Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:30][C:31]([CH:38]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:37])[C:32]([O:34]CC)=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CCO>[OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)=[CH:8][CH:9]=1)[CH2:3][N:40]1[CH2:41][CH2:42][CH2:43][CH:38]([C:31]([CH3:37])([CH3:30])[C:32]([OH:34])=[O:33])[CH2:39]1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc([C@H]3CO3)cc2)no1
Reactant: CCOC(=O)C(C)(C)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CC(C)(C(=O)O)C1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C

Procedure:
To a mixture of (S)-3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C-peak 1 (30 mg, 0.075 mmol) and ethyl 2-methyl-2-(piperidin-3-yl)propanoate (14.97 mg, 0.075 mmol) in EtOH (10 mL) was added cesium carbonate (147 mg, 0.451 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Fractions with correct mass were isolated and concentrated in vacuo. This residue was heated in 6N HCl/dioxane (1:1) at 60° C. for 3 days. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Fractions with correct mass were isolated and freeze-dried overnight. Obtained 6 mg of 2-(1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)-2-methylpropanoic. 1H NMR (400 MHz, MeOD) δ ppm 8.14 (2H, d, J=8.36 Hz), 7.57-7.64 (4H, m), 7.44-7.55 (3H, m), 5.09-5.27 (1H, m), 3.70 (2H, d, J=10.34 Hz), 3.57 (1H, br. s.), 3.23-3.27 (2H, m), 2.79-2.97 (1H, m), 1.73-1.95 (2H, m), 1.24-1.42 (2H, m), 1.15 (3H, d, J=2.86 Hz), 1.11 (3H, s), 0.76 (1H, dd, J=11.44, 9.68 Hz). MS (m+1)=571 HPLC Peak RT=3.35 minutes (Analytical Method A). Purity=92%.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:11][O:10][C:8]([C:7]1[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3][CH:4]=[CH:5][N:6]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1nccnc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1nccnc1Nc1ccccc1

Procedure:
A mixture of 9.5 g. of methyl 2-bromo-3-pyrazine carboxylate, 8.2 g. of aniline, 0.5 g. of p-toluene sulfonic acid and 100 ml. of water was stirred and refluxed for two hours. The reaction mixture was poured on ice, extracted with ethyl acetate, the organic extracts were dried and concentrated to yield an oil. The crude residue was eluted on a silica gel column with ethyl acetate-hexane (1:2) yielding the product of this example as a yellow solid, m.p. 72°-75° C.
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8])=[CH:5][CH:4]=1)=O.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C(C1C=CC=CC=1)(=O)C.[OH-].[Na+]>CO>[N:29]1([C:32]2[CH:33]=[CH:34][C:35]([C:38](=[O:40])[CH:39]=[CH:1][C:3]3[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:8])=[CH:24][CH:25]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27][O:26][CH2:31][CH2:30]1
Reactant: CC(=O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)c1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CC(=O)c2ccc(N3CCOCC3)cc2)cc1
Reaction time: 72 h
Yield: 90 %

Procedure:
To a stirred solution at room temperature of XI (210 mg, 0.62 mmol), 4′-morpholino acetophenone (227 mg, 1.11 mmol) or acetophenone derivative (1.5–2.0 equiv.) in MeOH (10 ml) was added a solution of NaOH (1.9 ml, 1N in H2O). A precipitate appeared. After 3 days, the reaction mixture was filtered off, rinsed with MeOH, air-dried and dried under vacuum to afford the title compound XXVf (295 mg, 0.56 mmol, 90% yield) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]1([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]1)[C:23](=[O:29])[NH:24]2>>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22]1([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]1)[C:23](=[O:29])[N:24]2[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Reactant: CC(C)c1nc(CCl)cs1
Agent: BrCC1CCCCO1
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3c(Cl)cccc32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-chloro-1′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one was obtained (62%) as a colorless solid: mp 147-148° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.31 (dd, J=8.0, 8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 2H), 6.65 (s, 1H), 6.33 (s, 1H), 5.94 (s, 2H), 5.09 (d, J=16 Hz, 1H), 4.93 (d, J=9.7 Hz, 1H), 4.91 (d, J=16 Hz, 1H), 4.76 (d, J=9.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.5, 176.1, 156.1, 149.5, 148.5, 144.1, 141.4, 130.3, 129.6, 128.1, 123.2, 116.9, 115.2, 108.5, 102.7, 101.4, 92.8, 76.9, 57.9, 40.2, 32.4, 22.7, 22.6; MS (ES+) m/z 455.3 (M+1), 457.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:21]([S:28][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: SCc1ccccc1
Reactant: CC(=O)c1cc(Br)ccc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(SCc2ccccc2)ccc1F
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
To a solution of 1-(5-bromo-2-fluorophenyl)ethanone (Matrix Scientific, 3 g, 13.8 mmol), Xantphos (0.800 g, 1.38 mmol), and N,N-diisopropylethylamine (4.83 mL, 27.6 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3 (0.633 g, 0.691 mmol). The vial was sparged with argon, sealed, and stirred at 80° C. for 10 minutes. After 10 minutes, the reaction was cooled to ambient temperature, and benzyl mercaptan (1.70 mL, 14.5 mmol) was added. The reaction was flushed with argon, sealed, and stirred at 80° C. After 45 minutes, the reaction mixture was concentrated, diluted with dichloromethane, and passed through a silica-gel pad, eluting with DCM. The filtrate was concentrated and purified by column chromatography, eluting with 10-60% ethyl acetate in heptane, to provide 1-(5-(benzylthio)-2-fluorophenyl)ethanone (3.6 g, quantative yield) as a yellow oil. m/z (ESI) 261.0 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CS(C)=O.[NH2:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:30][C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[O:13])[N:10]=1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1csc(-c2ccco2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C(Nc1nnn[nH]1)c1csc(-c2ccco2)n1
Reaction time: 3 h
Yield: 43.2 %

Procedure:
A solution of 2-(2-furyl)-4-thiazolecarboxylic acid (300 mg) and CDI (373.8 mg) in a mixed solvent of dry DMF (10 mg) and dry DMSO (2 ml) was prepared at 100° C. and allowed to react under the same condition for 1 hour. Then a solution of 5-aminotetrazole (156.9 mg) in dry DMF (2 ml) was added dropwise thereto and the reaction was continued for additional 3 hours. The solvent was removed from the reaction mixture. The residue was treated with water and acidified with 2N-HCl. The produced solids were filtered, washed sufficiently with water and then with ether, and dried to give yellow ocher solids of 2-(2-furyl)-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (174 mg, 43%), m.p. 275°-277° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:13])[N:6]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7](/[CH:13]=[CH:21]/[N:22]([CH3:24])[CH3:23])[N:6]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1nc(Oc2ccc(F)cc2F)ccc1C#N
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1nc(Oc2ccc(F)cc2F)ccc1C#N

Procedure:
A solution of 6-(2,4-difluorophenoxy)-2-methylnicotinonitrile (3.40 g, 14 mmol) in N,N-dimethylformamide dimethyl acetal (3.7 mL, 28 mmol) and DMF (5.00 mL) was heated at 140° C. in an oil bath for 18 h. The mixture was concentrated under reduced pressure to remove most of the DMF. The residue containing (E)-6-(2,4-difluorophenoxy)-2-(2-(dimethylamino)vinyl)nicotinonitrile (with some DMF) was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5].[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:4]=1[NH:5][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: COc1ccc(C(F)(F)F)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 60 h

Procedure:
To an ice cooled solution of 2-Methoxy-5-trifluoromethylaniline (311 mmol, 59.4 g) in 500 ml dry dimethylformamide is added sodiumhydride (438 mmol, 17.5 g 60%) followed by slow addition of 2-chloro-5-trifluoromethyl-nitrobenzene (311 mmol, 47.4 ml) and the mixture is stirred for 60 hours. More sodiumhydride (10 g 60%) is added and after stirring for additional two hours is another portion of 2-chloro-5-trifluoromethyl-nitrobenzene (5 ml) and sodiumhydride (2 g 60%) added. Upon completion is the reaction mixture poured into water and a black precipitate is formed. The crude product is filtered of and is washed with 1M HCl and petroleum ether yielding the title compound as grey crystals, M.p. 86°-88° C.
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[CH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[NH:8])=[O:7].CO[CH:21](OC)[N:22](C)C>CN(C)C=O.C(OCC)(=O)C>[C:9]1([SH:6]2(=[O:7])[CH:5]=[C:4]([C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=3)[N:22]=[CH:21][NH:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(OC)N(C)C
Reactant: N=S(=O)(C=Cc1ccccc1N)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=CN1
Temperature: 80 °C
Yield: 79.7 %

Procedure:
To a solution of 2 g (7.75 mmole) of S-(2-aminostyryl)-S-phenyl sulfoximine in 20 ml of dimethylformamide was added 1 g (8.5 mmole) of dimethylformamide dimethyl acetal and the mixture was heated at 80° C. for 15 minutes. The mixture was then cooled and diluted with 100 ml of ethyl acetate. The organic phase was washed 3 times with 75 ml of water, dried over magnesium sulfate and evaporated to an oil which was crystallized from ether/petrol to obtain 1.67 g (80%) of 1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide melting at 110°-111° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]2[C:7]([CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)=[CH:8][NH:9][C:10]=2[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:4].[C:25]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(=O)[CH2:26][CH2:27][CH3:28].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:25]1([CH2:26][CH2:27][CH3:28])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:15][CH2:16][O:17]1)=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:13]=[CH:12][C:11]=3[CH3:14])[CH3:35]
Reactant: CNC(=O)c1ccc(C)c2[nH]cc(CCO[Si](C)(C)C(C)(C)C)c12
Reactant: CCCC(=O)CC(=O)OCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C(=O)NC)c21
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole-4-carboxylic acid methylamide (100 mg, 0.289 mmol) and ethyl butyrylacetate (92 mL, 0.578 mmol) in CH2Cl2 (2 mL) was added BF3.OEt2 (0.11 mL, 0.867 mmol) dropwise at room temperature. After stirring overnight, the solution was diluted with CH2Cl2 (10 mL) and then washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 50% EtOAc in hexanes) to give 88 mg (82%) of title compound as a yellow solid. 1H NMR (CDCl3): 300 MHz δ 9.54 (bs, 1H), 7.12 (d, J=7.38 Hz, 1H), 6.89 (d, J=7.38 Hz, 1H), 6.05 (d, J=4.71 Hz, 1H), 4.15 (m, 2H), 3.96 (m, 1H), 3.86 (m, 1H), 3.03–2.83 (m, 7H), 2.48 (s, 3H), 2.00 (m, 2H), 1.37 (m, 1H), 1.25 (t, J=6.84 Hz, 3H), 1.22 (m, 1H), 0.87 (t, J=7.17 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:7][CH2:8][CH2:9][C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cn1cccc1CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cccc1CCNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
10 ml of a saturated potassium carbonate solution are added to a solution of 4.96 g of 2-(2-aminoethyl)-1-methylpyrrole in 20 ml of dioxane, with stirring. Then at 0° C. a solution of 10.1 g of p-chlorobenzene sulphonylchloride in 30 ml of dioxane is added dropwise. The mixture is then stirred for 3 hours at ambient temperature, the precipitate is removed by suction filtering, washed with ether and the organic phase is separated off. After drying over sodium sulphate 10 g of crude product are obtained which is chromatographed over a silica gel column with methylene chloride/cyclohexane (9:1).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15]Cl)[CH:2]=[CH2:3].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C=O)C>[CH2:1]([O:4][C:5](=[O:17])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCCl
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: C=CCOC(=O)NC1CC(=O)OC1OCCN1CCOCC1

Procedure:
Is prepared from [2-(2-chloro-ethoxy)-5-oxo-tetrahydro-furan-3-yl]-carbamic acid allyl ester by reaction with morpholine (2 eq) and KI (1 eq) in DMF.
Reaction SMILES: C(SCCC#N)CCCCCCCCC.[CH2:16]([S:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:28])=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:34]O>CS(O)(=O)=O>[CH2:16]([S:26]([CH2:29][CH2:30][C:31]([O:33][OH:34])=[O:32])(=[O:27])=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCS(=O)(=O)CCC(=O)O
Reactant: OO
Agent: CCCCCCCCCCSCCC#N
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCS(=O)(=O)CCC(=O)OO
Temperature: 10 °C
Yield: 87.6 %

Procedure:
The product of Example 9 was converted to the corresponding carboxylic acid by alkaline hydrolysis followed by acidification and then to the corresponding sulfone carboxylic acid by oxidation in accordance with a procedure found in U.S. Pat. No. 3,857,875 to Brady et al. A stirred mixture of 5 g of 3-(n-decylsulfonyl)propionic acid and 50 mL of methanesulfonic acid was heated to 40°±3° C. The 3-(n-decylsulfonyl)propionic acid dissolved only partially in the methanesulfonic acid at this temperature. Then 2.04 g of 90% hydrogen peroxide was added dropwise via pipette over ten minutes. Before the addition of the hydrogen peroxide was completed, the reaction mixture became thick from precipitation of a solid. After the addition of the 90% hydrogen peroxide was completed, the heating of the reaction mixture was continued at 40°±3° C. until the reaction time totalled ninety minutes beginning at the start of the addition of the hydrogen peroxide. The reaction mixture was then cooled in an ice bath at 10° C. The solid was then filtered from solution using a coarse sintered-glass funnel, then transferred to a beaker containing 200 mL of ice water prepared from deionized water. The product was washed twice with ice water, filtered and dried to provide 4.63 g of the desired product (87.6% of theoretical based upon the weight of starting 3-(n-decylsulfonyl)propionic acid). The product was found to have 5.32% active oxygen. The product was stabilized with an equal weight of boric acid and put through a #30 polyethylene sieve which provided a particle size of less than 600 microns. The stabilized product contained 2.58% by weight active oxygen.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[CH2:17][C@H:18]1[CH2:20][O:19]1>CN(C)C=O>[O:19]1[CH2:20][C@@H:18]1[CH2:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: ClC[C@H]1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1ccccc1n2C[C@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a stirred solution of carbazole (2.0 g, 12 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added 85% aqueous potassium hydroxide (0.95 g, 14.4 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was cooled in an ice bath and (R)-(−)-2-(chloromethyl)oxirane (2.77 g, 29.9 mmol) was added. The mixture was stirred overnight at room temperature, and then partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. The residue was purified by recrystallization from ethyl acetate/hexanes to afford the desired product as white crystals (0.8 g, 30%). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, 2H, J=7.5 Hz), 7.55-7.40 (m, 4H), 7.32-7.22 (m, 2H), 4.66 (dd, 1H, J=15.9, 3.3 Hz), 4.43 (dd, 1H, J=15.9, 4.8 Hz), 3.38 (m, 1H), 2.83 (t, 1H, J=4.5 Hz), 2.60 (dd, 1H, J=4.8, 2.4 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]1[CH2:8][C@@H:7]1[C:9]([OH:11])=O.C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@H:6]1[CH2:8][C@@H:7]1[C:9]([Cl:15])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@H]1C[C@@H]1c1cccs1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (0.110 g, 0.66 mmol) in dichloromethane (10 ml) in an ice-bath was added oxalyl chloride (0.58 ml, 6.60 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 50 ml round-bottom flask was charged with (R)-2-Amino-2-[4-(2-methyl-pentyloxy)-phenyl]-ethanol HCl (0.47 mmol), dichloromethane (6 ml) and triethylamine (0.31 ml, 2.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×10 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (0.088 g, 48% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (m, 2H), 6.99 (dd, J=5.2, 1.1 Hz, 1H), 6.81 (m, 3 H), 6.72 (d, J=3.3 Hz, 1H), 6.14 (d, J=6.3 Hz, 1H), 4.95 (m, 1H), 3.80 (m, 2H), 3.67 (m, 2H), 2.72 (dd, J=7.1, 4.8 Hz, 1H), 2.62 (m, 1H), 1.85 (m, 1H), 1.60 (m, 2H), 1.27 (m, 5H), 0.92 (d, J=6.8 Hz, 3H), 0.83 (m, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C22H30NO3S 374.5].
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]([CH:22]=[O:23])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>ClCCl.ClCCCl>[Si:24]([O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]([CH:22]=[O:23])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc2c(c1)c1ccccc1n2CCCCCCO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCn1c2ccccc2c2cc(C=O)ccc21

Procedure:
In Reaction 1, a reactant reacts with 1,2-dichloroethane at 0° C. to thus prepare a precursor 2, which is then further reacted in the presence of 10% HCl, affording a precursor 3. The reaction is progressed through reflux. Then, 9-(6-hydroxyhexyl)-9H-carbazole-3-carbaldehyde, dichloromethane, tert-butyldimethylsilyl chloride, and imidazole are reacted together, thus producing 4 (9-(6-(tert-butyldimethylsilyloxy)hexyl)-9H-carbazole-3-carbaldehyde) as a precursor. Then, the precursor 4 is dissolved in sodium borohydride and methanol to thus allow the obtained solution to react, yielding 5 ((9-(6-(tert-butyldimethylsilyloxy)hexyl)-9H-carbazol-3-yl)methanol as a precursor.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccc(Cl)cc4Cl)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccc(Cl)cc4Cl)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2,4-dichlorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 227°-229° C.) and piperazine.