Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:14][C:15]1[C:24]([NH:25][NH2:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:27])[CH:21]=2)[N:16]=1>>[Cl:14][C:15]1[C:24]2[N:23]([C:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:26][N:25]=2)[C:22]2[C:17]([N:16]=1)=[CH:18][CH:19]=[C:20]([Cl:27])[CH:21]=2
Reactant: NNc1nc2cc(Cl)ccc2nc1Cl
Reactant: COC(OC)(OC)c1ccccc1
Product: Clc1ccc2nc(Cl)c3nnc(-c4ccccc4)n3c2c1
Temperature: 120 °C

Procedure:
In a 250 ml. three-necked reaction flask equipped with mechanical stirrer and reflux condenser, there were placed 50.0 g. (0.274 mole) of trimethyl orthobenzoate that had been preheated to ca. 70° C. Stirring was commenced and 10.0 g (0.0437 mole) of 2,6-dichloro-3-hydrazinoquinoxaline, the product of Preparation L(a), were added thereto. The resulting reaction mixture was then heated at ca. 120° C., with continued stirring, for a period of 24 hours, followed by cooling to room temperature (~20° C.) and stirring overnight for approximately 16 hours to give a yellow slurry. The latter slurry was then filtered, and the recovered solid product was subsequently washed with two-50 ml. portions of ethanol and air-dried to constant weight to ultimately afford 9.8 g. (72%) of crude 4,8-dichloro-1-phenyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 305°-307° C. Mass Spectrum: m/e, 316/314 (P+).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[CH:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH2:33]([O:35][NH2:36])[CH3:34].C([O-])(=O)C.[Na+].O>O.CCO>[C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([CH:16]3[CH2:17][CH2:18][C:19](=[N:36][O:35][CH2:33][CH3:34])[CH2:20][CH2:21]3)[C:23]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]3)=[O:24])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCON
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2CCC(=O)CC2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCON=C1CCC(N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-Cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid (0.055 g, 0.12 mmol) in 1 ml of H2O/EtOH (2:1) was added ethoxyamine hydrochloride (0.024 g, 0.24 mmol) and sodium acetate (0.032 g, 0.24 mmol). The reaction mixture was stirred at room temperature for 24 h and treated with water. The aqueous layer was extracted with CH2Cl2 (3×) and the organic layer was dried with sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by HPLC to obtain 5-cyclohex-1-enyl-3-[(4-ethyoxyimino-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (0.015 g, 26%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH3:21][Si:22]([O:25][C:26](=[O:33])[CH2:27][O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])([CH3:24])[CH3:23]>C1COCC1>[CH2:13]([Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:33][C:26]([O:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:27][O:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH3:14]
Reactant: C[Si](C)(C)OCC(=O)O[Si](C)(C)C
Reactant: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[Si](CC)(CC)OC(=CO[Si](C)(C)C)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15.5 mL, 0.11 mol) in THF (100 mL) at −78° C. was added a 1.6 M hexanes solution of n-butyl lithium (70 mL, 0.11 mol) over 15 minutes. After stirring for an additional 15 minutes at this temperature, triethylsilylchloride (16.7 mL, 0.1 mol) was added over 10 minutes followed by the addition of trimethylsilyl-2-(trimethylsiloxy)acetate (24.4 mL, 0.1 mol) over 30 minutes. The reaction was stirred at −78° C. for 30 minutes and warmed to ambient temperature by removing the cryogenic bath. The THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate out the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 min and the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product as a mixture of geometrical isomers (4:1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O.Cl[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=[O:18].[CH3:26][S:27]([C:30]1[N:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>O>[CH3:26][S:27]([C:30]1[N:35]=[CH:34][C:33]([O:36][C:15]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CS(=O)(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cesium carbonate (10 g) was added to an N-methylpyrrolidinone (70 ml) solution of 2-chloro-5-nitrobenzaldehyde (5.0 g) and 6-(methylsulfonyl)-3-pyridinol (5 g) obtained in Reference Example 2, and stirred at room temperature for 3 hours. Water was added, then the formed crystal was collected by filtration to obtain the entitled compound as a pale brown solid.
Reaction SMILES: Br.CC1C=C(C)N2OC(=N)N=C2[N:4]=1.[N+]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[C:18]1([S:23]([NH2:4])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1
Reactant: Cc1cc(C)n2oc(=N)nc2n1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 1.6 g of 5,7-dimethyl-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-2-imine hydrobromide and 1.4 g of o-nitrobenzenesulfonyl chloride in 60 ml of anhydrous methylene chloride at 0° C. is added a solution of 1.0 g of triethylamine in 10 ml of anhydrous methylene chloride dropwise. After addition, the mixture is stirred at 0° C. for 0.5 hour and then at ambient temperature for 2.5 hours. The mixture is then filtered. The filtrate is concentrated under reduced pressure and then column chromatographied (silica gel) to yield 2-nitro-N-[5,7-dimethyl-2H-[1,2,4)oxadiazolo(2,3-a)pyrimidin-2-ylidene]]benzenesulfonamide.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[S:15](N)([NH2:18])(=[O:17])=[O:16]>O1CCOCC1>[NH2:18][S:15]([N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@H:2]1[CH3:1])(=[O:17])=[O:16]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(N)(=O)=O
Temperature: 110 °C

Procedure:
To a solution of tert-butyl (3R)-3-methylpiperazine-1-carboxylate ((the product from step i), 1.1 g) in dioxane (60 ml) was added sulfamide (1.06 g) and the reaction was heated at 110° C. for 18 h. The reaction mixture was then partitioned between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow oil. Yield: 1.44 g
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:20]1.C[Si](C=[N+]=[N-])(C)C>CO>[CH:1](=[N:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:20])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1ccccc1NN=Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccccc1NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
2-(N′-Benzylidene-hydrazino)-benzoic acid (5.0 g, 20.81 mmol) in 1:1 tetrahydrofuran and methanol (50 mL) was reacted with a solution of trimethylsilyl diazomethane in hexanes (2.0M, 12 mL, 25.0 mmol) at 0° C. for 1 hour then stirred at 25° C. for 48 hours. The solvent was removed under vacuum to give methyl 2-[2-benzylidenehydrazino]benzoate as a solid (6.00 g, 100%). 1H NMR (300 MHz, DMSO-d6) ppm 3.87 (s, 3 H) 6.84 (td, J=7.54, 1.10 Hz, 1 H) 7.41 (m, 3 H) 7.54 (m, 1 H) 7.74 (m, 3 H) 7.86 (dd, J=8.09, 1.47 Hz, 1 H) 8.21 (s, 1 H) 11.02 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH2:12]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]2[CH2:24][C:23]3([CH2:27][C:26](=[O:28])[CH2:25]3)[CH2:22]2)[CH2:17][CH2:16]1)[CH2:13][CH3:14]>C(OCC)C>[CH2:12]([C@H:15]1[CH2:16][CH2:17][C@H:18]([CH:21]2[CH2:22][C:23]3([CH2:27][C:26]([OH:28])([C:4]4[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=4)[CH2:25]3)[CH2:24]2)[CH2:19][CH2:20]1)[CH2:13][CH3:14]
Reactant: CCC[C@H]1CC[C@H](C2CC3(CC(=O)C3)C2)CC1
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H](C2CC3(C2)CC(O)(c2cc(F)c(F)c(F)c2)C3)CC1
Reaction time: 15 h

Procedure:
A mixture of 15 mmol of 3,4,5-trifluorophenylmagnesium bromide (prepared from 3,4,5-trifluorobromobenzene and magnesium turnings), 15 mmol of 4E and 50 ml of diethyl ether is stirred for 15 hours. After conventional work-up the product is obtained, which is processed further without purification.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C(C(O[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O)=CC=CC=1.Cl>CCOCC>[C:19]([O:18][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Brc1ccccc1
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)Oc1ccccc1

Procedure:
In this example, phenyl t-butyl ether is prepared. Grignard reagent, phenyl magnesium bromide, is formed by mixing 100 g magnesium turnings with 607.7 g bromobenzene and 6170 g anhydrus ethyl ether. After formation of the Grignard reagent, t-butyl per benzoate (449 g) in ether is added at 15° C.-25° C. under nitrogen with stirring. Reaction product is shaken with cold, dilute hydrochloric acid, then washed with dilue aqueous sodium hydroxide, and then washed with water. It is then dried and distilled to yield 269.2 G of product phenyl t-butyl ether which is analyzed to give 79.1% C (calc 80.0%) and 9.2% H (calc 9.3%).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C([O-])(O)=O.[Na+]>[C:22]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)(=[O:24])[CH3:23]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)C1(O)CC=C2C[C@@H]3[C@@H]4C=C[C@H](O)[C@@H]5OC1=C2[C@]45CCN3C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a suspension of morphine (0.5 g, 1.75 mmol) in saturated NaHCO3 solution (25 mL), acetic anhydride (0.5 mL, 5.25 mmol) was added dropwise and allowed to stir for 3 hours. Progress of the reaction was monitored by TLC and after the completion; reaction mixture was extracted 6 times with dichloromethane. Dichloromethane layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to get solid 3-acetylmorphine. 0.34 g (59% yield). GC-MS, 1H and 13C NMR confirmed the structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]([CH3:35])=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[O:28][C:29]=2[CH3:35])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2ccsc12)C(=O)OC
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(F)cc3)oc2C)c2ccsc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-benzo[b]thiophen-7-yl)-propionic acid methyl ester was reacted with 2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol [J. Med. Chem. (1998), 41(25), 5037-5054] in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid as light yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([C:16](=[N:18][OH:19])[NH2:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[C:20](O)(=O)[CH3:21]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([C:16]3[N:17]=[C:20]([CH3:21])[O:19][N:18]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)O
Reactant: CCNC(=O)Nc1nc2ccc(C(N)=NO)cc2s1
Product: CCNC(=O)Nc1nc2ccc(-c3noc(C)n3)cc2s1
Temperature: 110 °C

Procedure:
About 50 mg of 2-[(ethylamino)Carbonyl]amino-1,3-benzothiazole-6-carboxamideoxime was charged into about 1 mL of glacial acetic acid. The mixture was heated to about 110° C. then stirred at this temperature for about 12–20 hours. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was then further purified by preparative HPLC. 1H NMR 1.10 (t, 3H), 2.67 (s, 3H), 3.17 (m, 2H), 6.74 (s, 1H), 7.73 (d, 1H), 7.97 (d, 1H), 8.53 (s, 1H), 10.9 (s, 1H); LC/MS 2.69 min, 304 (M+1), 302 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:25])[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>N1C=CC=CC=1>[OH:25][C:8]1([C:4]2[CH:3]=[C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH:7]=[CH:6][CH:5]=2)[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:12]2
Reactant: COc1ccc(CN2CC3CCC(C2)C3(O)c2cccc(N)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(CN2CC3CCC(C2)C3(O)c2cccc(NS(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
8-(3-Amino-phenyl)-3-(4-methoxy-benzyl)-3-aza-bicyclo[3.2.1]octan-8-ol (2.11 g, 6.23 mmol) in pyridine (15 mL) at 0° C. was charged with methanesulfonylchloride (0.72 mL, 9.35 mmol) dropwise. The reaction was warmed to room temperature and judged complete by TLC after 3 h. Following a water addition (20 mL), the product was extracted with EtOAc (4×30 mL), the organic layer was washed with saturated aqueous NaCl solution (6×50 mL), dried over Na2SO4, filtered and concentrated to give a crude orange liquid. Flash chromatography provided the title compound as a yellow semi-solid (1.28 g, 49%). (TLC 50% EtOAc/Hexanes Rf 0.24); 400 MHz 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=8.7 Hz, 2H), 7.27 (m, 3H), 7.14 (dd, J=7.1, 2.1 Hz, 1H), 6.83 (d, J=8.7 Hz, 2H), 3.77 (s, 3H), 3.53 (m, 2H), 2.96 (s, 3H), 2.82 (m, 2H), 2.60 (m, 2H), 2.36 (br s, 2H), 1.78 (m, 2H), 1.36 (m, 2H); APCI MS m/z 417.1 (M+1)+; LCMS m/z 417.1 (M+1)+.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[C:6]1([CH3:16])[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1>>[CH3:1][NH:2][S:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH3:16])[CH:7]=1)(=[O:14])=[O:13]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CN
Solvent: CCO
Product: CNS(=O)(=O)c1cccc(C)c1

Procedure:
A round-bottom flask with methylamine solution 40% (0.9 ml, 28 mmol) in ethanol (2 ml, 34 mmol), was chilled to 0° C. in an ice bath with stirring under inert atmosphere. Then m-toluenesulfonyl chloride (0.8 ml, 6 mmol) was added slowly into the mixture. The mixture was allowed to stir at 0° C., while under inert atmosphere for 30 minutes. The progress of the reaction was monitored by LC/MS, which showed mostly desired product peak. The mixture was diluted with ethyl acetate and water and then extracted the organic layer with EtOAc (3×25 ml) and brine solution. The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. This gave N,3-dimethylbenzenesulfonamide (1.00 g, 98% yield) as a colorless oil. MS (ESI pos. ion) m/z: 186 (MH+). Calc'd exact mass for C8H11NO2S: 185. 1H NMR (400 MHz, chloroform-d): 2.35-2.46 (m, 3H), 2.64 (s, 3H), 4.91 (s, 1H), 7.36-7.46 (m, 2H), 7.64-7.73 (m, 2H).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].O.[N:18]1[C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:20][C:19]=1[C:27]1[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](=O)[C:31]=2[CH:30]=[CH:29][CH:28]=1>CO>[CH2:3]([NH:10][N:11]=[C:32]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:19]3[NH:18][C:26]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[N:20]=3)[C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Reactant: NNCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1ccc(CNN=C2c3ccccc3-c3c2cccc3-c2nc3cnccc3[nH]2)cc1
Temperature: 52.5 °C
Yield: 27.4 %

Procedure:
In a 10-ml round-bottomed flask, dissolve 100 mg of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, obtained in Example 1, in 3 ml of methanol, then add successively 197 mg of benzylhydrazine dihydrochloride and 138 mg of dry sodium acetate and heat at 50-55° C. for 5 hours. Pour the cooled reaction mixture into 10 ml of water, extract with ethyl acetate then twice with dichloromethane. Combine the organic phases, wash with a saturated aqueous solution of sodium chloride, dry over sodium sulphate then concentrate under reduced pressure. After purification by chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (93-7 by volume), we obtain 37 mg of N-benzyl-N′-[4-(1H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-ylidene]-hydrazine, in the form of a yellow foam with the following characteristics:
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Cl:7][C:8]1[C:13]2[CH2:14][NH:15][CH2:16][CH2:17][S:18][C:12]=2[CH:11]=[CH:10][CH:9]=1.Cl.C(N(CC)CC)C>ClCCl>[CH2:1]([S:3]([N:15]1[CH2:14][C:13]2[C:8]([Cl:7])=[CH:9][CH:10]=[CH:11][C:12]=2[S:18][CH2:17][CH2:16]1)(=[O:5])=[O:4])[CH3:2]
Reactant: Clc1cccc2c1CNCCS2
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethanesulphonyl chloride (1.28 g) in dichloromethane (10 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-ethylsulphonyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethyl acetate/hexane. Yield 2.53 g (m.p. 126°-128° C.).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)(=[O:20])=[O:19]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:26]1[C:25]2[C:29](=[CH:30][C:22]([NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:23][CH:24]=2)[NH:28][C:27]1=[O:31])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)NC(=O)C2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(NS(C)(=O)=O)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-methylsulfonylamino-2-oxindole to give 0.4 g of N-[3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-methanesulfonamide as a yellow-orange solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:30][CH2:31][CH:32]1[CH2:34][CH2:33]1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:28]=[CH:27][C:19]3[C:20](=O)[O:21]C(C)(C)[O:23][C:18]=3[CH:17]=2)=[C:11]([F:29])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:36]>C(O)(C)C>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:28]=[CH:27][C:19]([C:20](=[O:21])[NH2:36])=[C:18]([OH:23])[CH:17]=2)=[C:11]([F:29])[CH:10]=1)[CH2:30][CH2:31][CH:32]1[CH2:34][CH2:33]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N(CCC1CC1)Cc1ccc(Oc2ccc3c(c2)OC(C)(C)OC3=O)c(F)c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N(CCC1CC1)Cc1ccc(Oc2ccc(C(N)=O)c(O)c2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2-Cyclopropyl-ethyl)-[4-(2,2-dimethyl-4-oxo-4H-benzo[1,3]dioxin-7-yloxy)-3-fluoro-benzyl]-carbamic acid tert-butyl ester (I-1d-2: 15.8 g) was dissolved in 35 mL of a 2 M solution of ammonia in isopropanol. The resulting solution was then treated with 50 mL of a saturated aqueous ammonia solution and the resulting mixture heated at 80° C. After 8 hours, the reaction mixture was cooled to ambient temperature and concentrated with a rotary evaporator. The residue was diluted with ethyl acetate and the organic solution was washed twice with water, once with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in heptane to afford the title compound (I-1e-2).
Reaction SMILES: [F:1][C:2]1(F)[C:7]([N:8]2[CH2:13][CH2:12][C:11]([F:16])([CH2:14][OH:15])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH2:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[F:16][C:11]1([CH2:14][O:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1
Reactant: CC(=O)NC[C@H]1CN(C2=CC=C(N3CCC(F)(CO)CC3)C(F)(F)C2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(COS(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Yield: 75 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[3-fluoro-4-(4-fluoro-4-hydroxymethyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.76 mmol) with methanesulfonyl chloride (0.91 mmol) in dichloromethane (10 ml) at 10° C. in presence of triethylamine (1.3 mmol) followed by purification by using silica gel column chromatography in 75% yield. M.P. 182-183° C. and MS (M+1)=462 (MH+, 100%) M.F.=C19H25F2N3O6S.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11](Br)[CH:12]=[CH2:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[CH:12]=[CH2:11]
Reactant: N#Cc1ccc(O)cc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(C#N)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Fluoro-4-hydroxybenzonitrile (5.00 g, 36.5 mmoles) and allyl bromide (3.47 mL, 40.1 mmoles) in anhydrous DMF (40 mL) were treated with K2CO3 (10.0 g, 72.9 mmoles) and stirred overnight at 80° C. Reaction mixture cooled and diluted with ethyl acetate, washed with H2O (2×) and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound with no further purification.