Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>ClCCl.CN(C)C=O>[CH2:1]([N:8]([CH2:9][CH2:10][Cl:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCl)Cc1ccccc1
Yield: 79.1 %

Procedure:
33 g of N-benzyl-N-methyl-2-aminoethanol were dissolved in 300 ml of dichloromethane. 48 g of thionyl chloride and 2 drops of dimethylformamide were added to the solution at 0° C. The reaction mixture was then heated under reflux for 6 hours. The reaction mixture was worked up by evaporating it to dryness and taking up the residue three times in 300 ml portions of toluene and again evaporating to dryness. The remaining residue was dissolved in dichloromethane and the N-benzyl-N-(2-chloroethyl)-N-methylamine hydrochloride was crystallized by addition of diethyl ether to the solution. The crystals (m.p. 142° C.-145° C.) were filtered out and dissolved in ice water. The solution was adjusted to alkaline pH 9 by addition of aqueous sodium hydroxide solution and then extracted with toluene. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. 29 g of N-benzyl-N-(2- chloroethyl)-N-methylamine were obtained as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][N:6]=[C:5]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1>[Pd]>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Product: COc1cc(N2CCCC2)ncc1N
Yield: 96.3 %

Procedure:
The method described in Stage 12.2 is followed, starting from 1.5 g (6.72 mmol) of 4-methoxy-5-nitro-2-(pyrrolidin-1-yl)-pyridine, obtained in Stage 6.1, and 0.15 g of palladium on charcoal at 10%. We thus obtain 1.25 g of the expected product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].[NH4+].Cl>CN(C)C=O.CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:16]2[NH:23][N:22]=[N:21][N:17]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Product: c1cc(OCc2ccc3ccccc3n2)cc(-c2nnn[nH]2)c1
Temperature: 140 °C
Reaction time: 7 h
Yield: 48.8 %

Procedure:
A mixture of 8.8 g of 3-(2-quinolylmethyloxy)benzonitrile, 2.3 g of sodium azide and 1.9 g of ammonium chloride in 100 ml of dimethylformamide is stirred at 140° C. for 7 hours. An additional amount of sodium azide (1.2 g) and ammonium (1.0 g) is added and stirring resumed at 140° C. for 17 hours. The mixture is poured over ice and acidified with hydrochloric acid. The crude product solidifies and is filtered off to give 11 g of crude product. The crude product is slurried with hot methanol and filtered off. To a hot solution of this material is added enough water to cause trubidity. On cooling the compound crystallizes and is filtered off to yield 5.0 g of pure material having a M.P. of 200°-205° C. dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[CH3:10])=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Br)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
To a stirred solution of 5-Bromo-pyridine-2-carbaldehyde (10 g, 53.76 mmol) in tetrahydrofuran (200 mL) at 0° C. is added drop wise methyl magnesium bromide (45 mL, 64.51 mmol). Reaction mixture is stirred 0° C. for 6 hours and diluted using saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by combiflash using 25% ethyl acetate in hexane as an eluent to give the title compound (8 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.34 (d, J=6.52 Hz, 3H), 4.66-4.72 (m, 1H), 5.47 (d, J=4.76 Hz, 1H), 7.48 (d, 8.36 Hz, 1H), 8.021 (dd, J1=2.44 Hz, J2=8.44 Hz 1H), 8.58 (d, J=2.36 Hz, 1H). LC-Ms (m/z): 203.9 [M+H].
Reaction SMILES: C(O)C.[C:4]([C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:14][C@H:13]1[NH:23][C:24]([C:26]1[S:27][C:28]2[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=2[N:34]=1)=[O:25])=[O:10])#[N:5].[ClH:39].[NH2:40][OH:41].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C.O1CCCC1>[ClH:39].[NH2:5][C:4](=[N:40][OH:41])[C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[CH2:14][C@H:13]1[NH:23][C:24]([C:26]1[S:27][C:28]2[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=2[N:34]=1)=[O:25])=[O:10]
Reactant: NO
Reactant: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cccc(C#N)c3)sc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cccc(C(N)=NO)c3)sc2C1
Yield: 56.8 %

Procedure:
Ethanol (5.0 mL) and tetrahydrofuran (2.0 mL) were added to the compound obtained in Example 367 (270 mg) for dissoltion, and hydroxylamine hydrochloride (114 mg) and triethylamine (230 μL) were added to the solution at room temperature. The mixture was heated under reflux for 3 hours, and saturated aqueous sodium hydrogencarbonate and methylene chloride were added to the reaction mixture to partition the mixture, followed by extracting the formed aqueous layer with methylene chloride. The extract was combined with the organic layer, and the mixture was dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (methylene chloride:methanol=7:1), a sephadex column (methanol), and fractional reversed phase high performance liquid chromatography (acetonitrile-water-formic acid). The product was converted to a hydrochloride with 1N HCl, and subsequently, the salt was purified through use of a sephadex column (methanol), to thereby yield the title compound (175 mg) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[CH3:7][S:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[O:22][N:21]=[C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH2+:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH2:19]1)(=[O:10])=[O:9].C(N(CC)CC)C.O>ClCCl>[CH3:7][S:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[O:22][N:21]=[C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:3](=[O:4])[CH2:2][Cl:1])[CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH2:19]1)(=[O:9])=[O:10]
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Reactant: O=C(Cl)CCl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CCN(C(=O)CCl)CC3)n2)=NO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
To a solution of chloroacetyl chloride (22 mg) was added, at 0° C., a solution of 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (87 mg) and triethylamine (41 mg) in dichloromethane (1 ml). The reaction mixture was stirred at 0° C. for 15 minutes, and at room temperature for a further 18 hours. Then water was added thereto, and the aqueous phase was removed and extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 2-(3-{2-[1-(chloroacetyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (60 mg, 60%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)C.Cl>C(OCC)(=O)C>[N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH2:6][CH2:5][CH:4]=[O:3])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(CCc1ccc2ncccc2c1)OCC
Agent: Cl
Solvent: CCOC(C)=O
Product: O=CCCc1ccc2ncccc2c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 6-(3,3-diethoxypropyl)quinoline (23, Method A of Example 16, 520 g, 2.08 mol, 1.0 equiv) in ethyl acetate (EtOAc, 2.2 L) was cooled to 0° C. before a 2 N aqueous hydrochloric acid (HCl) solution (2.2 L) was added over 1 h while keeping the reaction temperature below 5° C. The resulting reaction mixture was stirred for an additional 2 h at 0-5° C. When TLC and HPLC/MS indicated the reaction was complete, the reaction was quenched with an ice cold 3 N aqueous sodium hydroxide (NaOH) solution at 0° C. until the pH was between 8 to 9. The layers were separated and the aqueous layer was extracted with ethyl acetate (EtOAc, 2 L). The combined organic layers were washed with brine (2 L), dried with sodium sulfate (Na2SO4), and concentrated under the reduced pressure to afford crude 3-(quinolin-6-yl)propanal (9, 385.3 g, 385.3 g theoretical, 100%) as a yellow oil, which was found to be identical to the material obtained from Method 1 in every comparable aspect. Since this crude material was found to be sufficiently pure, it was used directly in subsequent reaction without further purification.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[N:10][N:9]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=[C:8]2[C:7]=1[NH:21][C@@H:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([O:25]C)=[O:24])(=[O:5])[NH2:4]>CO.C1COCC1>[C:3]([C:6]1[CH:11]=[N:10][N:9]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=[C:8]2[C:7]=1[NH:21][C@@H:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([OH:25])=[O:24])(=[O:5])[NH2:4]
Reactant: COC(=O)[C@@H](Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cnn2cc(-c3ccccc3)cc2c1N[C@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 105.3 %

Procedure:
Sodium hydroxide (11.200 ml, 11.20 mmol) added in one portion to a heterogeneous mixture of (S)-methyl 2-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-2-phenylacetate (Example 121, 900 mg, 2.248 mmol) in MeOH (30 ml) and THF (15 ml). The reaction was allowed to stir at rt for ca. 2.5 hrs before removing the solvent in vacuo and cooling the flask in an ice bath. 1N aq. HCl was added and the yellow precipitate was then filtered and allowed to dry overnight. This afforded the title compound (915 mg, 100%) as a pale yellow solid. HPLC (condition B): retention time=0.87 min. LCMS (condition B): MH+ m/z 387.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (1 H, d, J=7.04 Hz), 8.23 (1 H, s), 8.10 (1 H, d, J=1.54 Hz), 7.66 (2 H, d, J=7.26 Hz), 7.55 (2 H, d, J=7.48 Hz), 7.36 (5 H, q, J=7.92 Hz), 7.12-7.29 (4 H, m), 5.93 (1 H, br. s.).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:9][C:8]1([NH:19][C:20]([O:22][CH3:23])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)(=O)=O.[C-:24]#[N:25].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[C:24]([CH2:6][CH:7]1[CH2:9][C:8]1([NH:19][C:20](=[O:21])[O:22][CH3:23])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)#[N:25]
Reactant: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1COS(C)(=O)=O
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1CC#N
Temperature: 23 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
A mixture of ((1RS,2SR)-2-(methoxycarbonylamino)-2-(3-nitrophenyl)cyclopropyl)methyl methanesulfonate (intermediate B8a) (4.53 g, 13.2 mmol, Eq: 1.00), potassium cyanide (1.11 g, 17.1 mmol, Eq: 1.3) and tetrabutylammonium iodide (486 mg, 1.32 mmol, Eq: 0.1) in DMSO (13 ml) was stirred at 23° C. for 18 h. Poured into ice water, extracted with EtOAc, washed organic layer with brine, reextracted combined aqueous layer with EtOAc, dried combined organic layer over Na2SO4. Removal of the solvent in vacuum left a dark brown oil (8370-1/1; HPLC 1.775 min 60%, 2.070 min 27%, 2.262 min 13%). The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 60% EtOAc in heptane) to give the methyl (1SR,2SR)-2-(cyanomethyl)-1-(3-nitrophenyl)cyclopropylcarbamate (2.318 g, 8.42 mmol, 64.0% yield) as a yellow gum. MS (ISP): m/z=276.1 [(M+H)+].
Reaction SMILES: C[Si](C)(C)[C:3]1[C:16]2[O:15][C:14]([CH3:18])([CH3:17])[S:13][C:12]=2[C:11]([C:19]([C:41]2[C:49]3[S:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=3[C:47]([Si](C)(C)C)=[C:46]3[C:42]=2[S:43][C:44]([CH3:60])([CH3:59])[O:45]3)([C:21]2[C:29]3[S:30][C:31]([CH3:34])([CH3:33])[O:32][C:28]=3[C:27]([Si](C)(C)C)=[C:26]3[C:22]=2[S:23][C:24]([CH3:40])([CH3:39])[O:25]3)[OH:20])=[C:5]2[S:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=12.[I-].[Na+].Cl[Si](C)(C)C.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:39][C:24]1([CH3:40])[S:23][C:22]2=[C:21]([C:19]([C:11]3[C:12]4[S:13][C:14]([CH3:18])([CH3:17])[O:15][C:16]=4[CH:3]=[C:4]4[C:5]=3[S:6][C:7]([CH3:10])([CH3:9])[O:8]4)([C:41]3[C:42]4[S:43][C:44]([CH3:59])([CH3:60])[O:45][C:46]=4[CH:47]=[C:48]4[C:49]=3[S:50][C:51]([CH3:53])([CH3:54])[O:52]4)[OH:20])[C:29]3[S:30][C:31]([CH3:33])([CH3:34])[O:32][C:28]=3[CH:27]=[C:26]2[O:25]1
Reactant: CC1(C)Oc2c(c(C(O)(c3c4c(c([Si](C)(C)C)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c4c(c([Si](C)(C)C)c5c3SC(C)(C)O5)OC(C)(C)S4)c3c(c2[Si](C)(C)C)OC(C)(C)S3)S1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CC1(C)Oc2cc3c(c(C(O)(c4c5c(cc6c4SC(C)(C)O6)OC(C)(C)S5)c4c5c(cc6c4SC(C)(C)O6)OC(C)(C)S5)c2S1)SC(C)(C)O3
Reaction time: 0.33 h

Procedure:
Tris-(8-trimethylsilyl-2,2,6,6-tetramethylbenzo[1,2-d:5,4-d']-bis(1,3)oxathiol-4-yl)methanol (0.62 g, 0.62 mmol) was dissolved in acetonitrile (150 mL). Sodium iodide (0.75 g, 6.0 mmol) and chlorotrimethylsilane (0.65 g, 6.0 mmol) was added in one portion. The mixture was stirred for 20 min and then poured onto diethyl ether/aq. NaHCO3. The aqueous layer was extracted with ether and the combined organic layers were washed twice with water, dried (Na2SO4), evaporated, chromatographed (silica gel; dichloromethane) and finally triturated with ethyl acetate to yield the product as slightly brown crystals.
Reaction SMILES: [O:1]=[C:2]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH2:3][C:4]([O:6]C)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1>C1(C)C(C)=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:21][C:4](=[O:6])[CH2:3][C:2](=[O:1])[C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)CC(=O)c1nccs1
Reactant: COc1cccc(N)c1
Solvent: Cc1ccccc1C
Product: COc1cccc(NC(=O)CC(=O)c2nccs2)c1
Reaction time: 6 h

Procedure:
To 30 mL of a xylene solution containing 2.3 g of methyl 3-oxo-3-(1,3-thiazol-2-yl)propionate, 1.4 mL of m-anisidine was added. The reaction mixture was stirred for 6 hours under reflux by heating. The solvent was removed under reduced pressure, and water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 3.3 g of a brown oily substance, N-(3-methoxyphenyl)-3-oxo-3-(1,3-thiazol-2-yl)propaneamide.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12](O)=[O:13])=[CH:10][N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].C[N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:18])=[O:13])=[CH:10][N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc(C(=O)O)c(NC(C)(C)C)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc(C(N)=O)c(NC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
4-(tert-Butylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (2.83 g, 11.73 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluoro-phosphate(V) (6.69 g, 17.59 mmol) were combined in a 250 mL round-bottomed flask followed by the addition of DMF (29 mL). After that ammonia hydrochloride-(3.14 g, 58.6 mmol) and DIEA (10.21 mL, 58.6 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and water (150 mL) was added. The resulting suspension was filtered, washed with water and dried under high vacuum overnight to afford 4-(tert-butylamino)-2-(methylthio)-pyrimidine-5-carboxamide (2.54 g, 10.57 mmol, 90% yield). MS (ESI) m/z 241.2
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=1.C1(C)C(C)=CC=CC=1>CO>[Cl:25][C:21]1[N:20]=[C:19]([NH:18][C:14]([C:3]2[NH:4][S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:24]=[N:23][CH:22]=1
Reactant: Nc1cncc(Cl)n1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Solvent: CO
Solvent: Cc1ccccc1C
Product: O=C(Nc1cncc(Cl)n1)C1=C(O)c2ccccc2S(=O)(=O)N1
Yield: 32.6 %

Procedure:
A mixture of 5.1 g (20 mmols) of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 3.0 g (23 mmols) of 2-amino-6-chloropyrazine and 400 ml of xylene was refluxed for 12 hours in a nitrogen atmosphere. The methanol formed by the reaction was removed with the aid of a 4 Å molecular sieve arranged in a Soxhlet attachment. After cooling, the reaction mixture was concentrated by evaporation, and the residue was purified by chromatography on a silicagel column, yielding 2.3 g (33% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][S:8]([NH:11][C:12]1[CH:13]=[C:14]([NH:18]C(=O)OC(C)(C)C)[CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:9])([O-:3])=[O:2].[ClH:29]>O1CCOCC1>[ClH:29].[NH2:18][C:14]1[CH:13]=[C:12]([NH:11][S:8]([CH2:7][C:6]2[CH:26]=[CH:27][CH:28]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)Cc2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(NS(=O)(=O)Cc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl (3-{[(3-nitrobenzyl)sulfonyl]amino}phenyl)carbamate (0.50 g, 1.2 mmol) and 4.0 M of hydrogen chloride were dissolved in 1,4-dioxane (3 mL) and stirred at rt for 2 h. The solvent was removed under vacuum and the white powder product (0.37 g, 98%) as a HCl salt was used in the next step without further purification. LCMS for C13H13N3O4S (M+H)+: m/z=308.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)[C:12]([NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)=[N:11]1.N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:46](Cl)(=[O:50])[C:47]([CH3:49])=[CH2:48].[OH-].[Na+]>O1CCCC1.O.C(O)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)[C:12]([NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:46](=[O:50])[C:47]([CH3:49])=[CH2:48])[CH:24]=2)=[N:11]1
Reactant: Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2c2cc[nH]n2)c1
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: C=C(C)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2c2cc[nH]n2)c1
Reaction time: 1.5 h
Yield: 38.5 %

Procedure:
Next, 39.5 g (0.08 mol) of the 1-(2,4,6-trichlorophenyl)-3-(3-aminobenzamido)-4-pyrazolyl-5-oxo-2-pyrazoline was dissolved in 800 ml of tetrahydrofuran, and then 16 ml (0.2 mol) of pyridine and 2 ml of nitrobenzene were added. Next, 21 g (0.2 mol) of methacrylic acid chloride was added dropwise while cooling with ice, followed by stirring for 1.5 hours, after which 800 ml of water was added. Extraction with ethyl acetate was carried out. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residual oil was dissolved in 250 ml of ethanol. An aqueous solution of 4.8 g (0.12 mol) of sodium hydroxide in 100 ml of water was then added to the solution followed by stirring for 30 min, and then 5 ml of acetic acid was added and the separated oil was crystallized from acetonitrile. Its recrystallization from ethanol was made to obtain 16.4 g (38%) of the title compound. Melting point: 227° to 230° C.
Reaction SMILES: [O:1]([C:8]1[CH:19]=[C:18]2[C:11]([NH:12][CH:13]=[C:14]2[CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO.ClCCl.O>[O:1]([C:8]1[CH:19]=[C:18]2[C:11](=[CH:10][CH:9]=1)[NH:12][CH:13]=[C:14]2[CH2:15][CH2:16][NH:17][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1c[nH]c2ccc(Oc3ccccc3)cc12
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: c1ccc(Oc2cccc(CNCCc3c[nH]c4ccc(Oc5ccccc5)cc34)c2)cc1

Procedure:
Combine 5-phenoxytryptamine (0.400 g, 1.59 mmol), 3-phenoxybenzaldehyde (0.377 g, 1.90 mmol) and molecular sieves 4 Å (0.40 g) in methanol (15 mL) and stir for 4 h. Filter and wash the molecular sieves several times with MeOH. Add NaBH4 (61.5 mg, 1.59 mmol) in portions to the filtrate and stir at room temperature for 1 h. Remove the MeOH under vacuum to give a residue, dilute the residue with dichloromethane/water, separate the layers, extract the aqueous layer with dichloromethane, combine the organic layers, and dry over Na2SO4. Concentrate in vacuo and chromatograph on silica gel eluting with dichloromethane/MeOH the title compound. Form the oxalate salt of the title compound: m.p. 196-198° C.; 1H NMR (300 MHz, DMSO-d6) 2.95-3.15 (m, 4H), 4.15 (s, 2H), 6.85-7.46 (m, 18H), 11.06 (br, 1H); MS (ELECTROSPRAY) m/e: 435.3 (M+1); HRMS (ES+) calcd for C29H27N2O2 (M+H) 435.2084 found 435.2073.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH2:31]=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1F)c1ccc2c(Cl)c[nH]c2c1
Reactant: C=O
Product: CN1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2F)CC1

Procedure:
Using alkylation method B, 3-chloro-N-[1-(2-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (250 mg, 0.58 mmol) and paraformaldehyde (174 mg, 5.8 mmol) afforded, after purification (SiO2: 10:2:2:1 DCM:EtOAc:hexane:isopropylamine), 160 mg (63%) of the title compound.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:34][CH2:35][N:30]([C:24]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:22])[CH2:31][CH2:32]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3c(C)cccc3C)CC2)c(OC)nc1C
Yield: 80 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound