
Reaction time: 0.25 h
Yield: 27.8 %

Procedure:
To a stirred solution of 3-bromo-4-methylbenzonitrile (3.5 g, 17.86 mmol) in dry THF at −78° C. was added n-BuLi (2N, 10.71 mL) dropwise. The mixture was stirred for 15 min., and added triisopropyl borate (6.71 g, 35.71 mmol). The reaction flask was kept in the cooling bath for 30 min., and at room temperature for 3 hours. The solvent was removed, and the residue was dissolved in ether. The organic phase was washed with 1N HCl solution and water, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was crystallized from a mixture of CH2Cl2 and hexane to give 5-cyano-2-methylphenylboronic acid (800 mg, 20%). 1H-NMR (CDCl3 400 MHz): δ7.50-7.78 (m, 2H), 7.30 (d, 1H), 2.42 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:32]1([CH2:38][CH2:39][S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:46][C:45]1[CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[O:16][C:42](=[O:43])[C:41]=1[S:40][CH2:39][CH2:38][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cccc(Oc2ccccc2)c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2cccc(Oc3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-phenoxyacetophenone (2.00 g, 9.43 mmol), lithium bis(trimethylsilyl)amide (2.36 g, 14.15 mmol), chlorotrimethylsilane (1.79 mL, 14.15 mmol), THF (100 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. 114-115° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 2.99 (t, 2 H), 6.76 (s, 1 H), 7.09 (m, 7 H), 7.34 (s, 1 H), 7.44 (t, 2 H), 7.56 (m, 2 H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].N1CCCCC1>C(O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=[C:32]2[S:28][C:29](=[O:34])[NH:30][C:31]2=[O:33])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)S1

Procedure:
Following a procedure similar to that described in Example 17, the desired compound was prepared from 2 g of 2-tritylaminothiazole-4-carbaldehyde, 0.7 g of 2,4-thiazolidinedione, 1 g of piperidine and 20 ml of ethanol. The resulting product was a pale brown powder having the following physical properties.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10].Cl.[CH3:17][S:18]SC>O.C(O)(=O)C.[Cu]>[CH3:15][C:14]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[S:18][CH3:17]
Reactant: CSSC
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: [Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Product: CSc1cc(C(=O)O)ccc1C
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (14.5 g) in water was added to a stirred, cooled suspension of 3-amino-4-methylbenzoic acid (30.23 g) in a mixture of acetic acid and concentrated hydrochloric acid at a temperature between 0° C. and 5° C. The mixture was stirred at 0°-5° C. for 1 hour and the resulting mixture was added to a stirred mixture of dimethyl disulphide (22 ml) and copper powder (0.25 g) in acetic acid while maintaining the temperature at about 35° C. Further copper powder (3 g) was added during the reaction in order to maintain the gas evolution. It was stirred for a further 1 hour then poured into water and the solid filtered off. It was treated with a mixture of ethyl acetate and cyclohexane, heated and the insoluble material was filtered off to give 4-methyl-3-methylsulphenylbenzoic acid (19.5 g) as a white solid, m.p. 174.6°-175.2° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH:41]4[CH2:43][CH2:42]4)=[C:24]([NH:27][C:28](=[O:38])[CH:29]=[CH:30][CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].Br[CH:45]1[CH2:49][CH2:48][O:47][C:46]1=[O:50]>O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH:41]4[CH2:42][CH2:43]4)=[C:24]([NH:27][C:28](=[O:38])[CH:29]=[CH:30][CH2:31][N:32]4[CH2:37][CH2:36][N:35]([CH:45]5[CH2:49][CH2:48][O:47][C:46]5=[O:50])[CH2:34][CH2:33]4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C1OCCC1Br
Reactant: O=C(C=CCN1CCNCC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=CCN1CCN(C2CCOC2=O)CC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.42 ml of triethylamine is added to 608 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(piperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline in 3.0 ml of tetrahydrofuran. The mixture is cooled in the ice bath and a solution of 215 mg of 3-bromodihydrofuran-2-one in 1.0 ml of tetrahydrofuran is added dropwise and the mixture is stirred for one hour with cooling. The ice bath is then removed and the mixture is stirred for about 48 hours at ambient temperature. The reaction mixture is chromatographed directly, without further processing, over a silica gel column, with methylene chloride/methanol (95:5 to 90:10) as eluant. The foamy crude product is crystallized by trituration with a little diethylether.
Reaction SMILES: Cl.NO.C1([NH:10][C:11]([CH3:21])=[CH:12][C:13]([CH:15]2[N:19]([CH3:20])[CH2:18][CH2:17][CH2:16]2)=[O:14])CCCCC1>CO>[CH3:21][C:11]1[CH:12]=[C:13]([C@@H:15]2[CH2:16][CH2:17][CH2:18][N:19]2[CH3:20])[O:14][N:10]=1
Reactant: CC(=CC(=O)C1CCCN1C)NC1CCCCC1
Agent: Cl
Agent: NO
Solvent: CO
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Hydroxylamine HCl (70 mg, 1.0 mmol) was added to a solution of 3-(cyclohexylamino)-1-(1-methyl-5-pyrrolidinyl)-2-butene-1-one (160 mg, 0.64 mmol, from step 12a above) in 5 mL of methanol, and the mixture was stirred at 20°±5° C. for 4 hr. The solvent was removed under vacuum at 25° C., and the residue suspended in 3 mL of water and 1 mL of H2SO4. The mixture was heated to 70° C. for 90 min, then cooled to room temperature and adjusted to pH 10 with 50% NaOH (4 g). The mixture was extracted with ethyl acetate, and the extracts were dried over Na2SO4 and concentrated. The residue was confirmed as title product by chromatographic analysis. The analytical data correspond to that given in Example 1.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH3+:22])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.CCN(CC)CC.[N:30]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[C:31]=[O:32]>C(Cl)Cl>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:31]([NH:30][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:32])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1
Reactant: COc1ccc(CN=C=O)cc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OCCCCCC[NH3+])c21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CNC(=O)NCCCCCCOc2cccc3c2C(N)=NS(=O)(=O)N3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
To a suspension of 6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexan-1-aminium chloride (166 mmol, 52 mg) (Example 280) in dry DCM (6 mL) was successively added Et3N (332 mmol, 46 μL) and 1-(isocyanatomethyl)-4-methoxybenzene (183 mmol, 26 μL). The reaction was stirred for 48 hours at room temperature then concentrated in vacuo. The residue was washed with water, dried, then purified on silica gel (20% to 100% EtOAc in hexanes) to give the desired product (64 mg, 81.0% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.296 (m, 2H), 1.371 (m, 4H), 1.791 (pentet, J=8 Hz, 2H), 2.980 (q, J=6 Hz, 2H), 3.695 (s, 3H), 4.086 (d, J=6 Hz, 2H), 4.131 (t, J=6 Hz, 2H), 5.836 (br. t, J=5 Hz, 1H), 6.141 (br. t, J=6 Hz, 1H), 6.585 (d, J=8 Hz, 1H), 6.727 (d, J=8 Hz, 1H), 6.840 (d, J=9 Hz, 2H), 7.137 (d, J=9 Hz, 2H), 7.433 (t, J=8 Hz, 1H), 7.803 (br. s, 1H), 8.321 (br. s, 1H), 10.926 (s, 1H). MS 476 (MH+).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][OH:25])[O:21][C:20]4=[O:26])=[CH:15][C:14]=3[F:27])=[CH:9][N:8]=2)=[N:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C.O>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][O:25][S:29]([CH3:28])(=[O:31])=[O:30])[O:21][C:20]4=[O:26])=[CH:15][C:14]=3[F:27])=[CH:9][N:8]=2)=[N:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](CO)OC4=O)cc3F)cn2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)cn2)n1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
In 14 ml of methylene chloride was dissolved 1 g of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one (compound 10). The solution was added with 0.46 g of methanesulfonylchloride 0.46 g and 0.75 ml of triethylamine at room temperature and stirred at the same temperature for 30 minutes. Water and brine were added to the reaction mixture for washing, followed by extraction. The organic layer was dehydrated, filtrated and concentrated in vacuo thereby to provide (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyl oxazolidin-2-one 1 g. Yield 82%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][OH:18]>>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCN(CCN2CCCCC2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CCN2CCCCC2)CC1

Procedure:
1-(2-(1-Piperidinyl)ethyl)-4-piperidone oxime is prepared from 1-(2-(1-piperidinyl)ethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[C@@H:43]([NH2:47])[CH2:42][C:41]2([CH3:49])[CH3:48].CCOC(C)=O>COCCOC>[Si:22]([O:21][C@@H:20]1[C@H:19]([CH2:15][O:14][Si:7]([C:10]([CH3:12])([CH3:11])[CH3:13])([CH3:9])[CH3:8])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:47][C@@H:43]3[C:44]4[C:40](=[CH:39][C:38]([Cl:37])=[CH:46][CH:45]=4)[C:41]([CH3:49])([CH3:48])[CH2:42]3)[CH:31]=2)[CH2:16]1)([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(Cl)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC1(C)C[C@H](N)c2ccc(Cl)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1(C)C[C@H](Nc2cc(O[C@@H]3C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C3)ccn2)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a mixture of [1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl](chloro)[(2,3-η)-(1Z)-1-phenylprop-1-ene-2,3-diyl]palladium(2+) (3.4 mg, 0.0000052 mol) and potassium tert-butoxide (32.0 mg, 0.000286 mol) under an atmosphere of argon was added 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-2-chloropyridine (0.1226 g, 0.0002596 mol) in 1.00 ml DME, followed by (1S)-5-chloro-3,3-dimethylindan-1-amine (0.048 g, 0.00025 mol) in 1 ml DME. The mixture was stirred overnight, and the solution was poured into 50 ml EtOAc, washed with 10 ml water and concentrated. The residue was purified by preparative plate chromatography (70% EtOAc/hexanes) to afford the title compound (28.0 mg, 18.0%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:42](=[O:43])[N:11]2[C:12]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:13]([CH:17]=[CH:18][S:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH2:14][S:15](=O)[C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)Cl.C(OCC)(=O)C.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:42](=[O:43])[N:11]2[C:12]([C:26]([O:28][CH:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:27])=[C:13]([CH:17]=[CH:18][S:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cccnc3)CS(=O)[C@H]12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cccnc3)CS[C@H]12
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of benzhydryl 7-tert-butoxycarbonylamino-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate-1-oxide (trans isomer) (12.3 g) in dimethylformamide (70 ml) was added phosphorus trichloride (5.5 g) at -40° C. After being stirred at the same temperature for 30 minutes, the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (100 ml). The separated organic layer was washed in turn with 5% aqueous sodium bicarbonate, water, and brine. The solvent was evaporated in vacuo to give benzhydryl 7-tert-butoxycarbonylamino-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate (trans isomer) (11.1 g).
Reaction SMILES: [C:1]1([S:7]([CH:9](Cl)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[Na].[CH3:21][SH:22]>C(Cl)Cl>[C:1]1([S:7]([CH:9]([S:22][CH3:21])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS
Reactant: O=S(c1ccccc1)C(Cl)c1ccccc1
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: CSC(c1ccccc1)S(=O)c1ccccc1
Yield: 82.6 %

Procedure:
220 mg of (alpha-chlorobenzyl) phenyl sulfoxide was dissolved in 5 ml. of acetonitrile, and with addition of 3 ml. of a 20% aqueous solution of sodium salt of methyl mercaptan, the mixture was stirred for four days at room temperature. Methylene chloride (50 ml.) was added, and the product was dried with anhydrous sodium sulfate. The solvent was removed at reduced pressure. The product was separated by column-chromatography (silica gel, chloroform). There was obtained (alpha-methylthiobenzyl) phenyl sulfoxide as colorless crystals having a melting point of 104° - 105° C. in a yield of 82.6%.