Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[C:11]([CH3:17])[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[C:11]([CH2:17][Br:19])[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2cc(Cl)c(C)cc2c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCc1nc2cc(Cl)c(CBr)cc2c(=O)[nH]1
Reaction time: 3.5 h

Procedure:
To a suspension of 2-acetoxymethyl-7-chloro-6-methyl-3,4-dihydroquinazolin-4-one (2.00 g, 7.5 mmol) in anhydrous carbon tetrachloride (120 ml) was added N-bromosuccinimide (1.47 g, 8.3 mmol) followed by dibenzoyl peroxide (7.0 mg) under argon. The reaction mixture was placed in a preheated oil bath at 120° C. and stirred at this temperature for 3.5 hours while illuminating. The solvent was removed in vacuo and the residue was twice purified by column chromatography using 40% ethyl acetate in chloroform as eluant (1.02 g, 40%), mp 190-195° C., 1H-NMR (DMSO-d6) 2.14 (s, 3H, CH3CO), 4.91, 4.97 (2×s, 4H, 2-CH2 and 6-CH2), 7.78 (s, 1H, 8-H), 8.36 (s, 1H, 5-H), 12.61 (s, 1H, N3—H). This product was used in the next experiment without any further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[NH:26][C:25]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:23][C:18]=2[O:17][CH2:16]1>C1COCC1>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:30][CH2:31][N:32]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:33][CH2:34]4)[NH:26][C:25]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: Cc1cccc(-c2[nH]c(C3CCNCC3)nc2-c2ccc3c(c2)OCO3)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2[nH]c(C3CCN(S(C)(=O)=O)CC3)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
Methanesulfonyl chloride (0.009 mL, 0.12 mmol) and diisopropylethylamine (0.026 mL, 0.15 mmol) were added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine (0.036 g, 0.10 mmol; see Example 9) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.011 g (25%) of the title compound as a yellow solid. MS (ESP+) m/z 441.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.74 (t, 1H, J=7.9 Hz), 7.34 (m, 1H), 7.28 (m, 1H), 7.03 (m, 3H), 6.08 (s, 2H), 3.92 (m, 2H), 3.25 (m, 1H), 2.94 (m, 2H), 2.90 (s, 3H), 2.66 (s, 3H), 2.23 (m, 2H), 2.03 (m, 2H).
Reaction SMILES: C(C1N=C(NCC2C=CC(C3C=CC=CC=3[C:25]3[N:29](C)[N:28]=[N:27][N:26]=3)=CC=2)C(N)=CN=1)CCC.[CH2:32]([C:36]1[N:41]=[C:40]([N:42]([CH3:61])[CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3C3NN=NN=3)=[CH:46][CH:45]=2)[C:39]([NH2:62])=[CH:38][N:37]=1)[CH2:33][CH2:34][CH3:35].C(N(CC)CC)C.[CH3:70][S:71](Cl)(=[O:73])=[O:72]>C(Cl)(Cl)Cl>[CH2:32]([C:36]1[N:41]=[C:40]([N:42]([CH3:61])[CH2:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:48]([C:25]3[NH:29][N:28]=[N:27][N:26]=3)[CH:49]=2)[C:39]([NH:62][S:71]([CH3:70])(=[O:73])=[O:72])=[CH:38][N:37]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1ncc(N)c(NCc2ccc(-c3ccccc3-c3nnnn3C)cc2)n1
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1ncc(N)c(N(C)Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCc1ncc(NS(C)(=O)=O)c(N(C)Cc2ccc(-c3ccccc3)c(-c3nnn[nH]3)c2)n1

Procedure:
2-n-Butyl-5-amino-4-{N-[N-methyl-(2'-(1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine, the product of Example 46, is dissolved in chloroform containing triethylamine and treated with one equivalent of methanesulfonyl chloride to give the title compound.
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=1[Cl:17])([CH2:3][CH3:4])[CH3:2].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][NH:16][C:12]1[CH:11]=[C:10]([Cl:17])[C:9]([O:8][C:7]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:6]=2)=[C:14]([Cl:15])[CH:13]=1)[CH3:29]
Reactant: CCC(C)c1cc(Oc2c(Cl)cc(N)cc2Cl)ccc1OC
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1cc(Cl)c(Oc2ccc(OC)c(C(C)CC)c2)c(Cl)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
To 4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamine (71.8 g, 0.21 mol) was added ethyl bromoacetate (35.26 g, 0.21 mol) and diisopropylethyl amine (27.92 g, 0.21 mol) in DMF (718 mL) were stirred at 120° C. for 18 h. The reaction mixture was poured in to ice-water. The product was taken up in ethyl acetate, washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography over flash silica gel (Hexane:Ethylacetate 90:10) to afford the pure product [4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-phenylamino]-acetic acid ethyl ester. (48.0 g, 54% yield)
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:2][CH2:3][CH3:4].[OH:19]OS([O-])=O.[K+].C([O-])(O)=O.[Na+].CO>O>[CH2:1]([C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N+:12]([O-:19])=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=S([O-])OO
Reactant: CCCCc1c2c(nc3c1CCCC3)CCCC2
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1c2c([n+]([O-])c3c1CCCC3)CCCC2
Reaction time: 24 h
Yield: 125.3 %

Procedure:
Into a 2 L round-bottomed flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen inlet are placed 38.0 g (0.16 mol) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine, 72.0 g (0.12 mol) of Oxone (Note 9), 28.5 g (0.34 mol) of NaHCO3, 790 mL of methanol and 240 mL of water. The resulting suspension is stirred at 45°-50° C. in an atmosphere of nitrogen for 24 hrs. (Note 10). The cooled reaction mixture is vacuum filtered, washing the residual salts with methanol (2×50 mL). The methanol is removed from the combined filtrates by means of a rotary evaporator and the resulting mixture is extracted with methylene chloride (3×100 mL). The combined extracts are washed with water (2×50 mL), dried using anhydrous magnesium sulfate and concentrated to dryness by means of a rotary evaporator. Residual solvent is removed at 0.1 mm, yielding 39 g (96%) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine-N-oxide as a pale yellow solid, mp 89°-92° C. (Note 11).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][CH2:29][NH:28][C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27]
Reactant: NCCc1ccccn1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NCCc2ccccn2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and 2-aminoethylpyridine. The crude product was used without further purification (26%, oil). HPLC-MS: m/z=376.2 (M+1); Rt: 2.25 min.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:32]1[N:36]2[C:37]3[C:42]([NH:43][CH2:44][C:35]2=[CH:34][CH:33]=1)=[CH:41][CH:40]=[CH:39][CH:38]=3>O1CCCC1>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:43]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]3[CH:32]=[CH:33][CH:34]=[C:35]3[CH2:44]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: c1ccc2c(c1)NCc1cccn1-2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
A mixture of 0.51 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 0.36 g of 1,1'-carbonyldiimidazole in 6 ml of tetrahydrofuran is stirred at room temperature for 1 hour. To the reaction mixture is added 0.17 g of 4,5-dihydropyrrolo-[1,2-a]-quinoxaline followed by heating at reflux for 60 hours. The volatiles are concentrated in vacuo to a residue which is dissolved in ethyl acetate. The organic layer is washed with 1N HCl, 1M NaHCO3, brine, dried with Na2SO4 and filtered through hydrous magnesium silicate. The volatiles are concentrated in vacuo to a residue which is chromatographed by elution with 1:2 ethyl acetate-hexanes to give 0.14 g of the desired product as a white solid, m.p. 206°-207° C.; MASS SPEC (CI) 408(MH+).
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8][C:9]1[CH:14]=[C:13](I)[C:12]([F:16])=[CH:11][C:10]=1[CH3:17])[CH3:7].[B:18](OC)([O:21]C)[O:19]C>C1COCC1>[CH2:6]([O:8][C:9]1[C:10]([CH3:17])=[CH:11][C:12]([F:16])=[C:13]([B:18]([OH:21])[OH:19])[CH:14]=1)[CH3:7]
Reactant: CCOc1cc(I)c(F)cc1C
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)c(F)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
In dried glassware, 2.5M n-BuLi in hexanes (18.01 mL, 45.02 mmol) was added over 15 minutes to a stirred solution of 1-ethoxy-4-fluoro-5-iodo-2-methyl-benzene [CAS: 918813-06-6](9.7 g, 34.63 mmol) in dry THF (100 mL) at −78° C. under N2. After stirring for 30 mins, trimethyl borate (7.72 mL, 69.27 mmol) was added over 10 mins. The mixture was stirred for 3.25 h at −78° C. then quenched by slow addition of 1M HCl (115 ml). The mixture was warmed to ambient temperature, diluted with water (115 ml) and extracted with EtOAc (2×100 ml). The combined organic extracts were washed with saturated sodium metabisulfite soln (250 ml), brine (100 ml) and dried (MgSO4). The almost colourless solution was evaporated to a cream solid, dried rt/vac/1 h (wt=6.2 g). This solid was stirred with Et2O/iso-hexane (1:1) (40 ml) and filtered under suction and washed with the mixture then iso-hexane, dried rt/vac/overnight to give (5-ethoxy-2-fluoro-4-methyl-phenyl)boronic acid (D94) (4.0 g);
Reaction SMILES: C(OC(=O)[NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:17]=2)=[CH:11][N:10]=1)=S)C.[Cl-].O[NH3+].C([N:38](CC)C(C)C)(C)C.C(O)C>CO>[NH2:38][C:6]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:17]=3)=[CH:11][N:10]2[N:5]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(F)c(NC(=O)OC(C)(C)C)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)nn3c2)ccc1F
Yield: 83.5 %

Procedure:
In the same manner as in Example 23-1 and using ethyl{[(5-{3-[(tert-butoxycarbonyl)amino]-4-fluorophenoxy}pyridin-2-yl)amino]carbonothioyl}carbamate (13.5 g, 30.0 mmol), hydroxylammonium chloride (14.7 g, 212 mmol), N,N-diisopropylethylamine (26.2 mL, 150 mmol), ethanol (75 mL) and methanol (75 mL) as starting materials, the title compound (9.00 g, 84%) was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:32]([O:33][CH3:34])=[CH:31][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:8]=2[CH:7]=1)[N:15]=[CH:14][C:13]([C:18]#[N:19])=[C:12]3[NH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=1[Cl:30].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[I-].[Na+]>COCCOC>[Cl:30][C:22]1[CH:23]=[C:24]([Cl:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=1[NH:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:32]([O:33][CH3:34])=[CH:31][C:9]=3[CH:10]=2)[N:15]=[CH:14][C:13]=1[C:18]#[N:19]
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCN5CCOCC5)c(OC)cc4cc23)c(Cl)cc1Cl

Procedure:
Following procedure 1 of Example 149, a mixture of 0.105 g (0.20 mmol) of 8-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.3 mL of morpholine and 0.01 g of sodium iodide in 10 mL of 1,2-dimethoxyethane is heated under reflux for 7 hours. The resulting solid is purified by silica gel chromatography, utilizing a 98:2 to 94:6 gradient of methylene chloride/methanol to give 0.089 g of 4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(3-morpholin-4-yl-propoxy)benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 205-208° C.
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](Cl)=[O:38]>ClCCl.C(Cl)(Cl)Cl>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37]([N:20]1[CH2:21][CH2:22][CH:17]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[CH:11]4[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]4[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH2:18][CH2:19]1)=[O:38]
Reactant: O=C(Cl)c1cccs1
Reactant: O=C1NC2CCCCC2N1C1CCN(C2CCNCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1cccs1)N1CCC(N2CCC(N3C(=O)NC4CCCCC43)CC2)CC1
Reaction time: 48 h

Procedure:
To a solution of (trans (+/−))-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one. 2TFA (180 mg, 0.31 mmol) in a mixture of dichloromethane and chloroform (1:4) was added diisopropylethylamine (0.2 mL, 1.1 mmol) followed by thiophene-2-carbonyl chloride (0.1 mL, 0.6 mmol) at room temperature. The mixture stirred 48 hours and then quenched with water. Diluted in dichloromethane (60 mL) and washed with 1N NaOH (5 mL) and brine (5 mL) and concentrated in vacuo. The crude was purified by high pH prep LCMS (acetonitrile/water) to provide 26 mg of the title compound as a white solid. 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 1.26-1.58 (m, 6H), 1.59-2.03 (m, 9H), 2.12-2.34 (m, 3H), 2.44-2.64 (m, 1H), 2.82-3.06 (m, 6H), 3.62-3.84 (m, 1H), 4.29-4.57 (m, 2H), 4.63 (s, 1H), 7.01 (d, J=5.08 Hz, 1H), 7.18-7.27 (m, 1H), 7.35-7.46 (m, 1H). MS (M+1): 417.3
Reaction SMILES: C([Cu])#N.[CH2:4]1[O:8][CH:5]1[CH:6]=[CH2:7].[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.CCOCC>[C:9]1([CH2:7]/[CH:6]=[CH:5]/[CH2:4][OH:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CC1CO1
Reactant: Br[Mg]c1ccccc1
Agent: N#C[Cu]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC/C=C/Cc1ccccc1
Temperature: -78 °C

Procedure:
Anhydrous CuCN (4.86 g, 54 mmol) was added to a solution of butadiene monooxide (38 g, 540 mmol) in anhydrous tetrahydrofuran (1.2 L) and the resulting mixture was stirred at −78° C. Commercial phenyl magnesium bromide solution (Aldrich) in ether (65 mmol) was added dropwise over a period of 10 min. The resulting reaction mixture was then allowed to warm to 0° C. and it was continued to stir until the reaction mixture was homogeneous. After this period, the reaction mixture was cooled to −78° C. and 0.58 mole of phenylmagnesium bromide solution in ether was added dropwise for 30 min. The reaction mixture was allowed to warm to 23° C. for 1 h. The reaction was quenched by slow addition of saturated aqueous NH4Cl (120 mL) followed by NH4OH (70 mL), saturated NH4Cl (500 mL) and then H2O (300 mL). The aqueous layer was thoroughly extracted with ethyl acetate (2×300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was distilled under vacuum (0.12 torr) at 95° C. to give trans-4-phenyl-2-butene-1-ol (75.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH2:16])[CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[ClH:1].[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH:3]=1
Reactant: C=C(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)CNCC3
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)CNCC3
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 153.1 %

Procedure:
To the product obtained in step B (40.0 mg, 0.12 mmol) was added triethylsilane (0.5 mL, 3.22 mmol), trifluoroacetic acid (0.35 mL, 4.51 mmol) and boron trifluoride-diethylether complex (0.65 mL, 4.51 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 24 h under a nitrogen atmosphere, quenched with 20% potassium carbonate solution (15 mL) and extracted with dichloromethane. The organic extract was washed with water followed by brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 9:1 dichloromethane/methanol). The product was converted to hydrochloride salt by dissolving in dichloromethane and treating with 2 M HCl in diethyl ether at 0° C. After stirring for 20 min the reaction mixture was concentrated in vacuo to give 6-chloro-8-(1-phenylethyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (32 mg, 90%, AUC HPLC 96.5%) as an off-white solid: mp 245-255° C. dec.; 1H NMR (CD3OD, 400 MHz) δ 7.38 (d, J=0.8 Hz, 1H), 7.31-7.20 (m, 5H), 7.20-7.14 (m, 1H), 4.39 (s, 2H), 4.27 (q, J=7.2 Hz, 1H), 3.67 (t, J=6.0 Hz, 2H), 3.18 (t, J=6.0 Hz, 2H), 1.67 (d, J=7.2 Hz, 3H); APCI MS m/z 312 [M+H]+
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>CC(N(C)C)=O>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:30](=[O:31])[O:29]3)=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: O=C1OC(Br)c2ccccc21
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OC3OC(=O)c4ccccc43)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 59.2 %

Procedure:
The title compound (122 mg) was prepared from 162 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 128 mg of 3-bromophthalide in the same manner as in Example 81, except that only DMA was used as the solvent and the reaction was carried out at room temperature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C=CC1C=NC(C(C#N)(C)C)=C(Cl)C=1)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=CCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)C=Cc1cnc(C(C)(C)C#N)c(Cl)c1
Product: CCOC(=O)CCCCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared analogously to step 4 of example B(29)where 4-(4-ethoxycarbonyl-but-3-enyl)-piperidine-1-carboxylic acid tert-butyl ester from step 2 above, was substituted in place of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-acrylic acid ethyl ester of that example. 1H NMR (400 MHz, CDCl3): δ 0.99–1.12 (m, 2H), 1.23–1.40 (m, 8H), 1.45 (s, 9H), 1.56–1.66 (m, 4H), 2.27–2.32 (m, 2H), 2.61–2.70 (m, 2H), 4.04–4.16 (m, 4H). ESIMS (MH+): 314.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH3:15][O:16][CH2:17][CH2:18][NH:19][CH3:20]>>[CH3:15][O:16][CH2:17][CH2:18][N:19]([CH3:20])[CH2:13][CH2:12][CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Reactant: CNCCOC
Product: COCCN(C)CCCc1ccc2c(n1)COC2=O
Yield: 85.1 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (76 mg, 0.4 mmol) and N-(2-methoxyethyl)methylamine (43 μL, 0.4 mmol) are reacted to provide the title compound as pale yellow oil (90 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH3:13][O:14][C:15]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:17]=1[C:16]1[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:15]=1[O:14][CH3:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1cccc(C=O)c1OC
Reactant: Nc1nccs1
Reactant: [C-]#[N+]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1cccc(-c2nc3sccn3c2NC(C)(C)C)c1OC

Procedure:
Compound 37 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-amino thiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,3-dimethoxybenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[F:28].C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:18][C:11]=2[CH:12]=1)[CH:24]=[O:25]
Reactant: OB(O)c1cc2cc(N3CCCCC3)ccc2o1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cc3cc(N4CCCCC4)ccc3o2)c(F)c1
Yield: 25.2 %

Procedure:
A mixture of 5-(piperidin-1-yl)benzofuran-2-ylboronic acid (50 mg, 0.204 mmol), 4-bromo-3-fluorobenzaldehyde (37 mg, 0.184 mmol), triethylamine (0.56 mL, 4.1 mmol) and bis(triphenylphosphine)palladium(II)chloride (14 mg, 0.02 mmol) in ethanol (5 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (15 mg, 15% yield). ESI-MS: 324.2 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.19 (t, 1H), 7.75 (d, 1H), 7.67 (d, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 7.14-7.11 (m, 2H), 3.13 (m, 4H), 1.77 (m, 4H), 1.59 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[CH:29]([C:31]1[N:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[S:34][C:35]=1[CH3:36])=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH2:27][N:12]1[C:29]([C:31]2[N:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[S:34][C:35]=2[CH3:36])=[C:9]2[C:10]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:15])[N:7]([CH3:14])[C:8]2=[O:13])=[N:11]1
Reactant: Cc1sc(NC(=O)OC(C)(C)C)nc1C=O
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Product: Cc1sc(NC(=O)OC(C)(C)C)nc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by tert-butyl 4-formyl-5-methyl-1,3-thiazol-2-ylcarbamate.