Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[OH:8].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[C:7]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:2]([Br:1])[CH:3]=1
Reactant: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(Br)c(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C

Procedure:
To a 250 mL round-bottomed flask with a teflon stir bar and a reflux condensor were added methyl (3-bromo-5-formyl-4-hydroxyphenyl)acetate (23.3 g, 85.3 mmol, prepared as described in Reference A above), dichloromethane (100 mL), benzyl bromide (15.32 g, 10.64 mL, 89.59mmol), and N-ethyldiisopropylamine (11.6 g, 15.6 mL, 89.5 mmol). The reaction mixture was heated to reflux for 14 h and then allowed to cool to room temperature. Dichloromethane (100 mL) was added and the organic layer was separated and washed with 200 mL of a 3% solution of NaOH in water. The organic layer was concentrated to give (4-benzyloxy-3-bromo-5-formyl-phenyl)acetic acid methyl ester (30.65 g) as oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[Cl:29][CH2:30][C:31]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20])=[O:32]
Reactant: O=C(Cl)CCl
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.08 h
Yield: 77 %

Procedure:
Triethylamine (0.7 g, 6.5 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.8 g, 2.6 mmol) in THF (50 mL). After stirring for 5 minutes, chloroacetyl chloride (0.4 g, 3.6 mmol) was added slowly. The resulting brown suspension was refluxed overnight. The mixture was cooled and quenched with methanol (1 mL). The mixture was concentrated, and the solid was stirred with 0.5N HCl (30 mL). The mixture was filtered, and the solid was slurried with ethanol (15 mL) to give 2-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.7 g, 76%): 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H), 2.35-2.65 (m, 2H), 2.85-2.94 (m, 1H), 4.19 (s, 2H, CH2), 5.10-5.18 (dd, J=5.1 and 13.3 Hz, 1H, CH), 7.50-7.66 (m, 3H), 8.80 (t, J=5.7 Hz, 1H, NH), 11.01 (s, 1H, NH).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([O:32][CH2:33][CH3:34])([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:27]=[C:26](I)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[CH:29]([CH3:31])[CH3:30])=[CH:14][CH:13]=1)[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br-].[CH:36]1([Zn+])[CH2:40][CH2:39][CH2:38][CH2:37]1.O>CN(C=O)C>[CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:27]=[C:26]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[CH:29]([CH3:31])[CH3:30])=[CH:14][CH:13]=1)([O:32][CH2:33][CH3:34])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: [Zn+]C1CCCC1
Reactant: CCOC([PH2]=O)(c1ccc(Nc2nc(I)nc3c2ncn3C(C)C)cc1)P(=O)(OCC)OCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC([PH2]=O)(c1ccc(Nc2nc(C3CCCC3)nc3c2ncn3C(C)C)cc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To {ethoxy-[4-(2-iodo-9-isopropyl-9H-purin-6-ylamino)-phenyl]-phosphinoylmethyl}-phosphonic acid diethyl ester (0.30 g, 0.48 mmol) in DMF (3.9 mL) was added PdCl2(PPh3)4 (17 mg, 0.024 mmol) followed by cyclopentylzinc bromide (0.5M THF, 3.9 mL, 1.9 mmol). The mixture was stirred at rt for 1 h, poured into water and extracted with EtOAc. The combined extracts, were washed with water, sat'd NaCl, then dried over MgSO4 and filtered. The material was used without purification in the next reaction.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH:9]([S:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH2:10][C:11]([OH:13])=[O:12])[CH2:7][S:8][C@H:3]12.O.CN1CCOCC1.[N:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44](Cl)=[O:45])=[N+:34]=[N-:35]>CC(C)=O>[N:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]([NH:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH:9]([S:14][C:15]3[NH:16][N:17]=[N:18][N:19]=3)[CH2:10][C:11]([OH:13])=[O:12])[CH2:7][S:8][C@H:3]12)=[O:45])=[N+:34]=[N-:35]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12
Reactant: [N-]=[N+]=NCc1ccccc1CC(=O)Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Product: [N-]=[N+]=NCc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Amino-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3 g., 0.008 mole) was suspended in 50 ml. of water. The suspension was cooled to 0° C. and then N-methylmorpholine (3 g., 0.03 mole) was added. After a solution was obtained, 50 ml. of acetone was added. An acetone solution of 2-azidomethylphenylacetyl chloride (prepared from 2 g. of 2-azidomethylphenyl acetic acid and 2 ml. of thionyl chloride in 100 ml. of methylene chloride) was added dropwise at 0° to 5° C. over 10 minutes. The resulting mixture was stirred for one hour and then the acetone was distilled off with the aid of vacuum. The aqueous layer was extracted once with 50 ml. of toluene. To the aqueous layer was added 50 ml. of ethyl acetate and the pH was adjusted to 2.6 using phosphoric acid (85% diluted with equal volume of water). The ethyl acetate layer was carbon treated and dried over anhydrous sodium sulfate. After filtration the solution was concentrated to give 7-(2-azidomethylphenylacetamido)-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-caboxylic acid as a foam-like product which weighed 3.6 g. NMR and IR spectroscopy data were consistent with the expected structure. A small sample was hydrogenated in water using Raney nickel as catalyst to give a product which was identical in every way to an authentic sample of 7-(2-aminomethylphenylacetamido)-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (III).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][F:28])C>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH2:27][F:28])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CCF
Solvent: CCO
Product: O=c1cc(CF)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.464 g, 1.69 mmol), (see Example 28) in ethanol (25 mL) was added 4-fluoro-but-2-ynoic acid ethyl ester (0.22 g, 1.69 mmol) (see Poulter, J Org Chem 1981, 46, 1532). The reaction mixture was heated at reflux for 14 hrs and then gradually cooled to room temperature. The solvent was removed under vacuum, and the residue purified by flash column chromatography (silica gel, 0-2% 7N NH3 in MeOH /CH2Cl2) to afford 0.358g of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-fluoromethyl-2,3-dihydro-oxazolo[3,2 a]-pyrimidin-7-one. [α]D25 −28.20 (c 0.5, CHCl3).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[C:29]2[CH2:33][NH:34][C:35](=[O:37])[CH3:36]>>[OH:7][C:3]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[C:4]=1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:30]1[NH:31][C:32]2[C:28]([C:29]=1[CH2:33][NH:34][C:35](=[O:37])[CH3:36])=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:23]
Reactant: CC(=O)NCc1c[nH]c2c(C)cccc12
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C2(C)C(=O)CC2=O)cc1
Product: CC(=O)NCc1c(C(C2=C(O)C(C)(c3ccc(C)cc3)C2=O)c2ccccc2)[nH]c2c(C)cccc12

Procedure:
Using general procedure C, 2-methyl-2-p-tolyl-cyclobutane-1,3-dione (from Example 4.1) was reacted with benzaldehyde and N-(7-methyl-1H-indol-3-ylmethyl)-acetamide (prepared from 7-methyl-1H-indole-3-carbaldehyde according to Example 10.1-10.3) to give the title compound as an off-white solid. MS: 477.4 ([M−H]−).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:9][CH2:8][NH:7]1.[C:19](Cl)(=[O:21])[CH3:20].N1C=CC=CC=1>CN(C)C=O>[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:9][CH2:8][N:7]1[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: ClCCCC1NCCc2c1[nH]c1ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)N1CCc2c([nH]c3ccccc23)C1CCCCl
Temperature: 5 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
17.1 g (60 millimoles) of 1-(3'-chloropropyl)-1,2,3,4-tetrahydro-β-carboline hydrochloride were dissolved in 240 ml of dimethylformamide while heating, and the solution was then cooled to 5° C. in an ice bath. 11.5 g (150 millimoles) of acetyl chloride and immediately thereafter 23.7 g (300 millimoles) of pyridine were added dropwise to the thoroughly stirred solution, the temperature not rising above 5° C. during this operation. Thereafter, stirring was continued for a further 2 hours at this temperature, after which the reaction mixture was poured onto ice water. The precipitate was filtered off under suction and washed thoroughly with water. 16.9 g (97%) of crystals of melting point 166°-168° C. (ethanol) were isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[N:16]2[CH:17]=[CH:18][CH:19]=[C:15]2[C:14](=[O:20])[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:12]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN(C)C=O>[C:38]([O:37][C:35](=[O:36])[CH2:34][C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[N:16]2[CH:17]=[CH:18][CH:19]=[C:15]2[C:14](=[O:20])[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:12]1=[O:30])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)C1C(=O)N(Cc2ccc(Cl)c(Cl)c2)C(=O)c2cccn21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CC1(C(=O)OCc2ccccc2)C(=O)N(Cc2ccc(Cl)c(Cl)c2)C(=O)c2cccn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred solution of 2-(3,4-dichlorobenzyl)-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid benzyl ester (9.4 g) in anhydrous dimethylformamide (40 ml) was added portionwise sodium hydride (63% dispersion in mineral oil, 0.7 g) under ice cooling, while a stream of nitrogen was passed over the mixture. The resulting mixture was stirred at 25° C. for 1 hour and thereto was added tert-butyl bromoacetate (4.3 g). The mixture was stirred at 25° C. for 15 hours, poured into water, and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (20:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (9.2 g, 78.0%) as colorless crystals, mp 86°-88° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:38][C:36]1[CH:35]=[CH:34][C:33]([CH3:39])=[C:32]([CH:37]=1)[O:31][C:17]1[N:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=2.[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[F:38][C:36]1[CH:35]=[CH:34][C:33]([CH3:39])=[C:32]([CH:37]=1)[O:31][C:17]1[N:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCNCC2)c2ccccc2n1-c1ccccc1
Reaction time: 8 h

Procedure:
A solution of the compound of step 2 (23 mg, 43.4 μmol) in DCM (8 ml) and TFA (2 ml) was stirred at room temperature for 1 h. The solvents were evaporated and the resulting solid dissolved in MOH and water and lyophilized overnight. The title compound was obtained in the form of the [2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone trifluoroacetic acid salt as a white solid. Yield: 21.0 mg.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:43])[C:7]([CH3:42])([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:41]=[CH:40][S:39][CH:38]=2)[CH:32]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)C.C(OC(=O)C(C)(OC1C=CC=CC=1)CC1C=CC(OCCC2N=C(C3CCCCC3)OC=2C)=CC=1)C>C(O)C>[CH:24]1([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][C:7]([CH3:42])([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:41]=[CH:40][S:39][CH:38]=5)[CH:32]=4)[C:6]([OH:43])=[O:5])=[CH:14][CH:13]=3)[N:19]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1cccc(-c2ccsc2)c1
Agent: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2cccc(-c3ccsc3)c2)C(=O)O)cc1
Temperature: 25 °C

Procedure:
5N NaOH (0.5 mL) was added to a solution of 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(3-thiophen-3-yl-phenoxy)-propionic acid ethyl ester and 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionic acid ethyl ester in ethanol (4 mL). The resultant mixture was refluxed under an atmosphere of nitrogen for 2 h, then cooled to ambient temperature. The reaction mixture was concentrated in vacuo, diluted with 1N HCl, and extracted with CH2Cl2. The organic layer was dried through a Varian ChemElut cartridge, concentrated in vacuo, and purified by LCMS. 1H NMR (400 MHz, CDCl3): δ 7.39-7.26 (m, 5H), 7.17 (d, 2H, J=8.60 Hz), 7.11-7.10 (m, 1H), 6.82-6.80 (m, 1H), 6.78 (d, 2H, J=8.60 Hz), 4.11 (t, 2H, J=6.26 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.13 (d, 1H, J=14.08 Hz), 2.93 (t, 2H, J=6.26 Hz), 2.87-2.81 (m, 1H), 2.28 (s, 3H), 1.99 (d, 2H, J=12.51 Hz), 1.77 (d, 2H, J=12.51), 1.67 (d, 2H, J=12.51), 1.57-1.46 (m, 2H), 1.45 (s, 3H), 1.37-1.19 (m, 2H). MS [ES+] m/z exact mass calcd for C32H36NO5S 546.2314, found 546.2308.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH:6]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])([CH3:8])[CH3:7]>CN(C=O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([NH:9][CH:6]([CH3:8])[CH3:7])(=[O:12])=[O:11])=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: CC(C)NS(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1
Reaction time: 18 h

Procedure:
288.8 mg (1.28 mmol) of tin(II) chloride dihydrate are added to a solution of 100 mg (0.26 mmol) of N-isopropyl-4′-nitrobiphenyl-4-sulfonamide (Example 11A) in 2.0 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated in vacuo and dried under high vacuum. 47 mg (63.2% of theory) of the title compound are obtained.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(OC(C)(C)C)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:32]1([C:35]2[C:36]([O:49][CH2:50][C:51]34[C:57]([F:59])([F:58])[CH:56]3[CH2:55][CH2:54][CH2:53][CH2:52]4)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=2)[C:40]([O:42]C(C)(C)C)=[O:41])[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[C:36]([O:49][CH2:50][C:51]34[C:57]([F:59])([F:58])[CH:56]3[CH2:55][CH2:54][CH2:53][CH2:52]4)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=2)[C:40]([OH:42])=[O:41])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Product: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 6, and making variations as required to replace tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo[4.1.0]heptan-1-yl)-methoxy)-2-fluorobenzoate, the title compound was obtained as a beige solid (0.12 g, 79%): MS (ES+) m/z 341.0 (M+1).
Reaction SMILES: O1C=CC(NC[C@@H:8]2[O:12][C:11](=[O:13])N(C3C=CC(N4CC[C@H](NC(=O)C)C4)=C(F)C=3)C2)=N1.Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][N:49]([C:58]4[CH:62]=[CH:61][O:60][N:59]=4)C(OCC(Cl)(Cl)Cl)=O)[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1.ClC(OC)=O>>[CH3:8][O:12][C:11]([NH:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][NH:49][C:58]4[CH:62]=[CH:61][O:60][N:59]=4)[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1)=[O:13]
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Reactant: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Agent: COC(=O)Cl
Agent: Cl
Product: COC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4-(3(S)-aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (360 mg, 0.63 mM) and methyl chloroformate gave the desired product (280 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12](O)=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:17])=O.CN(C)C1C=CC=CC=1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([Cl:17])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n(-c2ccc(Cl)nn2)n1
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Cl)n(-c2ccc(Cl)nn2)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the mixture of 12.6 /0.04 moles/ of 3-chloro-6-(3-methyl-5-hydroxy-1-pyrazolyl)-pyridazine and 48 ml of phosphorus oxychloride, 7.28 g /0.04 moles/ of dimethyl aniline are dropped under stirring at 0° C. during half an hour, then the reaction mixture is stirred at room temperature for one hour and at boiling temperature for 2 hours. Excess of the phosphorus oxychloride is evaporated under reduced pressure, then the residue is poured into water and set aside overnight. The separated precipitate is filtered, washed with water and dried. Yield: 10.5 g (93%); m.p.: 123°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:28][C:29]1([CH3:35])[CH2:34][O:33][CH2:32][CH2:31][NH:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:28][C:29]1([CH3:35])[CH2:34][O:33][CH2:32][CH2:31][N:30]1[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:15][N:14]=1)=[O:18]
Reactant: CC1(C)COCCN1
Reactant: O=C(O)c1ccc(C#Cc2cccc(F)c2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCCN1C(=O)c1ccc(C#Cc2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
(50 mg, 0.21 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 1, step 2) was dissolved in DMF (0.5 ml) and Hunig's Base (44 μl, 0.31 mmol, 1.2 equiv.), 3,3-dimethylmorpholine (36 mg, 0.25 mmol, 1.5 equiv.) and TBTU (73 mg, 0.23 mmol, 1.1 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 80:20. The desired (3,3-dimethyl-morpholin-4-yl)[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone (61 mg, 87% yield) was obtained as a light yellow oil, MS: m/e=339.2 (M+H+).
Reaction SMILES: [OH-:1].[Na+].[ClH:3].C(C1[S:7][C:8]2[CH2:9][CH2:10][C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[C:13](=[C:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:14]=2[CH:15]=1)#N.[CH2:27]([OH:29])[CH3:28]>>[ClH:3].[CH3:22][N:19]1[CH2:20][CH2:21][C:16](=[C:13]2[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[CH2:10][CH2:9][C:8]3[S:7][C:28]([C:27]([OH:1])=[O:29])=[CH:15][C:14]2=3)[CH2:17][CH2:18]1
Reactant: CN1CCC(=C2c3ccccc3CCc3sc(C#N)cc32)CC1
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CN1CCC(=C2c3ccccc3CCc3sc(C(=O)O)cc32)CC1
Reaction time: 8 h
Yield: 67 %

Procedure:
A 2 mol/L aqueous sodium hydroxide solution (20 mL) was added to an ethanol (10 mL) solution of Compound 1 (1.5 g, 4.2 mmol), and the mixture was stirred overnight while refluxing and heating. Ethanol was distilled off under a reduced pressure, and 6 mol/L hydrochloric acid was added to the resulting residue. The precipitated crystals were collected by filtration, and sufficiently washed with water. The crystals were dried over phosphorus pentoxide at 50° C. under a reduced pressure, to give 0.96 g (67%) of the captioned compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]([NH2:30])[CH2:28][CH3:29])=[N:25][CH:26]=1>>[CH2:15]([O:14][C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:30][C@H:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][N:25]=3)[CH2:28][CH3:29])[N:7]=2)[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Reactant: CC[C@H](N)c1ccc(F)cn1
Product: CCOc1cc(Nc2nc(N[C@@H](CC)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 28 using 6-chloro-N-(5-ethoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 26) and [(1S)-1-(5-fluoropyridin-2-yl)propyl]amine (Intermediate 35) as the starting materials. LCMS: 402 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 11.00 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 8.10 (d, 1H), 7.60 (m, 1H), 7.20 (m, 1H), 6.30 (m, 1H), 5.80 (s, 1H), 5.00 (m, 1H), 4.10 (q, 2H), 2.00 (m, 2H), 1.40 (d, 3H), 1.10 (t, 3H).