Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl.[NH2:21][OH:22]>CCO>[OH:22][NH:21][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(C(=N)NO)cc1
Temperature: 70 °C
Yield: 97.8 %

Procedure:
To a mixture of 4-Methoxy-benzonitrile (1.07 g, 8 mmol) and DIEA (4.11 ml, 24 mmol) in EtOH (12.5 ml) was added 1.7 g of Hydroxylamine hydrochloride (24 mmol) and the reaction was heated at 70° C. for 48 h. Half of the solvent was removed under reduced pressure. The mixture was poured in DCM (100 ml) and water (30 ml). 2.5 ml of NaOH 1N was added until pH=9-10. The organic layer was separated and the aqueous phase was extracted with DCM. The organics layers were combined, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure to afford 1.3 g (98%) of N-Hydroxy-4-methoxy-benzamidine as a colorless oil which can be used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH:16]2[CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: NC1CC1
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(Br)cc1C(F)(F)F
Yield: 96.2 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and cyclopropylamine (0.27 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-cyclopropyl-2-(trifluoromethyl)benzenesulfonamide (0.51 g, 96%) was provided after purification. MS (ESI) m/z 344. HPLC purity 100.0% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)[CH:22]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37].CCOCC>CO>[ClH:37].[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[CH:22]=2)[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOCc3ccccc3)CC2)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: c1ccc(COCCC2CCN(c3cncc(OC[C@@H]4CCCN4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (120 mg, 0.24 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (2 mL) under Ar at room temperature. The mixture was stirred at room temperature overnight. After the solvent was evaporated, the residue was dissolved in deionized water. The aqueous solution was washed three times with EtOAc, then filtered over a cotton plug. The water was removed under reduced pressure at 35° C., and the residue was purified by preparative HPLC (ACE AQ 150×21.2 mm; UV detection at 254 and 280 nm; flow 10.0 mL/min; gradient of 0 to 50% CH3CN in water [both containing 0.05 vol % CF3COOH] in 25 min, to 100% in another 5 min; tR 12.8-19.4 min) to obtain, after evaporation, the trifluoroacetate (131 mg). This salt was treated with PL-HCO3 MP anion exchange resin (Polymer Laboratories) in MeOH to afford the free amine, which was dissolved in MeOH (0.5 mL) and treated again with 2N anhydrous HCl/ether (2 mL) under Ar protection at room temperature. The mixture was stirred at room temperature overnight. After the solvent was evaporated, the residue was dissolved in deionized water (approx. 25 mL). The solution was filtered over a cotton plug, and the water was removed under reduced pressure at 35° C. After lyophilization from water, the hydrochloride (103 mg) was obtained as a yellow glass. [α]20D+1.8 (c 0.555 g/L, MeOH). 1H NMR (D2O, 400 MHz) δ 7.89 (s, 1H), 6.67 (s, 1H), 7.32 (s, 1H), 7.26-7.18 (m, 5H), 4.49 (m, 3H), 4.37 (m, 1H), 4.17 (m, 1H), 3.63 (m, 2H), 3.44 (t, 2H, J=6.8 Hz), 3.27 (t, 2H, J=6.8 Hz), 2.82 (m, 2H), 2.16-2.13 (m, 1H), 2.02-1.93 (m, 2H), 1.90-1.79 (m, 1H), 1.60 (m, 2H), 1.42 (m, 1H), 1.38 (m, 2H), 1.11 (m, 2H). 13C NMR (D2O, 100 MHz) δ 156.4, 148.8, 137.0, 128.2, 128.0, 127.7, 121.8, 117.3, 114.3, 72.0, 67.2, 58.1, 47.5, 45.6, 34.5, 31.2, 30.0, 25.4, 23.0. HRMS (ESI) calcd for C24H34N3O2 (M+H+) m/z 396.2651, found 396.2637. Anal. Calcd. for C24H33N3O2.3.0HCl.0.85H2O: C, 55.41; H, 7.30; N, 8.08; Cl, 20.44. Found: C, 55.64; H, 7.57; N, 8.21; Cl, 20.43.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.C([N:34](CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH2:34])=[O:27])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
A mixture of 0.115 g (0.26 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1), 0.105 g (1.04 mmole) of triethylamine, 0.148 g (0.39 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes, then 0.045 g (0.84 mmole) of ammonium chloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.075 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-2).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[C:26]([CH3:31])=[N:27][O:28][C:29]=1[CH3:30]>>[CH3:31][C:26]1[C:25]([CH2:24][N:15]2[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:22])[CH:12]=3)[C:14]2=[O:21])=[C:29]([CH3:30])[O:28][N:27]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: Cc1noc(C)c1CN1C(=O)N(c2cnn(Cc3c(C)noc3C)c2)C(=O)C1(C)C

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 4-(chloromethyl)-3,5-dimethylisoxazole. MS 413 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.08 μM.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:47][N:48]([CH3:55])[CH2:49][C:50]([CH3:54])([CH3:53])[CH2:51][NH2:52]>C(Cl)(Cl)Cl.CS(C)=O.C(Cl)Cl>[CH3:47][N:48]([CH3:55])[CH2:49][C:50]([CH3:54])([CH3:53])[CH2:51][NH:52][C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:27]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:29]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CN(C)CC(C)(C)CN
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)CC(C)(C)CNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Temperature: 85 °C
Yield: 11.5 %

Procedure:
3-Fluoro-N-[4-(2-methylsulfanyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-morpholin-4-yl-benzamide (457 mg, 0.908 mmol) and MCPBA (447 mg, 1.998 mmol) in CHCl3 (5 ml) is stirred at room temperature for 1 h. The mixture is diluted with CHCl3 (5 ml) washed with sat'd NaHCO3 solution (5 ml), water (5 ml), dried over Na2SO4 and concentrated to give a yellow solid. The yellow solid is mixed with N,N,2,2-tetramethyl-1,3-propanediamine (1.18 g, 9.08 mmol) and DIPA (1.58 ml, 9.08 mmol) in DMSO (2 ml), and heated to 85° C. for 4 h. The resulting mixture is diluted with CH2Cl2 (2 ml), washed with 0.01 N NaOH, dried over Na2SO4, concentrated. The residue is purified by column chromatography on silica gel (EtOAc) to give N-{4-[2-(3-dimethylamino-2,2-dimethyl-propylamino)-pyrimidin-4-yloxy]-naphthalen-1-yl}-3-fluoro-5-morpholin-4-yl-benzamide as a white solid (60 mg). 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 8.08 (s, 1H), 8.01 (d, 1H), 7.92 (m, 2H), 7.57 (t, H), 7.51 (t, 1H), 7.30 (d, 2H), 7.21 (d, 1H), 6.82 (dt, 1H), 5.87 (s, 1H), 4.33 (m, 1H), 3.23 (s, 1H), 2.27 (s, 6H), 2.21 (m, 2H), 2.02 (m, 2H), 1.82 (m, 2H), 1.57 (m, 3H), 1.39 (m, 3H), 0.98 (s, 6H); MS 586.37 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[C:16](OC(=O)C)(=O)[CH3:17]>O>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]=[C:16]2[CH3:17])([O-:15])=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Solvent: O
Product: Cc1nc2ccccc2c2c([N+](=O)[O-])cnn12
Yield: 50 %

Procedure:
20.4 g (0.1 mole) of 5-(o-aminophenyl)-4-nitropyrazole are heated with 100 ml of acetic anhydride for 2 hours under reflux. The solution obtained is poured into water, the precipitate that solidifies is filtered off, washed with water, dried, then boiled in a ten times' quantity of xylene for 5 hours. Thus, 11.4 g (50%) of 1-nitro-5-methylpyrazolo[1,5-c]quinazoline are obtained. M.p.: 178°-179° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CON(C)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1CCCCC1>[C:26]1([C:25](=[O:32])[C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C#Cc1ccccc1
Reactant: CON(C)C(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C(C#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
Place lithium diisopropylamide (10 mL of a 1.5M solution in cyclohexane) and tetrahydrofuran (40 mL) under an argon atmosphere and cool to 0° C. Add, by dropwise addition, phenylacetylene (1.65 mL, 15 mmol). Remove the cooling bath and stir for 30 minutes as room temperature. Cool the yellow solution to 0° C. and add, by dropwiseaddition, N-methoxy-N-methylbenzamide (3.04 mL, 20 mmol). Remove the cooling bath and stir for 30 minutes at room temperature. Pour onto ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield an oil. Purify by silica gel chromatography (2% ethyl acetate/hexane) then purify further by distillation (2X) to yield 1.9 g of the title compound; bp 210° C. in vacuo.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:17]=1.Cl[C:19]1[N:20]([CH3:32])[C:21](=[O:31])[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[N:24]=1.C(N(CC)CC)C>O1CCCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:19]4[N:20]([CH3:32])[C:21](=[O:31])[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][N:26]=5)[N:24]=4)[CH2:15][CH2:16]3)=[CH:9][S:8][C:7]=2[CH:17]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(c3csc4cc(F)ccc34)CC2)nc(-c2ccncn2)cc1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 74.6 %

Procedure:
To a solution of 4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride (200 mg, 0.74 mmol) and 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (160 mg, 0.70 mmol) in tetrahydrofuran (10 mL) was added triethylamine (212 mg, 2.1 mmol). The mixture was stirred at 90° C. for 6 h. The solvent was evaporated off in vacuo and the residue was treated with water and chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from ethyl acetate gave 2-[4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (220 mg, 96%) as colorless crystals.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]([OH:40])([C:27]([S:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)([CH3:29])[CH3:28])[CH2:25][OH:26].[C:41]1([C@H:47]([CH3:51])[C:48](O)=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(OCC)(=O)C>ClCCl>[C:41]1([C@H:47]([CH3:51])[C:48]([O:26][CH2:25][C:24]([C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[F:16])([OH:40])[C:27]([S:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)([CH3:29])[CH3:28])=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: COc1ccc(CSC(C)(C)C(O)(CO)c2ccc(F)cc2F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CSC(C)(C)C(O)(COC(=O)[C@@H](C)c2ccccc2)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 11.7 g (56.7 mmol) of 1,3-dicyclohexylcarbodiimide in 38 ml of dichloromethane was added dropwise to a mixture of 14.0 g (38.0 mmol) of (±)-2-(2,4-difluorophenyl)-3-((4-methoxyphenyl)methylthio)-3-methylbutane-1,2-diol, 6.3 g (41.8 mmol of (S)-(+)-2-phenylpropionic acid, 0.47 g (3.8 mmol) of 4-dimethyl-aminopyridine, and 190 ml of dichloromethane with stirring under ice-cooling, followed by stirring for 3 hours. The mixture was warmed to room temperature, and the stirring was continued for 12 hours. Ethyl acetate was added to the reaction mixture, and the precipitated insoluble matter was removed by filtration. The filtrate was washed successively with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography using a mixed solvent of hexane and ethyl acetate (10:1) as an eluent. The solvent was removed from each fraction by distillation under reduced pressure to obtain diastereomers (A-1) and (A-2) of 2-(2,4-difluoro-phenyl)-2-hydroxy-3-((4-methoxyphenyl)methylthio)-3-methylbutyl (S)-(+)-2-phenylpropionate in a yield of 9.3 g (49%) and 8.7 g (46%), respectively, as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1.C[O-].[Na+].Cl.[C:19](=O)([O:22]C)[O:20][CH3:21]>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:19]([O:20][CH3:21])=[O:22])[C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCCC2
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1CCCc2ccc(OC)cc2C1=O
Temperature: 110 °C
Yield: 91 %

Procedure:
To 3-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (20.32 mg, 107 mmol) dissolved in dimethyl carbonate (500 ml) was added sodium methoxide (28.85 g, 534 mmol), and the resulting mixture was stirred at reflux with heating (110° C.) for 6 hours. The reaction mixture was mixed with 2 N hydrochloric acid (320 ml) under ice cooling and was concentrated under reduced pressure to remove the organic solvent, and then the aqueous layer was extracted with ethyl acetate (200 ml, 150 ml×3). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 150 g, ethyl acetate/hexane=1/19). The objective fractions were concentrated under reduced pressure to obtain methyl 3-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (24.20 g, 97.5 mmol, 91%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11](=[O:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]nc(-c2cccc(I)c2)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(-c2cccc(I)c2)oc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
5-(3-Iodophenyl)-1,3,4-oxadiazol-2(3H)-one (778 mg, 2.70 mmol) obtained in Step 1 was dissolved in DMF (14 mL), and the mixture was stirred at room temperature for 1 hour after adding potassium carbonate (840 mg, 4.05 mmol) and methyl iodide (0.20 mL, 3.24 mmol). The mixture was stirred after adding water, and the precipitated solid was filtered off and dried to give 5-(3-iodophenyl)-3-methyl-1,3,4-oxadiazol-2 (3H)-one (736 mg, 90%).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].CO>C1COCC1.O>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1)#[N:22]
Reactant: CCOC(=O)CCCOc1ccc(-c2ccc(C#N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(OCCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
To a solution of 4-(4′-cyanobiphenyl-4-yloxy)butyric acid ethyl ester (3.78 g, 12.7 mmol) in THF (50 ml) was added a solution of NaOH (1.0 g, 25 mmol) in water (1.5 ml). The mixture was stirred at room temperature for 1.5 h and then at 67° C. for 3 h. More NaOH (1 g) in water (1 ml) was added, and stirring at room temperature was continued for 15 h. MeOH (10 ml) was added, and after stirring at room temperature for 1.5 h the mixture was diluted with water (150 ml) and acidified with concentrated, aqueous HCl (6.6 ml). The product was isolated by filtration and washed with water (approx 20 ml). The solid was suspended in MeCN (50 ml), heated to reflux (no dissolution) and allowed to cool to room temperature. Filtration and drying under reduced pressure yielded 2.70 g (76%) of 4-(4′-cyanobiphenyl-4-yloxy)butyric acid as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7]([Cl:10])(=[O:9])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([N+:12]([O-:14])=[O:13])[C:6]=1[S:7]([Cl:10])(=[O:8])=[O:9]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)sc(Cl)c1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 55.8-g (0.22 mol) sample of 2,5-dichloro-3-thienylsulfonyl chloride was added in small portions to a stirred solution of 150 ml concentrated nitric acid and 150 ml concentrated sulfuric acid. After the addition was completed, the reaction mixture was stirred at about 25° C overnight. The reaction mixture was then diluted with ice water and filtered to give the crude 2,5-dichloro-4-nitro-3-thienylsulfonyl chloride product. The product was washed with water and dried. Recrystallization from methylene chloride gave the product as a brown solid, m.p. 89° -91° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.Cl.C[NH:33][O:34][CH3:35].C(N(CC)CC)C>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:33][O:34][CH3:35])=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CONC(=O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.2 %

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoyl chloride hydrochloride (100 mg; 0.23 mmol) was suspended in dichloromethane (10 ml), N,O-dimethyl hydroxylamine hydrochloride (38 mg; 0.45 mmol) added followed by triethylamine (0.16 ml; 1.1 mmol). The resulting mixture was stirred at ambient temperature for 18 h. The mixture was evaporated to dryness under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, dried (MgSO4) and evaporated to dryness under reduced pressure. The title compound (4 mg; 4%) was obtained by high performance liquid chromatography. 1H NMR (250 MHz; CD3OD) δ: 3.74 (3H, s), 6.00 (2H, s), 6.94 (1H, d,), 7.04-7.08 (2H, m), 7.50-7.70 (2H, m), 7.85 (2H, d), 8.00-8.20 (3H, m), 8.59 (1H, d); m/z (ESMS): 415.1 [M+H]⊕.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[NH:26][C:9]2[CH2:10][C@@:11]3([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[C@H:16]([CH2:17][C:8]=2[C:7]=1[CH3:27])[CH2:15][NH:14][CH2:13][CH2:12]3)=[O:5])[CH3:2].[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH:35]=O.C([BH3-])#N.[Na+].[ClH:41]>CO.C(O)(=O)C>[ClH:41].[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[NH:26][C:9]2[CH2:10][C@@:11]3([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[C@H:16]([CH2:17][C:8]=2[C:7]=1[CH3:27])[CH2:15][N:14]([CH2:35][C:31]1[O:30][CH:34]=[CH:33][CH:32]=1)[CH2:13][CH2:12]3)=[O:5])[CH3:29]
Reactant: O=Cc1ccco1
Reactant: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@H]1CNCC[C@@]1(c1cccc(OC)c1)C2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@H]1CN(Cc3ccco3)CC[C@@]1(c1cccc(OC)c1)C2
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1.3 g (3.3 mmol) of (±)-trans-2-diethylaminocarbonyl-8a-(3-methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline, 0.28 ml (4.95 mmol) of acetic acid, 0.33 ml (3.96 mmol) of 2-furaldehyde were dissolved in 50 ml of MeOH under nitrogen atmosphere. 0.415 g (6.6 mmol) of sodium cyanoborohydride were added and the solution stirred for 15 h. Additional acetic acid (0.1 ml), 2-furaldehyde (0.3 ml) and sodium cyanoborohydride (0.2 g) were added. After two hours of stirring the reaction mixture was cooled to 0° C. and 50 ml of 5N hydrochloric acid were added. The solvent was removed in vacuo, the aqueous solution was extracted with Et2O, the pH was adjusted to 8 with 20% NaOH and then extracted with AcOEt. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was dissolved in acetone/MeOH and the solution brought to acidic pH with HCl/Et2O . The precipitate was filtered, yielding 1.7 g of the title compound. M.p.=105° C. dec.