Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][CH2:16][C:10]2([O:14][C:13](=[O:15])[NH:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][CH2:16][C:10]2([O:14][C:13](=[O:15])[N:12]([C:20]3[CH:25]=[N:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CNC(=O)O2)C1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)CN(c1ccc([N+](=O)[O-])nc1)C(=O)O2
Yield: 81.5 %

Procedure:
Following general N—C coupling procedure 1, 2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester (0.546 g, 2.130 mmol) (Reference: German Patent DE10 2005 030051A1 (28 Dec. 2006)), was combined with 5-bromo-2-nitropyridine (0.432 g, 2.130 mmol, 1.0 eq) which gave 3-(6-Nitro-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester as a brown solid (0.709 g, 1.735 mmol) in 81% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (br. s., 9H) 1.55-1.73 (m, 2H) 1.89-2.17 (m, 3H) 3.41 (br. s., 2H) 3.65 (br. s., 2H) 3.78-3.88 (m, 1H) 3.95 (d, J=8.03 Hz, 1H) 8.34 (d, J=9.03 Hz, 1H) 8.54 (br. s., 1H) 8.61 (dd, J=9.03, 3.01 Hz, 1H) MS m/z 379.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][C@@H:20]([CH3:22])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:23])[CH:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][C@@H:20]([CH3:22])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:23])[CH:10]=1)[C:4]#[C:5][CH3:6]
Reactant: C[C@H]1CCC[C@H](C)N(c2cc(Cl)ncn2)C1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N2C[C@@H](C)CCC[C@@H]2C)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
0.10 g of sodium hydride (60% oil suspension) was suspended in 3 ml of tetrahydrofuran. 0.5 ml of tetrahydrofuran solution of 0.16 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.5 ml of tetrahydrofuran solution of 0.30 g of 1-(6-chloropyrimidin-4-yl)-trans-2,6-dimethyl hexahydro-1H-azepine at room temperature, and stirred for 5 hours at 60° C. After the reaction mixture was cooled to near room temperature, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.25 g of 1-(6-(2-butynyloxy) pyrimidin-4-yl)-trans-2,6-dimethyl-hexahydro-1H-azepine (hereinafter, referred to as Compound (43)).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH2:30][CH3:31])=[O:27])=[C:21]([Cl:32])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>CN(C)C=O>[Cl:32][C:21]1[CH:20]=[C:19]([O:18][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:43]4[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:24]=[CH:23][C:22]=1[NH:25][C:26]([NH:28][CH2:29][CH2:30][CH3:31])=[O:27]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCCBr)cc23)cc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCCN4CCN(C)CC4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[6-(3-bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea. N-(4-{[6-(3-Bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea (50 mg), potassium carbonate (40 mg), and N-methylpiperazine (50 μl) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 44%) of the title compound.
Reaction SMILES: [CH2:1]1[CH:10]2[C:4](=[N:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9]2=[O:11])[CH2:3][CH2:2]1.[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19]>CN(C)C=O.[Cl-].[NH4+]>[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:8]2[C:9](=[O:11])[CH:10]3[CH2:1][CH2:2][CH2:3][C:4]3=[N:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]2=3)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=C1Nc2ccccc2N=C2CCCC12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1C2CCCC2=Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70993.1 %

Procedure:
A suspension of 2,3,9,10a-tetrahydrobenzo[b]-cyclopenta[e][1,4]diazepin-10(1H)-one (25.00 g, 0.125 mmol) in N,N-dimethylformamide (DMF) (150 mL) was cooled to 0° C. and sodium hydride (60% dispersion in liquid paraffin, 5.00 g, 0.125 mol) was added. The mixture was stirred at the same temperature for 10 minutes and then at 20° C. for 5 minutes. After the resulting solution was cooled to 0° C., 4-nitrobenzyl bromide (28.32 g, 0.131 mol) was added and the mixture was stirred at 20° C. for 10 minutes. This reaction mixture was poured in saturated aqueous ammonium chloride solution (500 mL) and the resulting precipitate was recovered by filtration, rinsed with water, and recrystallized from dichloromethane-ethanol to provide 29.76 g (yield 71%) of the title compound. Samples for analysis were recrystallized from chloroform-ethanol. m.p. 185°-188° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][S:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:18]>O>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][S:12](=[O:18])[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: c1ccc(CN2CC3CSCC(C3)C2)cc1
Solvent: O
Product: O=S1CC2CC(CN(Cc3ccccc3)C2)C1
Reaction time: 1 h

Procedure:
A 200-mL flask was equipped with a magnetic stirrer, an ice bath, and a condenser with nitrogen inlet. To a stirred, chilled (5° C.) solution of the amine (27, 1.4 g, 6 mmol) in methanol (60 mL) was added dropwise a solution of NaIO4 (1.35 g, 6.3 mmol) in water (15 mL) over 30 min. After stirring for one hour, the suspension was filtered and washed with methanol (50 mL); the washings and filtrate were combined and concentrated to a residue which was partitioned between H2CCl2 and water (40 mL each). Additional extracts (HCCl3, 3×40 mL) of the aqueous layer were combined with the initial extract, and the solution was dried (Na2SO4) and concentrated to afford an oil which solidified upon standing. Recrystallization (HCCl3 /pentane) of the solid gave 1.15 g (76.9%) of crystalline (49); mp 140°-141° C. IR (KBr) cm-1 3085, 3065, 3030, 2955, 2920, 2895, 2815, 1495, 1020, 740, 705; 1H NMR (DCCl3) δ1.59 [bd, 1 H, H(9), J=13.3 Hz], 1.86 [bd, 1 H, H(9), J=13.2 Hz], 2.20 [d, 2 H, H(2,4)ax, J=11.7 Hz], 2.37 bs, 2 H, H(1,5)], 2.62 [d, 2 H, H(6,8)ax, J=12.0 Hz], 2.78 [d, 2 H, H(2,4)eq, J=11.8 Hz], 3.51 [d, 2 H, H(6,8)eq, J=11.7 Hz], 3.55 [s, 2 H, ArCH2 ], 7.26-7.39 (m, 5 H, Ar--H); 13C NMR (DCCl3) ppm 31.86 [t, C(9)], 32.59 [d, C(1,5)], 57.42 [t, C(2,4)], 58.59 [C(6,8)], 62.88 (ArCH2), 127.20, 128.39, 129.12, 137.67; 15N NMR (DCCl3) ppm 49.37 [N(7)]. Anal. Calcd. for C14H19NOS: C, 67.43; H, 7.68. Found: C, 67.61; H, 7.73.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH2:14][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][C:17](=[O:19])[CH:18]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C(Cl)Cl.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:19]=[C:17]1[C:18]2[C:2]3[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=3[NH:12][C:13]=2[CH2:14][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16]1
Reactant: COC(=O)c1cccc(NC2=CC(=O)CN(C(=O)OCc3ccccc3)C2)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C(=O)OCc1ccccc1)C3
Yield: 71.7 %

Procedure:
A mixture of benzyl 3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (0.13 g, 0.28 mmol), palladium acetate (0.013 g, 0.06 mmol), tri-o-tolylphosphine (0.72 g, 0.19 mmol), and triethylamine (0.36 g, 0.36 mmol) in acetonitrile (2 mL) was heated in a sealed tubule flushed with nitrogen at 100° C. for 9 h. The cooled reaction mixture was diluted with DCM (3×50 mL) and water (10 mL). The organic layer was separated, washed with water, dried (Na2SO4), and concentrated. The remaining residue was chromatographed on silica gel, eluted with gradient 0-100% EtOAc in hexane to give the title compound (0.076 g, 72%). 1H NMR (CDCl3-d1) δ 9.62 (s, 1H), 7.24-7.50 (m, 8H), 5.18 (s, 2H), 4.88 (s, 2H), 4.27 (s, 2H), 3.98 (s, 3H). MS (ESI) m/e [M+1]+ 379.0.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Si:17]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](=O)[CH2:34][CH2:35][CH2:36][CH3:37])=[C:28]([O:39][CH3:40])[CH:27]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[Si:17]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:28]([O:39][CH3:40])[CH:27]=1)([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCCC(=O)Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC(=CC(=O)OCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
5.25 g (0.120 mol) of sodium hydride (as a 55% w/w dispersion in mineral oil) was washed with hexane and then suspended in 70 ml of tetrahydrofuran. A solution of 26.0 ml (0.131 mol) of ethyl diethylphosphonoacetate in 30 ml of tetrahydrofuran was added dropwise over a period of 40 minutes to the suspension, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 10 minutes. A solution of 27.83 g (79.4 mmol) of 1-(4-t-butyldimethylsilyloxymethyl-2-methoxyphenyl)-2-oxohexane [prepared as described in step (ii) above] in 50 ml of tetrahydrofuran was then added to the mixture, which was then heated under reflux for 2.5 hours. At the end of this time, the reaction temperature was allowed to reduce to room temperature, and then a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The resulting aqueous mixture was then extracted with diethyl ether. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after it was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 250 g of silica gel, using a 1:9 by volume mixture of ethyl acetate and hexane as the eluent, to give 32.95 g (yield 98.7%) of the title compound as an oily substance.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=1>>[C:4]12[C:5](=[O:7])[O:14][C:1](=[O:13])[C:2]3[C:3]1=[C:12]([C:19]1[C:18]([CH:22]=3)=[CH:17][N:16]=[CH:21][CH:20]=1)[CH:11]=[CH:10][CH:9]=2
Reactant: O=Cc1cccnc1
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Product: O=C1OC(=O)c2cc3cnccc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and pyridine-3-carboxaldehyde:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.O.CCOC(C)=O.CCCCCC.C(Cl)[Cl:30]>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]=1[Cl:30]
Reactant: ClCCl
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(Cl)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)OC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Propan-2-yl 4-amino-6-chloro-5-fluoropicolinate (1.191 g, 5.12 mmol) was almost completely dissolved in CH2Cl2 (40 mL). Water (40 mL) was added. Chlorine was bubbled through the solution for 5 min. After 30 min, an aliquot of the reaction mixture was analyzed by GC, showing desired product and only 1.7% starting material. The aqueous layer was separated and extracted with CH2Cl2 (50 mL). The combined organic extracts were washed with satd aq NaHCO3 solution and then brine. The extracts were dried (MgSO4) and concentrated under reduced pressure to yield an orange oil. Flash chromatography (120 g silica column; 0-50% EtOAc-hexane gradient) afforded a bright yellow crystalline solid (394 mg, 28%): 1H NMR (400 MHz, CDCl3) δ 5.29 (septet, J=6.3 Hz, 1H, CHMe2), 5.19 (br s, 2H, NH2), 1.40 (d, J=6.3 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, CDCl3) δ 163.2 (CO2R), 143.3 (d, JF-C=5 Hz, C2), 142.8 (d, JF-C=270 Hz, C5), 141.0 (d, JF-C=26 Hz, C4), 135.3 (d, JF-C=17 Hz, C6), 114.9 (s, C3), 70.6 (CHMe2), 21.6 (s, Me); 19F NMR (376 MHz, CDCl3) δ −136.5.
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.[CH3:41][C:42]([CH3:44])=O.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:30][CH2:31][N:32]([CH:42]([CH3:44])[CH3:41])[CH2:33][CH2:34]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C(C)C)CC2)C4)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
A mixture of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (27.1 mg, 0.05 mmol), acetone (200 μL) and Ti(i-PrO)4 (300 μL) was stirred at the room temperature for 2 h and diluted with MeOH (5 mL). NaBH4 (190 mg, 5 mmol) was added into the reaction mixture and the mixture was stirred at the room temperature for 16 h and concentrated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (490:10:1) afforded the title compound (2.06 mg, 7%). 1H NMR (DMSO-d6) δ 1.22 (s, 3H, CH3), 1.24 (s, 3H, CH3), 1.25-1.45 (4H), 1.80-2.30 (6H), 3.33-3.60 (2H), 3.70 (m, 1H), 3.90-4.19 (2H), 4.35-4.50 (2H), 5.47 (m, 1H, NH), 6.22 (m, 1H), 6.81 (m, 1H), 6.89-6.99 (2H), 7.32-7.38 (1.5H), 7.68 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.18 (br s, 1H, NH), 11.22 (d, J=6 Hz, 1H, NH); ESI-MS m/z 585.5 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[C:4]=1[CH:11]([OH:13])[CH3:12]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:11]([C:4]1[C:5](=[O:10])[N:6]([CH3:9])[N:7]=[CH:8][C:3]=1[N:2]([CH3:14])[CH3:1])(=[O:13])[CH3:12]
Reactant: CC(O)c1c(N(C)C)cnn(C)c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(N(C)C)cnn(C)c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
In chloroform was dissolved 5-dimethylamino-4-(1-hydroxy)ethyl-2-methyl-3(2H)-pyridazinone (355 mg) followed by addition of active manganese dioxide (2.0 g), and the mixture was stirred at 50° C. for 24 hours. After the oxidizing agent was filtered off, the filtrate was concentrated and the residue was washed with n-hexane and diethyl ether and dried. Yellow powder, 178 mg. 1 H-NMR (CDCl3) E: 2.6.7(3H,s), 2.94(6H,s), 3.69(3H,s), 7.66(1H,s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:25][C:13]1[S:12][C:11]2[CH:26]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:8]=[CH:9][C:10]=2[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: C1CCNCC1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(OCCCCN3CCCCC3)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and piperidine were converted to yield 1-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-piperidine as yellowish oil, MS: 448 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][C:13](=[CH2:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.S(C1C=C(C(C)(C)C)C(O)=CC=1C)C1C=C(C(C)(C)C)C([OH:31])=CC=1C.ClC1C=C(C=CC=1)C(OO)=O>C(Cl)CCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][C:13]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:19][O:31]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: C=C(CS(=O)(=O)c1ccc(OC)cc1)C(=O)OCC
Reactant: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: CCOC(=O)C1(CS(=O)(=O)c2ccc(OC)cc2)CO1

Procedure:
To 2[(4-methoxybenzenesulfonyl)methyl]-acrylic acid, ethyl ester (38.4 g, 0.152 mol) in 200 mL of ethylene dichloride is added a small amount of the radical inhibitor 4,4′-thiobis-(6-t-butyl-3-methylphenol) [Ref: J.C.S. Chem. Commun., 1972, pp 64-65]. Technical grade m-chloroperoxybenzoic acid (MCPBA, 154 g) is added portionwise over about 45 minutes. The reaction becomes a heavy white slurry. Additional ethylene dichloride (150 mL) is introduced to facilitate stirring. The reaction is refluxed overnight, then cooled and concentrated under reduced pressure. The residue is mixed with ethyl acetate (250 mL) and aqueous sodium sulfite. Solid potassium bicarbonate is then slowly added. The phases are separated , and the aqueous phase is extracted with additional ethyl acetate (100 mL). The combined organic phases are washed with several portions of aqueous potassium bicarbonate, then saturated brine, and finally dried over magnesium sulfate. Filtration and evaporation provides the crude product as a pale yellow oil. Chromatography on silica gel, eluting with a gradient of 40% to 60% ethyl acetate in hexanes, affords the title compound. m.p. 77-79° C.;
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([OH:12])=[O:11])[C:7]1[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=1[S:5]2.[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:10]([O:12][CH2:19][CH3:20])=[O:11])[C:7]1[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=1[S:5]2
Reactant: Cc1nc2sc3ccccc3n2c1C(=O)O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2sc3ccccc3n12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Subsequently, 6.0 g of 2-methylimidazo[2,1-b]benzothiazole-3-carboxylic acid was suspended in 100 ml of dry dimethylformamide. Under ice cooling, 1.5 g of 60% sodium hydride was added to the suspension. After stirring for 30 minutes, 6.0 g of ethyl iodide was added to the mixture followed by heating at 40° C. overnight. After completion of the reaction, the solvent was removed under reduced pressure. Ether and water were added to the residue, which was fractionated. The residue obtained from the ether phase was crystallized with n-hexane to give 4.0 g of ethyl 2-methylimidazo[2,1-b]benzothiazole-3-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]=2[N:4]([CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[C:3]1=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[CH:28][CH:27]=1.O.[NH:38]1[C:42]([NH2:43])=[N:41][N:40]=[N:39]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]=2[N:4]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([NH:43][C:42]3[NH:41][N:40]=[N:39][N:38]=3)=[O:21])=[CH:23][CH:24]=2)[C:3]1=[N:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[CH:30][CH:31]=1
Reactant: CCCOc1ccc2c(c1)n(C)c(=Nc1ccc(-c3ccsc3)cc1)n2Cc1ccc(C(=O)O)cc1
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCOc1ccc2c(c1)n(C)c(=Nc1ccc(-c3ccsc3)cc1)n2Cc1ccc(C(=O)Nc2nnn[nH]2)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To the title compound of Example 18, Step G (0.18 mmol, 88 mg) was added a solution of 1H-tetraazol-5-amine monohydrate (0.72 mmol, 74 mg), HOBt (0.72 mmol, 110 mg), EDC (0.72 mmol, 138 mg) and DIEA (1.08 mmol, 300 μL) in DMF (4 mL). The reaction mixture was stirred at 40° C. overnight, then concentrated under reduced pressure. The residue was taken up in 4:1 dioxane/H2O, acidified with TFA, and purified by reverse-phase chromatography (20-80% MeCN in H2O, both containing 0.1% TFA). Lyophilization afforded the title compound as a white solid. H1 NMR (500 MHz, d6-DMSO): 8.06 (d, J=6.7 Hz, 2H), 7.88 (m, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.65 (dd, J=3.0, 5.0 Hz, 1H), 7.57 (d, J=4.4 Hz, 1H), 7.50-7.45 (m, 2H), 7.38 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.0 Hz, 1H), 7.05 (m, 1H), 5.55 (s, 2H), 4.04 (t, J=6.6 Hz, 2H), 3.58 (s, 1H), 3.43 (s, 3H), 3.19 (m, 2H), 1.78 (m, 2H), 1.01 (t, J=7.4 Hz, 3H). LC-MS (ESI, Method B): 1.79 min, m/z 565.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([CH:14]=[O:19])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Yield: 105.8 %

Procedure:
[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (7.50 g, 26.2 mmol) in dry ether (150 ml) was reduced with an excess LiAlH4. The reaction mixture was quenched by careful addition of water and extracted with CHCl3. The mixture was dried and concentrated under reduced pressure to give (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (6.30 g, 93%).