Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]([NH:14][C:15]2[NH:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[C:18]([CH3:20])[N:19]=2)=[O:13])[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].[NH4+].[Cl-]>C(Cl)Cl>[C:38]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]([NH:14][C:15]2[NH:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[C:18]([CH3:20])[N:19]=2)=[O:13])[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: Cc1nc(NC(=O)c2cc(CN)cnc2C(F)F)[nH]c1-c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cnc(C(F)F)c(C(=O)Nc2nc(C)c(-c3ccc(C(F)(F)F)cc3)[nH]2)c1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Dissolve 5-(aminomethyl)-2-(difluoromethyl)-N-[4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]pyridine-3-carboxamide (0.047 g, 0.110 mmol) in DCM (3 mL). Add triethylamine (0.038 mL, 0.276 mmol) followed by acetyl chloride (9.830 μL, 0.138 mmol), and stir overnight. Pour the reaction into saturated aqueous NH4Cl (15 mL) solution, and extract with EtOAc (2×10 mL). Combine the organic extracts; dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to dryness to give the title compound (0.039 g, 75% yield) as a light yellow solid. LCMS (m/z) 468 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.[NH2:20][C:21]1[N:26]=[C:25]2[CH2:27][C:28]3([CH2:38][C:24]2=[CH:23][CH:22]=1)[C:36]1[C:31](=[N:32][CH:33]=[CH:34][CH:35]=1)[NH:30][C:29]3=[O:37].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:37]=[C:29]1[NH:30][C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:36]2[C:28]21[CH2:27][C:25]1=[N:26][C:21]([NH:20][C:8](=[O:10])[CH2:7][N:6]3[C:5]4[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=4[N:3]([C:15]4[S:16][CH:17]=[CH:18][N:19]=4)[C:2]3=[O:1])=[CH:22][CH:23]=[C:24]1[CH2:38]2
Reactant: O=C(O)Cn1c(=O)n(-c2nccs2)c2ccccc21
Reactant: Nc1ccc2c(n1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1c(=O)n(-c2nccs2)c2ccccc21)Nc1ccc2c(n1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [2-oxo-3-(1,3-thiazol-2-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid (62 mg, 0.23 mmol, described in Intermediate 33), (±)-2-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 5), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH2:12])[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]1)=[O:4].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1>>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:12][C:5]2([C:3]([OH:2])=[O:4])[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]2)=[O:20])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C1(N)CCC=CCC1
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Product: COc1ccc(C(=O)NC2(C(=O)O)CCC=CCC2)cc1OCCc1cccc(C)c1

Procedure:
1-Amino-cyclohept-4-enecarboxylic acid methyl ester (K. Hammer et al., Tetrahedron 53 (1997), 2309-2322) was coupled to 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid analogy to step 1 of example 3. The ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: Cl[Si:2]([CH3:12])([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl-].[NH4+].[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][Si:2]([CH3:12])([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:16]
Reactant: CCO
Reactant: CCCCCCCC[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCCCC[Si](C)(C)OCC

Procedure:
An amount of 29.2 g of chlorodimethyloctylsilane, i.e. 0.14 mol, is gradually introduced over 2 h 30 into the reaction mixture. 75.4 g of absolute ethanol are added in order to prevent the mixture setting solid due to the formation of ammonium chloride crystals.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22].O>C(O)CCC>[S:17]1[CH:21]=[CH:20][N:19]2[C:2]([CH2:5][C:6]3[CH:16]=[CH:15][C:9]4[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=4[CH:7]=3)=[CH:3][N:22]=[C:18]12
Reactant: Nc1nccs1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Solvent: O
Solvent: CCCCO
Product: CSc1nc2ccc(Cc3cnc4sccn34)cc2s1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (500 mg, 1.84 mmol) and thiazol-2-amine (370 mg, 3.68 mmol) in 1-butanol (22 mL) was heated at reflux overnight. The mixture was cooled to rt and water (120 mL) was added. The mixture was extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylthio)benzo[d]thiazole as a yellow solid (350 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.4 Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.16 (d, J=0.9 Hz, 1H), 6.99 (d, J=4.5 Hz, 1H), 6.71 (dd, J=0.9 Hz, J=4.5 Hz, 1H), 4.24 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 318 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(#N)C>[CH3:21][O:20][C:3]1[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:1][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCc1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Yield: 15.7 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (154 mg, 1.118 mmol) and 4-bromomethyl-benzenesulfonamide (104 mg, 0.418 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-25% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 15.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[N:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:12]([C:7]2[CH:6]=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=2)=[O:14])[CH2:31][CH2:30]1
Reactant: O=C(O)c1cnc2cc(F)ccc2n1
Reactant: C[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](NC(=O)c2cnc3cc(F)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-fluoroquinoxaline-2-carboxylic acid (35 mg, 0.18 mmol) in dimethylformamide (4 mL) was treated with 1,1′-carbonyldiimidazole (29 mg, 0.18 mmol) and the reaction stirred for 16 hours at ambient temperature. After this time the reaction mixture was treated with trans-4-methylcyclohexylamine hydrochloride (27 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.29 mmol) and the reaction stirred 2 hours at ambient temperature. The solvent was evaporated to a solid (700 mg). The solid was dissolved in chloroform (10 mL) and added to diethyl ether (30 mL) The organic solution was washed with water (1×25 mL) and brine. The remaining organic solution was dried over anhydrous MgSO4, filtered, and concentrated to a solid (35 mg) HPLC (10 micron silica, 250×20 mm i.d.) of this material using a gradient of chloroform to 10% ethanol (in chloroform) afforded 20 mg (39%) of 434:
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH2:23][C:22](=O)[CH2:21][CH2:20]2>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[C:17]([Br:16])[CH:18]=4)[CH2:23]3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: O=C(Nc1ccccc1)N1CCN(C2CCc3cc(Br)ccc3C2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 6-bromo-3,4-dihydro-1H-naphthalen-2-one. 1H NMR (400 MHz, CDCl3): 7.37-7.21 (m, 6H), 7.06-7.02 (m, 1H), 6.96-6.94 (m, 1H), 6.33 (s, 1H), 3.55-3.53 (m, 4H), 2.94-2.64 (m, 9H), 2.12-2.08 (m, 1H), 1.69-1.61 (m, 1H).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47]>O1CCCC1.O>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
1.1 g (2.06 mmol) of 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride was dissolved in a mixture of 40 mL of tetrahydrofuran and 10 mL of water, then 570 mg (4.12 mmol) of potassium carbonate and 362 mg (2.2 mmol) of n-hexyl chloroformate were added and stirred for two hours at room temperature. The solvent was then distilled off, the residue was mixed with about 50 mL of saturated saline solution and the resulting solution was extracted three times with 20 mL of dichloromethane. The extracts were dried over sodium sulfate and evaporated down. The crude product thus obtained was purified by column chromatography (100 g silica gel; dichloromethane+5% ethanol). Yield: 78% of theory, C35H42N6O5 (626.8); Rf value: 0.49 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=627; (M+H+Na)++=325; (M+2H)++=314.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Br:11]Br>Br.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Br:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: Br
Solvent: c1ccccc1
Product: N#CC(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 57 %

Procedure:
4-Chlorophenylacetonitrile (303.2 g., 2.0 mole) is heated to 90°C. on a steam bath and 48% hydrobromic acid (5drops) is added. Bromine (336 g., 2.1 mole) is then added dropwise to the stirred melt over a 1-hour period at 90° -95°C. The reaction mixture is heated an additional 15 minutes and then cooled. Benzene (300 ml.) is then added and 100 ml. of the benzene is removed by distillation at 80°C. The solution is cooled, filtered and the benzene removed to afford 435.5 g. of crude product which is extracted with 3 liters of hexane at 50°-55°C. Isopropanol (100 ml.) is added to the hexane solution which is then cooled to 25°C. The product is collected by filtration to afford 235.2 g. (57% yield) of 4-chlorophenyl-α-bromoacetonitrile, m.p. 46°-49°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:11])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH:8]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)C.O1CCCC1>[CH3:1][O:2][C:3]1[C:4](=[O:11])[CH:5]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][C:7]([CH3:9])([CH3:10])[CH:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC1=CC(C)(C)CCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CC(C)(C)C=C(OC)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of 2-methoxy-4,4-dimethyl-cyclohex-2-enone (12.5 g, 81.1 mmol) and diethyl oxalate (12.1 mL, 89.2 mmol) in ethyl ether was treated with a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran under argon atmosphere. The reaction was stirred at room temperature for 2 hours, poured into a 10% NaH2PO4 solution (500 mL) and extracted with diethyl ether (300 mL×2). The organic extracts were washed with brine, dried on Na2SO4 and evaporated to dryness. The crude material was taken up with hexane, stirred and filtered to give the title compound (16.8 g, 81.5% yield) as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:29][O:30][C:31]1[CH:54]=[CH:53][C:34]([CH2:35][O:36][C:37]([NH:39][C:40]2[N:48]=[CH:47][N:46]=[C:45]3[C:41]=2[N:42]=[CH:43][N:44]3[CH2:49][C:50](O)=[O:51])=[O:38])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:44]1[CH:43]=[N:42][C:41]2[C:45]1=[N:46][CH:47]=[N:48][C:40]=2[NH:39][C:37]([O:36][CH2:35][C:34]1[CH:53]=[CH:54][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)=[O:38])[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc(OC)cc3)ncnc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [6-N-(4-methoxybenzyloxycarbonyl)-adenin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 10.56 (s, 1H), 10.59 (s, 0.55H), 9.31 (brs, 0.55H), 9.11 (brs, 0.45H), 8.57 (s, 0.45H), 8.56 (s, 0.55H), 8.40 (d, 0.55H), 8.39 (d, 0.45H), 8.31 (s, 0.55H), 8.30 (s, 0.45H), 8.03–7.99 (m, 1H), 7.93 (d, 0.55H), 7.91 (d, 0.45H), 7.39 (d, 1H), 6.95 (d, 2H), 5.38 (s, 1.1H), 5.17 (s, 0.9H), 5.14 (s, 2H), 4.48 (s, 0.9H), 4.23 (q, 0.9H), 4.08 (s, 1.1H), 4.07 (q, 1.1H), 3.76 (s, 3H), 3.72 (t, 1.1H), 3.54 (t, 1.1H), 3.45 (t, 0.9H), 3.29 (t, 0.9H), 1.27 (t, 1.35H), 1.15 (t, 1.65H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[CH3:15][O:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][CH2:18][CH2:17][O:16][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COCCBr
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCOC)c(OC)c1
Yield: 10.2 %

Procedure:
A mixture of ethyl 4-hydroxy-3-methoxybenzoate (9.8 g, 50 mmol), 2-bromoethyl methyl ether (8.46 ml, 90 mmol) and potassium carbonate (12.42 g, 90 mmol) in acetone (60 ml) was heated at reflux for 30 hours. The mixture was allowed to cool and the solids removed by filtration. The volatiles were removed from the filtrate by evaporation and the residue triturated with hexane to give ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate ( 1.3 g, 89%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[O:6][N:5]=1)([CH3:3])[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: CC(C)c1noc(N2CCCCC2=O)n1
Reactant: NC1CC1
Product: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1

Procedure:
The title compound is prepared from 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-2-one and cyclopropylamine following a procedure analogous to that described for Intermediate 66.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[Cl:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=O>C(O)C.O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=3[Cl:22])[CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)c(Cl)c1
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N2CN(c3ccccc3)CC2=O)c(Cl)c1

Procedure:
2-Phenylamino-N-(2-chloro-4-sulphamoylphenyl)-acetamide (34.0g) was dissolved in ethanol (300 ml) and paraformaldehyde (6.0g) in water (600 ml) added. The mixture was refluxed 4 hours, cooled and worked up as in Example 2(c) to yield 20 g m.p. 206°
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[F:1][C:2]1[C:3]([NH:17][S:29]([CH3:28])(=[O:31])=[O:30])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(COc2ncc(F)c(N)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(COc2ncc(F)c(NS(C)(=O)=O)n2)cc1
Reaction time: 0.33 h
Yield: 25.4 %

Procedure:
To a solution of 5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-ylamine (0.100 g, 0.43 mmol) in anhydrous THF (4 mL) was added LiHMDS (1.07 mL of 1.0M, 1.07 mmol) dropwise at room temperature, and the resulting orange solution was stirred for 20 min. Methanesulfonyl chloride (0.108 g, 0.94 mmol) was added in one portion and the turbid, light orange solution was stirred for 60 min. The reaction was quenched with brine (5 mL) and the THF phase was separated. The aq. phase was extracted w/EtOAc (5 mL), and the organics were combined, dried over Na2SO4, filtered, and concentrated to an orange gummy residue. The residue was purified by flash chromatography (SiO2, 0→100% EtOac/hexanes) to give 0.034 g (26%) of the title compound as a white solid: mp 145-148° C.; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.33 (d, J=7.9 Hz, 2H), 7.17 (d, J=7.9 Hz, 2H), 5.35 (s, 2H), 3.37 (s, 3H), 2.35 (s, 3H); HPLC-MS (ESI) m/z 312 (M+H)+, 310 (M−H)−.
Reaction SMILES: [CH2:1]([C@@:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:12][CH3:13])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[O:27]1CCCC1>>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:1][CH2:2][CH2:3][OH:27])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:9][C:8]2=[O:10])[CH2:12][CH3:13])=[CH:19][CH:18]=1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](CC)c2ccc(Br)cc2)C(=O)O1
Reactant: C1CCOC1
Product: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.242 mmol) in tetrahydrofuran (10 mL) was added BH3 THF (3 mL, 1 mol/L) at 0° C. under nitrogen. The formed mixture was stirred for 2 h. Then the reaction was quenched by water, followed by 3 mol/L NaOH and H2O2 (3 mL). The PH of the mixture was adjusted to <7 with 5% HCl. The organic phase was separated, extracted by EtOAc, and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (15 mg, 15%). LC-MS Method 3 tR=1.36, min, m/z=432, 434; 1H NMR (CDCl3): δ=0.99 (t, 3H), 1.29 (m, 1H), 1.63 (m, 1H), 1.98 (m, 4H), 2.20-2.42 (m, 2H), 2.48 (m, 1H), 3.08 (m, 1H), 3.49 (m, 1H), 5.30 (m, 1H), 6.92 (m, 2H), 7.26 (m, 4H), 7.35 (m, 2H).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:30])=[N:25][CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:21][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(OC3CCCCC3)cc2)=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 5.29 g) in THF (dry) (100 mL) was added 2-chloroethanesulfonyl chloride (5.57 ml) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(cyclohexyloxy)phenyl)-5-methylpyrazin-2-amine (7.5 g) in THF (dry) (75 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 2 days. The mixture was quenched with water/THF at 0° C. carefully and water was added to form precipitates which were washed with EtOAc and water and dried in vacuo to give crude title compound (4.7 g). The part of this material (ca. 4.3 g) was crystallized from DMSO (200 mL)-EtOH (40 mL)/water (400 mL) to give 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide as light-yellow crystals (3.6 g), which was recrystallized from DMSO (100 mL)-EtOH (15 mL)/water (100 mL) at 80° C. to room temperature to give the title compound (3.09 g) as light-yellow crystals.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@@H:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][NH:8]1)[CH3:4].C(N(CC)CC)C.[C:30](OCC)(=[O:36])[C:31](OCC)=[O:32]>C(Cl)(Cl)Cl>[CH2:3]([N:5]1[C:31](=[O:32])[C:30](=[O:36])[N:8]2[CH2:9][C@@H:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[C:16]([C@@H:7]2[CH2:6]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:4]
Reactant: CCNC[C@@H]1NC[C@H](c2ccccc2)c2ccccc21
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1C[C@H]2c3ccccc3[C@H](c3ccccc3)CN2C(=O)C1=O
Yield: 60.8 %

Procedure:
To a stirred solution of cis-1,2,3,4-tetrahydro-1-(ethylamino)methyl-4-phenyl-isoquinoline dihydrochloride (19.5 g, 0.057 m) in chloroform (250 ml) maintained under nitrogen at ambient temperature was added triethylamine (26.0 g, 0.25 m) and then in one portion diethyl oxalate (36.4 g, 0.23 m) and the mixture heated to reflux for 5 hours. The mixture was cooled and washed with 10% HCl (3×150 ml) and water (200 ml) and dried over MgSO4. The solvent was evaporated to a yellow oil, which was dissolved in 200 ml ethanol, decolorized with Norite. Upon cooling and standing, a white solid crystallized which was collected by filtration and dried to give 11.2 g of cis-1,3,4,6,7,11b-hexahydro-2-ethyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline-3,4-dione.