Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[O:33]1[C:37](B(O)O)=[CH:36][C:35]2[CH:41]=[CH:42][CH:43]=[CH:44][C:34]1=2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C>[O:33]1[C:34]2=[CH:44][CH:43]=[CH:42][C:41]2=[CH:35][CH:36]=[C:37]1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:14][C:12](=[O:13])[CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=1)[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccc(I)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccccc2-c2ccc3cccc-3o2)cc1
Temperature: 125 °C
Reaction time: 0.1 h
Yield: 80 %

Procedure:
To 2-(4-tert-Butyl-phenyl)-N-(4-iodo-phenyl)-3-(4-nitro-phenyl)-propionamide (1056 mg, 2 mmol) in 8 ml 1,2-dimethoxyethane, 4 ml ethanol, and 2 ml water was added benzo[b]furan-2-boronic acid (972 mg, 6 mmol), bis(tri-o-tolylphosphine)palladium(II)dichloride (158 mg, 0.2 mmol), and sodium carbonate (1060 mg, 10 mmol). The reaction mixture was stirred at 125° C. for 6 min, filtered, and concentrated. Chromatography of the residue (20% ethyl acetate in hexane) afforded N-(4-Benzofuran-2-yl-phenyl)-2-(4-tert-butyl-phenyl)-3-(4-nitro-phenyl)-propionamide as a yellow foam (830 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:38](=[O:39])[CH2:37][C:32]2[NH:31][C:30]3[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=3[S:34](=[O:35])(=[O:36])[N:33]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (100.6 mg, 0.345 mmol) in N,N-dimethylformamide (3.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 120.8 mg, 0.362 mmol), 4-dimethylaminopyridine (10.6 mg, 0.086 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (70.9 mg, 0.362 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo, and dried under high vacuum to afford the crude product, (1S,2R,3S,4R)-3-{(4-fluorobenzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a faintly yellow oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C27H31FN4O7S2 606.16, found 607.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:25][CH2:26][CH2:27][C:28](Cl)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O1CCCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:7]2[N:6]([CH2:28][CH2:27][CH2:26][Cl:25])[C:5]3[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][C:4]=3[CH2:10][CH2:9][C:8]=2[CH:11]=1
Reactant: Brc1ccc2c(c1)CCc1cc(Br)ccc1N2
Reactant: O=C(Cl)CCCl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: ClCCCN1c2ccc(Br)cc2CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
2,8-Dibromo-10,11-dihydro-5H-dibenz[b,f]azepine (1.41 g. 4.0 mmol, prepared according to K. Smith et al., Tetrahedron, 48, 7479 (1992)), was dissolved in toluene (25 ml). Triethylamine (0.60 ml, 4.4 mmol) and 3-chloropropionyl chloride (0.50 ml, 5.2 mmol) were added to thee stirred solution at room temperature. Stirring was continued at room temperature for 1 h and at reflux temperature for 2.5 h. The reaction mixture was cooled, filtered and evaporated in vacuo. The crude 3-chloro-1-(2,8-dibromo-10,11-dihydro-5H-dibenz[b,f]-azepine-5-yl)propan-1-one was used in the next step without further purification. A solution of lithium aluminium hydride (0.326 g, 8.56 mmol) in dry tetrahydrofuran (30 ml) was cooled in an ice bath and concentrated sulphuric acid (0.428 g, 4.28 mmol) was added dropwise. The solution was stirred at room temperature for 0.5 h. A solution of the above product (1.90 g, 4.28 mmol) was added dropwise and stirring was continued for 0.5 h. The reaction was then quenched by careful addition of ethyl acetate (5 ml) followed by water (0.8 ml). Filtration of the mixture and evaporation of the filtrate in vacuo afforded 1.51 g (82%) 2,8-dibromo-5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine as a foam, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][OH:32])=[CH:30][C:25]=2[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH:16]1([C:14]2[N:13]([CH3:19])[C:12]3[CH:20]=[C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:32][CH2:31][C:29]5[CH:28]=[CH:27][C:26]6[O:22][CH2:23][CH2:24][C:25]=6[CH:30]=5)=[CH:3][C:4]4=[O:21])[CH:9]=[CH:10][C:11]=3[N:15]=2)[CH2:18][CH2:17]1
Reactant: OCc1ccc2c(c1)CCO2
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc5c(c4)CCO5)cc3=O)cc21
Temperature: 100 °C
Yield: 29 %

Procedure:
A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (2,3-dihydrobenzofuran-5-yl)methanol (100 mg), cesium carbonate (326 mg) and DMF (3 ml) was heated at 100° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (40 mg) as a white solid.
Reaction SMILES: [Br-].[C:2]([C:6]1[CH:31]=[CH:30][C:29]([C:32]([O:34]C)=[O:33])=[CH:28][C:7]=1[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:4]C)=[O:3].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O.C(#N)C.C1(C2CCCCCCCC=2)CCCCCCNN=1>O>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)/[CH:41]=[CH:8]/[C:7]1[C:6]([C:2]([OH:4])=[O:3])=[CH:31][CH:30]=[C:29]([C:32]([OH:34])=[O:33])[CH:28]=1
Reactant: COc1cccc(C=O)c1
Reactant: COC(=O)c1ccc(C(=O)OC)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: C1=C(C2=NNCCCCCC2)CCCCCCC1
Agent: [Br-]
Solvent: O
Solvent: CC#N
Product: COc1cccc(/C=C/c2cc(C(=O)O)ccc2C(=O)O)c1

Procedure:
20 G. of 2,5-bis(carbomethoxy)benzyltriphenylphosphonium bromide and 7.65 g. of m-methoxybenzaldehyde were added to 100 ml of acetonitrile and 22 ml of diazabicyclononene was added. After 16 hours the mixture was added to water and extracted with ethyl acetate. The extract was washed, dried and evaporated. The residue was refluxed for 1 hour in 250 ml of methanol and 250 ml of water containing 10 g. of potassium hydroxide. The solution was cooled and extracted with chloroform. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed, dried and evaporated to afford cis and trans 3'-methoxystilbene-2,5-dicarboxylic acid. 7.8 G. of this compound was hydrogenated for 11/2 hours in 800 ml of ethanol containing 1.5 g. of 5% palladium on carbon catalyst. The solution was filtered and evaporated to give 2-(m-methoxyphenethyl)-benzene-1,4-dicarboxylic acid which was cyclized according to the procedure set forth in Example I, A to afford 2-carboxy-8-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 220°-222° C. Similarly, other 8-substituted compounds of this invention may be obtained by reacting 2,5-bis(carbomethoxy) benzyltriphenylphosphonium bromide with a m-substituted benzaldehyde having a halogen such as fluoro, chloro or bromo, a lower alkyl of 1-4 carbons, or a lower alkoxy such as ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentyloxy, n-hexyloxy and the like. By reacting an o-substituted benzaldehyde or a p-substituted benzaldehyde with 2,5-bis(carbomethoxy) benzyltriphenylphosphonium bromide a 2-carboxy-9-substituted-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene or a 2-carboxy-7-substituted 10,11-dihydro-5-oxo-5 H-dibenzo[a,d]cycloheptene is obtained, respectively. For example 2-carboxy-7-methyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p of 235° C. was obtained from p-methylbenzaldehyde; 2-carboxy-8-methyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 196°-197° C. was obtained from m-methylbenzaldehyde; and 2-carboxy-9-methyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 232°-234° C. was obtained from o-methylbenzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].F[C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([F:26])=[CH:19][C:18]=1[F:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:22]1[CH:17]=[C:18]([F:27])[CH:19]=[C:20]([F:26])[C:21]=1[N+:23]([O-:25])=[O:24])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and 1,2,4-Trifluoro-5-nitro-benzene (0.559 ml, 4.87 mmol) are dissolved in 10 ml of dimethylformamide. After addition of potassium carbonate (1.3 g, 9.74 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=12.C(N(CC)C(C)C)(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.[Cl-].[Li+]>CN1CCCC1=O>[CH3:42][C:39]([O:38][C:36]([N:33]1[CH2:34][CH2:35][CH:30]([NH:29][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]3[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=23)[CH2:31][CH2:32]1)=[O:37])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C

Procedure:
A solution of ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (14.8 g, 52.6 mmol, e.g. which can be as prepared in Intermediate 3, first or alternative preparation thereof) in N-methyl-2-pyrrolidinone (140 ml) was treated with N,N-diisopropylethylamine (22.9 ml, 131 mmol) followed by 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (11.6 g, 57.9 mmol, commercially available e.g. from AstaTech) and the mixture was heated at 120° C. for 24 hours. The reaction mixture was cooled and poured into aqueous lithium chloride solution (5% LiCl, 1 L) and the aqueous phase was extracted with ethyl acetate (3×250 ml). The combined organic extracts were dried (Na2SO4) and the solvent was evaporated. The residue, an oil, was purified by column chromatography using a column of silica gel (ART9385, 500 ml) made up in 4:1 hexane:ethyl acetate, eluting with 4:1 hexane:ethyl acetate (500 ml) and then 2:1 hexane:ethyl acetate until the product eluted. The fractions containing the product were pooled and the solvent was evaporated to give the title compound (18.55 g) as an oil which solidified on standing. LCMS m/z 446 [MH+]; TRET=3.69 min.
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:13])=O>>[C:1]1([CH2:7][C:8]([Cl:13])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(=S)Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: S=C(Cl)Cc1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A quantity of 762 g (4.536 mol) of 2-phenylthioacetic acid is stirred at room temperature for 3 hours with thionyl chloride (375 ml, 5.14 mol), then stirred at 40° C. for 3 hours. Rotary evaporation followed by bulb-to-bulb distillation gives 777 g (4.166 mol, 92%) of 2-phenylthioacetyl chloride.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[OH:3].[OH2:7]>>[CH2:4]([OH:7])[C@@H:2]([OH:3])[C@H:1]([OH:6])[C@H:4]([OH:7])[C@@H:2]([OH:3])[CH2:1][OH:6]
Reactant: O
Reactant: CC(O)C(=O)O
Product: OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO

Procedure:
It appeared that the fatty acid soap could be well acidified with 3-5 parts by weight of lactic acid per 100 parts by weight of reaction product. In example XXIII poorly water-soluble crystals of non-esterified dulcitol, which formed in the first water extraction, are eliminated by filtration.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([OH:20])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3].O.C(=O)([O-])O.[Na+].[C:29]([O:35][CH2:36]I)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:18]([O:20][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:19])=[C:8]([C:10]3[N:11]4[CH:17]=[N:16][CH:15]=[C:12]4[S:13][CH:14]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3csc4cncn34)C[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3csc4cncn34)C[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 42.1 mg of (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylic acid 10 ml of water was added 1.3 ml of a 0.1 N aqueous sodium hydrogen carbonate solution, and the mixture was stirred at room temperature for 1 hour to form a solution, which was then lyophilized. The lyophilized product was dissolved in 1 ml of dry DMF, 0.034 ml of iodomethyl pivalate was added under the atmosphere of argon at −30° C., and the mixture was stirred for 1.5 hours during which the temperature was raised up to −10° C. The reaction mixture was diluted with 20 ml of ethyl acetate, and washed with semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 3 ml, The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=15:1) and on Sephadex LH-20 (chloroform:methanol=1:1) in this sequence to give 27.2 mg of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9]2[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH:15]([CH3:17])[CH3:16])[S:5]1(=[O:19])=[O:18].[F:20][C:21]1[CH:29]=[C:28]2[C:24]([C:25]([C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH:31]=3)=[CH:26][NH:27]2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[F:14][C:10]1[C:9]2[N:4]([CH2:3][CH2:2][N:33]3[CH2:34][CH2:35][C:30]([C:25]4[C:24]5[C:28](=[CH:29][C:21]([F:20])=[CH:22][CH:23]=5)[NH:27][CH:26]=4)=[CH:31][CH2:32]3)[S:5](=[O:19])(=[O:18])[N:6]([CH:15]([CH3:17])[CH3:16])[CH2:7][C:8]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: CC(C)N1Cc2cccc(F)c2N(CCCl)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)N1Cc2cccc(F)c2N(CCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)S1(=O)=O
Temperature: 100 °C

Procedure:
A suspension of 1-(2-chloroethyl)-3,4-dihydro-8-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (1.35 g), 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (31.45 g, 6.7 mmol) and Na2CO3 (3.6 g, 34.6 mmol) in water (8 ml) was heated at 100° C. under argon atmosphere for 30 hours. After cooling to room temperature the product was extracted with dichloromethane. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by flash chromatography using as eluent CH2Cl2 /MeOH (97:3) yielding 3,4-dihydro-8-fluoro-1-{2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide as a pale brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[N:3]=1.[NH4+:10].[Cl-]>C1(C)C=CC=CC=1>[Br:9][C:4]1[N:3]=[C:2]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:10]=2)[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(Br)nc(Br)c1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2cc(C)cc(Br)n2)c1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Dibromocompound 2,6-dibromo-4-methylpyridine (1 mmol), 2-tributylstannyl-picolines (1 mol) and (Ph3Ph)4Pd (0.01 equiv) were heated under N2 in toluene (50 mL) for 16 h. Upon cooling to room temperature aqueous saturated NH4Cl solution (20 mL) was added. The mixture was stirred for further 30 min and then filtered over Celite. The precipitate was washed with CH2Cl2 (50 mL) and the organic phase was separated. The aqueous phase was extracted with toluene. The combined organic phases were dried (MgSO4) and the solvent was removed. Concentrated HCl (30 mL) was added to the residue followed by extracting with CH2Cl2. The aqueous phase was cautiously neutralized by solid NaOH. The product was then extracted with CH2Cl2 and dried. The solvent was removed and the product purified by chromatography on silica gel with CH2Cl2/hexane (1:2) as eluent. Yield: 25%. Anal. C12H11BrN2: Calcd: C, 54.77; H, 4.21; N, 10.65. Found: C, 54.54; H, 4.30; N, 10.45. MS (ESIMS): m/z: 262.0.
Reaction SMILES: C(Cl)Cl.Cl.[CH3:5][C:6]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[N:20][O:21][CH3:22])[C:17]([NH2:19])=[O:18]>O>[CH3:5][C:6]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[C:16](=[N:20]\[O:21][CH3:22])/[C:17]([NH2:19])=[O:18]
Reactant: CON=C(C(N)=O)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CO/N=C(/C(N)=O)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
Methylene chloride (60 ml) and conc. hydrochloric acid (20 ml) were added to 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (Z=at least 98%) (6.25 g, 0.02 mol), and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, water (150 ml) was added. The mixture was extracted with methylene chloride (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crystals. The crystals were recrystallized from n-hexane/ethyl acetate to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (5.41 g, Yield: 86.7%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3[CH:22]=[CH:21][O:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH:32]([F:34])[F:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:33][CH:32]([F:34])[O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][O:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3[CH:22]=[CH:21][O:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: FC(F)Oc1ccccc1CBr
Reactant: Cn1cc(-c2cc(O)cc(S(C)(=O)=O)c2)c2ccoc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(OCc3ccccc3OC(F)F)cc(S(C)(=O)=O)c2)c2ccoc2c1=O
Temperature: 80 °C
Yield: 57.8 %

Procedure:
A capped mixture of 4-(3-hydroxy-5-methylsulfonylphenyl)-6-methylfuro[2,3-c]pyridin-7-one (25 mg, 0.08 mmol), 1-(bromomethyl)-2-(difluoromethoxy)benzene (28 mg, 0.12 mmol), and Cs2CO3 (50 mg, 0.15 mmol) in DMF (900 uL) was heated to 80° C. for 3 h. The mixture was filtered and the filter cake was washed with ACN (500 uL), the filtrate was purified by prep-HPLC to afford the title compound (22 mg, 58%) as a white solid. LCMS (M+H)+=476.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][C:17]([NH:19][CH2:20][C@H:21]2[O:25][C@@H:24]([N:26]3[CH:33]=[C:32]([CH2:34][CH3:35])[C:30](=[O:31])[NH:29][C:27]3=[O:28])[CH2:23][C@@H:22]2[OH:36])=[O:18])=[C:11]([CH3:37])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:34]([C:32]1[C:30](=[O:31])[NH:29][C:27](=[O:28])[N:26]([CH:33]=1)[C@@H:24]1[O:25][C@H:21]([CH2:20][NH:19][C:17](=[O:18])[CH2:16][C:12]2[C:13]([CH3:15])=[CH:14][C:9]([OH:8])=[CH:10][C:11]=2[CH3:37])[C@@H:22]([OH:36])[CH2:23]1)[CH3:35]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3c(C)cc(OCc4ccccc4)cc3C)O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3c(C)cc(O)cc3C)O2)c(=O)[nH]c1=O
Yield: 76 %

Procedure:
24 mg of 5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridine were dissolved in 50 ml of methanol and the solution was hydrogenated over 15 mg of 5% palladium-on-charcoal catalyst at room temperature and under atmospheric pressure for 72 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 15 mg of 2',5'-dideoxy-5-ethyl-5'-[2-(4-hydroxy-2,6-dimethylphenyl)acetamido]uridine of melting point 221°-225° C. (decomposition).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]1[C:26]([C:32](O)=[O:33])=[N:27][CH:28]=[C:29]([F:31])[CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:26]3[C:25]([F:24])=[CH:30][C:29]([F:31])=[CH:28][N:27]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ncc(F)cc1F
Product: C[C@@]1(c2cc(NC(=O)c3ncc(F)cc3F)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R1=Me) and 3,5-difluoro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.