Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[OH:2][C:3]([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[C:4]#[N:5].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C)C=O>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:2][C:3]([C:6]([F:7])([F:9])[F:8])([C:10]([F:11])([F:12])[F:13])[C:4]#[N:5])=[CH:17][CH:16]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: N#CC(O)(C(F)(F)F)C(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Product: N#CC(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionitrile sodium salt (43 g.), 4-chlorobenzyl chloride (25.6 g.) and dimethylformamide (200 ml.) is stirred at ambient temperature for 5 days, then evaporated in vacuo. Water is added to the residue, and the mixture is extracted with 1,2,2-trichloro-1,1,2-trifluoroethane. The extract is dried with sodium sulphate, and evaporated. The residue is distilled to give 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionitrile, b.p. 54°-64° C. at 1 mm. pressure (41.0 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11][OH:12]>>[CH3:11][O:12][C:3](=[O:2])[CH2:4][CH2:5][NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: CO
Product: COC(=O)CCNCc1ccc(OC)cc1

Procedure:
A solution of p-methoxybenzyl amine (690 mg, 722 μL, 8.01 mmol) in dry methanol (5 ml), under nitrogen was cooled to 0° and treated drpwise with a solution of metacrylate (951 μL, 1.0 g, 7.28 mmol) in MeOH (1.0 ml) added over 2 min. After 15.5 h the clear solution was distilled at atmospheric pressure to remove MeOH. The high boiling residue (>170) formed 3-(4-Methoxy-benzylamino)-propionic acid methyl ester (1.88 g, Quantitative) 1H (300 MHz, CDCl3) 1.78 (bs, 1H), 2.45 and 2.53 (t, J=3.0 Hz, 2H), 2.77 and 2.87 (t, J=3.0 Hz, 2H), 3.46 and 3.67 (s, 3H), 3.64 and 3.73 (s, 3H), 3.88 (m, 2H), 6.78 and 6.85 (m, 2H), 7.17 and 7.23 (m, 2H).
Reaction SMILES: [Mg].Br[CH:3]1[CH2:5][CH2:4]1.[C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)#N.C([O:16]CC)C>II>[CH:3]1([C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:16])[CH2:5][CH2:4]1
Reactant: N#Cc1ccncc1
Reactant: CCOCC
Reactant: BrC1CC1
Agent: II
Agent: [Mg]
Product: O=C(c1ccncc1)C1CC1
Reaction time: 3 h
Yield: 43 %

Procedure:
Dry magnesium powder (0.760 g, 31.2 mmol), which had been previously crushed in a mortar with a pestle, was charged into a dry round bottom flask under a nitrogen atmosphere. To this was added diethyl ether (20 mL), followed by bromocyclopropane (3.77 g, 2.49 mL, 31.2 mmol). A small amount of iodine (0.002 g) was added to initiate formation of the Grignard reagent. The reaction was heated to a gentle reflux for a short period of time (˜1 hour) until all of the magnesium metal had reacted. The flask was then cooled in an ice bath and to this was added 4-cyanopyridine (1.62 g, 15.6 mmol). The mixture was stirred for 3 hours, and then carefully quenched with sat. ammonium chloride (3 mL). The reaction was then acidified with 15% aq. hydrochloric acid (3 ML). The mixture was stirred for 20 minutes, and then made basic by the addition of 10 N sodium hydroxide until the pH was approximately 9. To this solution was added ethyl acetate (300 mL), and the aqueous layer was extracted with water (30 mL). The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness giving the title compound as a yellow oil (1.0 g, 43%). 1H NMR (300 MHz, DMSO-d6): δ 1.15 (m, 4H); 2.93 (s, 1H); 7.91 (d, 1H; J=6.0 Hz); 8.83 (d, 1H, J=6.0 Hz).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1[C:21]([NH2:25])=[N:22][O:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]=[C:12]1[C:20]1[C:21]([NH2:25])=[N:22][O:23][N:24]=1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccccc1

Procedure:
Phenacylbromid (0.1 g, 0.49 mmol) is added to an efficiently stirred suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.1 g, 0.4 mmol) [A. V. Sergievskii, O. A. Krasnoshek, S. F. Mel'nikova, I. V. Tselinskii, Russian Journal of Organic Chemistry, 2002, 38, 915-917] and potassium carbonate (0.172 g, 1.24 mmol) in dry DMF (5 ml) at room temperature. After 4 hours the reaction mixture is diluted with ethyl acetate and the organic phase is washed repeatedly with brine. Drying of the solvent, filtering and evaporation of the solvent under reduced pressure gives the title compound in crude form. The title compound is obtained in pure form by chromatography over silicagel, m.p. 202-204° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].OC1CCCO1.[CH3:13][CH:14]([CH2:17][OH:18])[CH:15]=[O:16].[H][H]>O>[CH2:5]([OH:6])[CH2:4][CH2:3][CH2:2][OH:1].[CH3:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16]
Reactant: O=CCCCO
Reactant: CC(C=O)CO
Reactant: [H][H]
Agent: OC1CCCO1
Solvent: O
Product: CC(CO)CO
Product: OCCCCO
Reaction time: 0.5 h

Procedure:
420 ml of the solution containing 4-hydroxy-butanal, 2-hydroxy-tetrahydrofuran, and 2-methyl-3-hydroxypropanal was charged to a stainless jacket-stirring reactor equipped with a metal powder-sintered filtering core followed by adding 9.38 g of the thus-obtained hydrogenation catalyst (65% of which has a granularity less than 50 μm). A temperature in the reactor was controlled at 115° C. and a pressure in the reactor was maintained at 60 kg/cm2G by the supply of hydrogen to effect hydrogenation for 2 hours under stirring. After the supply of hydrogen was cut off, the stirring was stopped and the solution was set still for 30 minutes to precipitate the catalyst. The solution was filtrated via the filtering core by the hydrogen pressure in the reactor, then about 400 ml of the top layer of the solution was removed and analyzed by gas chromatograph to obtain a result of 16.64 wt % of 1,4-butanediol, 3.25 wt % of 2-methyl-1,3-propanediol, 80.11 wt % of other reactants and water. Another 400 ml aqueous solution of 4-hydroxy-butanal, 2-hydroxy-tetrahydrofuran, and 2-methyl-3-hydroxypropanal was then added to the reactor and subjected to hydrogenation for 2 hours under the same condition. This process was repeated for 50 batches. The conversion thereof was maintained consistently at about 95-98%, which was calculated by the results obtained from gas chromatograph (GC) according to the following equation: ##EQU1## wherein HBA1 represents the concentration of the solution of 4-hydroxy-butanal, 2-hydroxy-tetrahydrofuran, and 2-methyl-3-hydroxypropanal obtained ma GC analysis before hydrogenation; and
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:11]1([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ccc(N2CCOCC2)cn1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cn1

Procedure:
5-Morpholin-4-yl-pyridin-2-ylamine was prepared by adapting the procedure described in J. Med. Chem., 2005, 48(7), 2388-2406. Briefly, 5-bromo-2-nitro-pyridine was reacted with morpholine and potassium carbonate in DMSO at 60-70° C. to afford 4-(6-nitro-pyridin-3-yl)-morpholine in 84% yield. Reduction with palladium on carbon under a hydrogen atmosphere provided 5-morpholin-4-yl-pyridin-2-ylamine in 70% yield. This was converted into 3-hydroxy-7-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester in 25% yield by adapting the procedure described in Example 2, where glacial acetic acid was used instead of p-toluenesulphonic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCC1>CO>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18](/[C:19](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH:11]([CH3:13])[CH3:12])/[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: CC(C)Oc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 77.5 %

Procedure:
5-Chloro-2-isopropoxy-benzaldehyde (3 g, 15.1 mmol) and 6-chlorooxindole (2 g, 12.6 mmol) were mixed in anhydrous methanol (30 mL) at room temperature. Then pyrrolidine (1.07 g, 15.1 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-6-chloro-3-(5-chloro-2-isopropoxy-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (3.4 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:4]3[C:9]([S:10][C:11]=2[N:12]=[CH:13][N:14]=1)=[CH:8][CH:7]=[C:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=3.C(=O)([O-])[O-].[K+].[K+].[N:27]1([C@H:33]2[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CC#N>[O:30]1[CH2:29][CH2:28][N:27]([C@H:33]2[CH2:34][CH2:35][C@H:36]([NH:39][C:2]3[C:3]4[C:4]5[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:8][C:9]=5[S:10][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:37][CH2:38]2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)Cc1ccc2sc3ncnc(Cl)c3c2c1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc2sc3ncnc(N[C@H]4CC[C@H](N5CCOCC5)CC4)c3c2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl]acetate (500 mg, 1.63 mmol, 1.00 equiv) in MeCN (100 mL) was added potassium carbonate (2.2 g, 15.92 mmol, 10.00 equiv), TEA (495 mg, 4.89 mmol, 3.00 equiv) and trans-4-(morpholin-4-yl)cyclohexan-1-amine (1.5 g, 8.14 mmol, 5.00 equiv) subsequently at room temperature under nitrogen. The resulting solution was stirred overnight at 80° C. and cooled down to r.t. The reaction was quenched with water, extracted with 3×100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with dichloromethane/methanol (20/1) to give 300 mg (40%) of the corresponding ethyl 2-(4-(((trans)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)acetate as an off-white solid. LCMS: (ES, m/z) 455 (M+H+). 1H-NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 7.88-7.85 (d, 1H), 7.71 (s, 1H), 7.42-7.40 (d, 1H), 5.33-5.31 (d, 1H), 4.30-4.21 (m, 1H), 4.19-4.09 (q, 2H), 3.81 (s, 2H), 3.75 (s, 4H), 2.61 (s, 4H), 2.38 (s, 3H), 2.05 (s, 2H), 1.55-1.52 (d, 2H), 1.45-1.41 (m, 2H), 1.31-1.27 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[CH:5]=1)([O-:3])=[O:2].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:6]([CH3:11])[CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1C
Yield: 102 %

Procedure:
The product was prepared by procedures which are well known in the art, that is, by the alkylation of 4-nitro-2-methylphenol (2.508 g, 0.0164 mol) with ethyl bromoacetate (3.00 g, 0.018 mol) in acetonitrile (50 mL) in the presence of potassium carbonate (2.76 g) to afford ethyl 4-nitro-2-methylphenoxyacetate (4.0 g, 100%); hydrogenation of the latter (4.0 g, 0.0164 mol) in ethanol (250 mL) in the presence of 10% palladium on carbon (1.0 g) to afford ethyl 4-amino-2-methylphenoxyacetate; which was then dissolved in CH2Cl2 (50 mL) and treated with pyridine (4.0 mL), followed by methanesulfonyl chloride (1.88 g) in CH2Cl2 (5.0 mL) to afford 3.27 g (69.4%) of N-[4-(ethoxycarbonylmethoxy)-3-(methyl)phenyl]methanesulfonamide, m.p. 83°-84° C., after purification by column chromatography on silica.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](O)=[O:8].[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([NH:28][C:7]([C:6]1[C:5]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)=[CH:13][C:4]=2[O:3][C:2]=1[CH3:1])=[O:8])[CH2:25][CH2:26][CH3:27]
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Reactant: CCCCN
Product: CCCCNC(=O)c1c(C)oc2cc(Oc3ccnc4ccsc34)ccc12

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic acid 100 and butylamine in a similar manner as that described for example 102. 1H NMR (CD3CN) δ 8.48 (1H,d, J=5.3 Hz), 7.91 (1H, d, J=5.6 Hz), 7.81 (1H, d, J=8.6 Hz), 7.53 (1H, d, J=5.6 Hz), 7.41 (1H, d, J=2.3 Hz), 7.20 (1H, dd, J=8.6, 2.3 Hz), 6.62 (1H, d, J=5.3 Hz), 6.62 (1H, bm), 3.40 (2H, q, J=6.9 Hz), 2.65 (3H, s), 1.60 (2H, m), 1.42 (2H, m), 0.97 (3H, t, J=7.3 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>[I-].[K+].CC(C)=O>[CH2:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc2ccc(O)cc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2ccc(C(=O)OCC)cc2c1
Reaction time: 15 h
Yield: 81 %

Procedure:
A mixture of ethyl 7-hydroxynaphthalene-2-carboxylate (37.5 g), anhydrous potassium carbonate (24.0 g), potassium iodide (0.5 g), and allyl bromide (29.0 g) was heated in refluxing acetone (200 ml) with stirring for 15 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in ethyl-acetate, washed with 2% sodium hydroxide solution and water, dried and evaporated to give a solid. Crystallisation from petroleum ether (b.p. 40-60) afforded ethyl 7-allyloxynaphthalene-2-carboxylate (36 g), m.p. 60°-61°.
Reaction SMILES: [CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH2:8].C1(C)C=C[C:12]([S:15](O)(=O)=O)=[CH:11]C=1>CC(C)=O.O>[CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([S:15][CH2:12][CH:11]=[O:8])[CH:2]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1=CCCCCC1
Solvent: CC(C)=O
Product: O=CCSC1C=CCCCC1
Yield: 100 %

Procedure:
A solution of 108.13 g (0.443 mole) of 3-[2,2-diethoxyethyl)thio]-1-cycloheptene in 1000 ml of acetone/water, 9:1 was treated with 1.1 g of p-toluenesulfonic acid hydrate and heated under reflux for 1.0 hour, cooled, and concentrated. The residue was partitioned between ether/10% sodium bicarbonate. The aqueous phase was further extracted with ether. The organic extracts were pooled, dried over magnesium sulfate, and evaporated to afford 75.30 g (0.443 mole, 100%) of 2-[(1-cyclohepten-3-yl)thio]acetaldehyde as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([F:17])[CH:6]=1)[C:3]#[N:4].[S]>C1(OC2C=CC=CC=2)C=CC=CC=1.CC(C)=O>[CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([F:17])[CH:6]=1)[C:3]#[N:4]
Reactant: CC(C#N)c1ccc(C2CCCCC2)c(F)c1
Agent: [S]
Solvent: CC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C#N)c1ccc(-c2ccccc2)c(F)c1
Temperature: 250 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A mixture of 6.93 g of α-methyl-4-cyclohexyl-3-fluorophenylacetonitrile (nD20 1.5182) and 3.46 g of sulphur in 15 ml of diphenyl ether was subjected to heating with stirring at 250° C. for 4 hours. The resulting reaction liquid was diluted with acetone, and the insoluble substances therein were removed by filtration. The filtrate was concentrated and then distilled to obtain 5.06 g of α-methyl-(2-fluoro-4-biphenylyl)acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(-c2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
Platinum(IV) oxide (9.7 mg) was added to a solution of 9-(3′-methoxybiphenyl-4-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (17.4 mg) in THF (dry) (15 mL) and MeOH (15 ml) and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Silica-gel was added to the filtrate and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (6.5 mg) as colorless gum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].Cl.[Br:13][C:14]1[CH:21]=[CH:20]C=C[C:15]=1[CH2:16]N.N1C=CC=CC=1.C([N:30]([CH2:33][CH3:34])CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Br:13][C:14]1[CH:21]=[CH:20][C:34]([CH2:33][NH:30][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: NCc1ccccc1Br
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(NCc1ccc(Br)cc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
2-Bromobenzenesulfonyl chloride [(X), 5.9 g, 23.5 mmol] was added dropwise to a stirred 0° C. suspension of 2-bromobenzylamine hydrochloride [(II), R=(4-bromophenyl)methyl, 4.79 g, 19.6 mmol], pyridine (7.9 mL, 97.9 mmol) and 4-dimethylaminopyridine (0.23 g, 1.96 mmol) in dichloromethane (10 mL). The reaction mixture was then stirred at room temperature for 1 hour, then triethylamine (2.73 mL, 19.6 mmol) was then added at 0° C. After stirring overnight at room temperature, the reaction was diluted with dichloromethane (100 mL) then washed with water (50 mL), 0.5N HCl (2×50 mL), water (50 mL), saturated aq. NaHCO3 (2×50 mL) and water (50 mL). The dichloromethane solution was dried (brine, MgSO4) and silica gel (80 mL) was added. The solution was concentrated and the adsorbate was flash chromatographed (4:1 petroleum ether:ethyl acetate) to provide the title compound as a white solid (5.92 g, 75%): mp 108°-110° C.; NMR (CDCl3, 300 MHz): d 8.08 (m, 1H, ArH), 7.70 (m, 1H, ArH), 7.55-7.30 (m, 4H, ArH), 7.08 (d, 2H, ArH), 5.42 (t, 1H, NH), 4.07 (d, 2H, CH2); Anal. (C13H11Br2NO2S) C, H, N.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][NH:14][C:15](=[O:29])[NH:16][CH:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C:18]([OH:20])=O)=[CH:11][CH:10]=1)=O)(C)(C)C.[OH:32][C:33]1[C:41]2[N:40]=NNC=2C=CC=1.[CH:42](N(C(C)C)CC)(C)[CH3:43].CN(C)CCCN=C=NCC>CN(C=O)C>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]([NH:16][CH:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C:18]([N:40]2[CH2:41][CH2:33][O:32][CH2:43][CH2:42]2)=[O:20])=[O:29])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)NC(Cc2cccc(O)c2)C(=O)O)cc1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: Nc1ccc(CNC(=O)NC(Cc2cccc(O)c2)C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
Acid derivative 175 (1 equivalent) was dissolved in 2 ml of DMF. Amine (1.1 equivalent), Hydroxybenzotriazole (HOBO (1.2 equivalent), diisopropylethylamine (DIEA) (2.2 equivalent) and 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (EDAP) (1.2 equivalent) were added successively and the reaction mixture is stirred for 20 h at room temperature. The reaction mixture is concentrated and 100 ml of AcOEt are added. The organic phase are washed with NaHCO3 saturated, 10% citric acid and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt) to afford the amide as white solid (80 mg, 73%). 1H NMR (DMSO): δ 1.48 (s, 9H), 1.60 (m, 2H), 1.72 (m, 2H), 2.62 (m, 1H), 2.80 (dd, 1H, J=13.4, 5.2 Hz), 3.77 (m, 2H), 3.98 (m, 2H), 4.08 (d, 2H, J=5.3 Hz), 4.90 (m, 1H), 6.14 (d, 1H, J=8.8 Hz), 6.43 (t, 1H, J=5.3 Hz), 6.60 (m, 3H), 7.05 (d, 1H, J=8.5 Hz), 7.08 (d, 2H, J=8.2 Hz), 7.36 (d, 2H, J=8.2 Hz), 9.25 (s, 1H), 9.27 (s, 1H). The protected urea (78 mg) was dissolved in 2 μl of DCM and 2 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture was concentrated and purified by precipitation using AcOEt/Hexane to afford the urea deprotected 176 as yellow solid (75 mg, 92%). HPLC method B tr=15.77 mn (92.3%). ESI-MS m/z: 399.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:23]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1>C1COCC1>[NH2:23][C@H:16]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:11]=1
Reactant: CON(C)C(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@@H](N)Cc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h

Procedure:
To a solution of compound 61 (1.50 g, 2.75 mmol) in THF (20 mL) was added DBU (1.5 mmol, 229 μL). After 10 minutes, TLC analysis indicated complete consumption of starting material. 1 M aq. HCl (30 mL) and EtOAc (25 mL) were added and the layers were separated. The organic layer was extracted with 1 M aq. HCl and the combined aqueous layers were basified with Na2CO3 until pH 10. This layer was extracted with EtOAc (3×) and the latter combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The title compound was obtained as a colorless oil (yield: 0.75 g, 2.34 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ=7.62 (s, 1H), 7.33 (d, J=8.14 Hz, 2H), 7.09 (d, J=8.43 Hz, 2H), 4.02-3.95 (m, 1H). 3.57 (s, 3H), 3.16 (s, 3H), 2.98 (dd, J=13.30, 5.56 Hz, 1H), 2.65 (dd, J=13.25, 7.71 Hz, 1H), 1.93 (s, 2H), 1.49 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3) δ=175.13, 152.66, 137.04, 131.64, 129.29, 118.28, 79.54, 60.96, 52.38, 40.41, 31.82, 27.94 ppm. [α]D23=+19.6 (c=1, CHCl3). HRMS: calcd. for C16H25N3O4 324.19178 [M+H]+. found 324.19193.