Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)[Cl:30]>Cl>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:30]
Reactant: ClCCl
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 0.67 h

Procedure:
11.83 g of Boc-Phe-Met-OMe (see Biochemistry, 8, 4183 (1969), incorporated herein) is dissolved in 100 ml methylene chloride after which HCl is passed into the solution for about 40 minutes. After evaporation of the solution to dryness, 75 ml ethyl acetate is added, resulting in a precipitate. The solid substance is separated by filtration, washed with petroleum ether, and dried. Melting point 123°-124° C. Rf in To:EtOH (8:2)=0.43 on SiO2.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C:16]([CH3:17])=[CH:15][C@@H:14]2[CH2:18][N:11]1[C:12](=[O:23])[N:13]2[O:19][CH2:20][CH:21]=[CH2:22])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[OH:8][CH2:9][C@@H:10]1[C:16]([CH3:17])=[CH:15][C@@H:14]2[CH2:18][N:11]1[C:12](=[O:23])[N:13]2[O:19][CH2:20][CH:21]=[CH2:22]
Reactant: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Into a 100-mL round-bottom flask, was placed tetrahydrofuran (30 mL), (2S,5R)-2-[[(tert-butyldimethylsilyl)oxy]methyl]-3-methyl-6-(prop-2-en-1-yloxy)-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (Intermediate 148, 3.2 g, 9.45 mmol, 1.00 equiv) and it was cooled to 0° C., then TBAF (14.2 mL 1N in THF, 1.50 equiv) was added dropwise. The resulting solution was stirred for 1 h at 0° C. in a water/ice bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:2). This resulted in 1.6 g (75%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(O)(=O)C.[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCNCC2)cc1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCN(C3CCOCC3)CC2)cc1
Reaction time: 0.33 h
Yield: 21.1 %

Procedure:
A solution of Compound 143 (0.166 g, 0.44 mmol) in dichloroethane was added with acetic acid (0.176 mL, 3.08 mmol) and tetrahydro-4-pyranone (0.224 mL, 2.42 mmol) followed by stirring for 20 minutes. The mixture was added with sodium triacetoxyborohydride (0.345 g, 1.63 mmol) followed by stirring at room temperature overnight. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=7:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 154 (44.2 mg, 0.093 mmol, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15]C(O)=O)[N:6]=[CH:5]2.C([N:21](CC)CC)C.ClC(OC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][NH2:21])[N:6]=[CH:5]2
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCn1ncc2cc(Br)ccc2c1=O
Agent: COC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NCCCn1ncc2cc(Br)ccc2c1=O
Temperature: 0 °C

Procedure:
6-Bromo-2-(3-carboxypropyl)phthalazin-1(2H)-one (9.3 gm, 0.03 mole, prepared in Example XIV) was dissolved in 185 ml acetone by adding 4.7 ml triethylamine (0.0335 mole). The slightly cloudy solution was clarified, cooled to <10° C. and 3.8 gm methyl chloroformate (0.04 mole) was added over about 5 minutes. Stirred with cooling for another 30 minutes, then added a solution of 4 gm sodium azide (0.062 mole) in 25 ml water. Stirred for 30 minutes, added to 400 ml ice water and extracted three times with 80 ml methylene dichloride. This solution was dried, 4 ml of trifluoroacetic acid was added, and the solution refluxed for 18 hours. Methanol (100 ml) was added and the solution shaken with dilute potassium carbonate solution to free the base. The resulting solution was acidified with 10 ml of 30% HBr in acetic acid, diluted with 900 ml ether, filtered and washed with ethyl acetate. The product weighed 6.3 gm and showed a single spot on tlc, Rf =0.28 (using 10% methanol in chloroform on an ammonia treated silica plate).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][O:17][CH3:18])=[CH:11][CH:10]=1.Cl.[CH3:32][O:33][NH2:34].C([O-])(=O)C.[Na+].O>CO>[CH3:32][O:33][N:34]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:23][C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])=[CH:21][C:20]=2[Cl:30])=[CH:10][CH:11]=1)[CH2:16][O:17][CH3:18]
Reactant: CON
Reactant: COCC(=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC(=NOC)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
296 mg of 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-ethanone, 56 mg of O-methylhydroxylamine hydrochloride and 55 mg of sodium acetate are stirred in 4 ml of methanol at room temperature for 24 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, the title compound is obtained in the form of an E/Z mixture. 1H-NMR (CDCl3) 300 MHz: 2.30 (m, 2H), 3.32+3.46 (s+s, 3H), 3.93+3.99 (s+s, 3H), 4.18 (t, 2H), 4.29 (m, 2H), 4.53-4.61 (m, 4H), 6.11 (t, 1H), 6.83 (s, 2H), 6.91 (d, 2H), 7.62 (d, 2H)
Reaction SMILES: O[C@@H:2]([CH3:23])[C@@H:3]([N:7]([CH3:22])[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[N:7]([CH3:22])[C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](O)[C@H](C(=O)O)N(C)C(=O)OCCCCCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1N(C)C(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 23.4 %

Procedure:
To a stirred mixture of (2R,3S)-3-hydroxy-2-[methyl-(5-phenylpentoxycarbonyl)-amino]-butanoic acid (0.04 g, 0.14 mmol) in dry CH2Cl2(5.0 mL), under nitrogen atmosphere at 0° C., Et3N (0.06 mL, 0.41 mmol) and subsequently TBTU (0.05 g, 0.17 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by column chromatography, eluting with Cy:EtOAc (from 100:0 to 0:100) to afford the title compound (0.01 g, 23%), as a mixture of two rotamers (1:1.5 ratio), as a colorless oil. [α]25D −16.66 (c 0.1, CHCl3). 1H NMR (DMSO-d6) δ 1.29-1.41 (m, 10H), 1.53-1.69 (m, 8H), 2.58 (t, J=7.6 Hz, 4H), 2.93 (s, 6H), 3.98-4.11 (m, 4H), 4.77-4.89 (m, 2H), 5.24-5.33 (m, 1H, major rotamer), 5.35-5.43 (m, 1H, minor rotamer), 7.13-7.32 (m, 10H).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:22])=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Br:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH:6]([CH3:22])[CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc2c(cc1Br)C(C)CNC(C)C2
Reaction time: 3 h
Yield: 93432.5 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.028 g, 0.069 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3 hours at 20 C. The product mixture was diluted with water (10 mL), extracted twice with EtOAc (10 mL), the combined organic phases were washed with brine (10 mL), dried with Na2SO4 and concentrated to give 0,020 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 730 (s, 1 H), 6.64 (s, 1 H), 6.06 (m, 1 H), 5.47 (d, J=17 Hz, 1 H), 5.30 (d, J=11 Hz, 1 H), 4.56 (s, 2 H), 3.03 (m, 2 H), 2.90 (dd, J=9, 14 Hz, 1 H), 2.80 (m, 1 H), 2.65 (d, J=14 Hz, 1 H), 2.55 (dd, J=10, 14 Hz, 1 H), 1.77 (bs, 1 H), 1.30 (d, J=7 Hz, 3 H), 1.20 (d, J=6 Hz, 3 H).
Reaction SMILES: CC(C)(S([NH:6][C@H:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)[CH3:8])=O)C.Cl>O1CCOCC1>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([C@@H:7]([NH2:6])[CH3:8])[CH2:10][CH2:11]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](NS(=O)C(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzyl 4-((1S)-1-(1,1-dimethylethylsulfinamido)ethyl)piperidine-1-carboxylate (1.825 g, 4.98 mmole) was dissolved in dioxane (10 mL) and 4N HCl in dioxane (5 mL, 1.3 eq.) was added. The mixture was stirred for 3 hours at room temperature. The solvents were removed by rotary evaption to give the title compound as ahydrochloride salt (1.3 g). 1H NMR (400 MHz, CD2Cl2) δ 8.46 (s, 2H), 7.44-7.27 (m, 5H), 5.11 (s, 2H), 4.26 (d, J=13.57 Hz, 2H), 3.24-3.12 (m, 1H), 2.86-2.61 (m, 2H), 1.99-1.86 (m, 3H), 1.38 (d, J=6.33 Hz, 3H), 1.34-1.23 (m, 2H). HRMS(C) tR=1.87 min; MS m/z 263.1760 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]=1[N+:23]([O-:25])=[O:24].Cl.[CH3:27][O:28][CH2:29][CH:30]([NH2:33])[CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:33][CH:30]([CH2:29][O:28][CH3:27])[CH2:31][CH3:32])[C:10]=1[N+:23]([O-:25])=[O:24]
Reactant: CCC(N)COC
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Product: CCC(COC)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 79.3 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl-ester (3.0 g, 7.19 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine HCl (2.01 g, 14.4 mmol) were treated substantially as described in Part C of Example 19a to produce 2.11 g (79%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 370.2 [(M+H)+, 100].
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][CH:25]([C:34]4[CH:39]=[CH:38][C:37]([S:40][CH3:41])=[CH:36][CH:35]=4)[CH:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[OH:27])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][CH:25]([C:34]4[CH:35]=[CH:36][C:37]([S:40][CH3:41])=[CH:38][CH:39]=4)[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:3])=[O:4]
Reactant: CSc1ccc(C(Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)C(O)c2ccccc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSc1ccc(C(Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)C(=O)c2ccccc2)cc1
Temperature: 21 °C
Reaction time: 2 h

Procedure:
To a solution of the crude oil from Step 3 in CH2Cl2 (5 mL) at 21° C. was added Dess-Martin periodinane (255 mg, 0.6 mmol) portionwise. The resulting reaction mixture was stirred 2 h at 21° C., then diluted with a sodium bicarbonate solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 50:50) provided the 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-1-phenyl-propan-1-one compound as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]1[CH2:28][O:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:23]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[O:21][CH3:20])[C:14](=[O:19])[CH2:13][CH2:12]2
Reactant: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1
Reactant: COc1ccccc1OCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCC(O)CN1C(=O)CCc2cc(-c3ccc(F)cc3F)ccc21
Yield: 49.3 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (180 mg, 0.69 mmol) (PT-012, made as in Example 1B, above) and 2-((2-methoxyphenoxy)methyl)oxirane (162 mg, 0.90 mmol) in anhydrous N,N-dimethylformamide (2 ml) was added caesium carbonate (326 mg, 1.00 mmol) in a 5 ml Personal Chemistry microwave reaction vial. The reaction vial was sealed, and subjected to microwave irradiation at 180° C. for 40 minutes. The reaction was cooled, poured into water (10 mL), extracted with ethyl acetate (2×30 mL), and the combined organic phases washed with water (30 mL), 2N sodium carbonate (30 mL), brine (40 mL), dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 6-(2,4-difluorophenyl)-1-(2-hydroxy-3-(2-methoxyphenoxy)propyl)-3,4-dihydroquinolin-2(1H)-one (148 mg, 0.34 mmol, 49%) (compound No. 88)). LCMS mz 440.0 (M+H), 462.0 (M+Na), anal HPLC >95% in purity. 1H NMR (400 MHz; CDCl3) δ 7.46 (d, J=8.6 Hz, 1H); 7.36 (m, 2H); 7.31 (bs, 1H); 6.88-7.03 (m, 6H); 4.36 (m, H); 4.27 (s, 1H), 4.26 (d, J=2.3 Hz, 1H); 4.15 (dd, J=9.8 and 5.5 Hz, 1H); 4.00-4.10 (m, 2H); 3.88 (s, 3H), 2.99 (m, 2H); 2.76 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]2[O:13][C@@H:14]([CH2:17]OS(C)(=O)=O)[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([C:31]2[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=2)[CH2:26]1.Br.C([O-])(O)=O.[Na+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]2[O:13][C@@H:14]([CH2:17][N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([C:31]4[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=4)[CH2:26]3)[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc([C@H]2CCCNC2)c1
Reactant: CS(=O)(=O)OC[C@H]1COc2cc(OCc3ccccc3)ccc2O1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4cc(OCc5ccccc5)ccc4O3)C2)c1
Temperature: 150 °C

Procedure:
To a solution of methanesulfonic acid (R)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl ester (129 mg, 0.368 mmol) and (R*)-3-(piperidin-3-yl)phenol.HBr (100 mg, 0.387 mmol) in acetonitrile was added solid KI (40 mg) and NaHCO3 (98 mg 1.162 mmol). The mixture was heated under microwave irradiation at 150° C. for 1 h. Solid material was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved to DCM and washed twice with water and brine. The organic phase was dried (Na2SO4), and evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc/heptane) to give the desired product (66.2 mg).
Reaction SMILES: C1(N[N:8]=[C:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][C:11]3[CH:17]=[CH:18][CH:19]=[N:20][C:10]2=3)C=CC=CC=1.[K+].[Br-].[C:23](#N)[CH3:24].O>C1(OC2C=CC=CC=2)C=CC=CC=1>[N:20]1[C:10]2[C:9]3[NH:8][C:24]4[C:23]([C:15]=3[CH2:14][C:13](=[O:16])[NH:12][C:11]=2[CH:17]=[CH:18][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:15]=4
Reactant: O=C1CCC(=NNc2ccccc2)c2ncccc2N1
Reactant: CC#N
Agent: [Br-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: O=C1Cc2c([nH]c3ccccc23)-c2ncccc2N1

Procedure:
Prepared according to general procedure B from 72.4 mg (0.27 mmol) 7,8-dihydro-5H-pyrido[3,2-b]azepine-6,9-dione 9-(phenylhydrazone) in 30 ml diphenyl ether. Recrystallization from ethanol afforded a brown solid. Yield: 17 mg (25%); m.p. >330° C.; IR (KBr): 3054 cm−1 (CH-arom.), 2974 cm−1 (CH-aliph.), 1675 cm−1 (C═O), 1H-NMR (d6-DMSO, 400 MHz): δ (ppm)=3.66 (s, 2H, azepine-CH2), 7.06-7.09 (m, 1H, arom. H), 7.18-7.22 (m, 1H, arom. H), 7.40 (dd, 1H, 8.2/4.5 Hz, arom. H), 7.47 (d, 1H, 8.2 Hz, arom. H), 7.62 (dd, 1H, 8.2/1.4 Hz, arom. H), 7.70 (d, 1H, 8.0 Hz, arom. H), 8.48 (dd, 1H, 4.5/1.4 Hz, arom. H), 10.22 (s, 1H, NH), 11.70 (s, 1H, NH); 13C-NMR (DMSO-d6, 100.6 MHz): δ (ppm)=31.9 (azepine-CH2), 111.9, 118.4, 119.1, 122.5, 122.8, 129.3, 144.3 (tert. arom. C), 108.9, 126.3, 132.0, 132.5, 137.5, 140.5 (quat. arom. C), 171.1 (C═O); C15H11N3O (249.27); purity (HPLC): 98.8% (ts=3.25 min, acetonitrile/water 35:65).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CCOC(=O)c1ccc(Cl)s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
Ethyl 5-chlorothiophene-2-carboxylate (2.7 g, 14.1 mmol) was added in portions to concentrated sulfuric acid (5 mL) and the stirred solution was cooled to below 0° C. with a methanol/ice bath. Fuming nitric acid (1.78 g, 1.2 mL, 28.3 mmol) was added slowly, keeping the temperature below 0° C. throughout the addition. On completion of addition the stirred mixture was removed from the cold bath and warmed to ambient temperature for 2 hours. The reaction was quenched by addition to ice/water (100 mL) resulting in formation of a sticky solid. The product was extracted into dichloromethane (2×100 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent was removed to afford an orange oil. The crude material was purified by silica gel chromatography using a 95:5 mixture of hexane and ethyl acetate as eluent to afford the title product as a solid (2.23 g, 67% yield). 1H NMR (CDCl3) δ: 8.14 (1H, s), 4.37 (2H, q, J=7.11 Hz), 1.37 (3H, t, J=7.11 Hz).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]C)=O.[NH2:11][C:12]([NH2:14])=[S:13].[OH-].[K+]>C(O)C.O>[SH:13][C:12]1[N:11]=[C:7]([OH:9])[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:14]=1
Reactant: COC(=O)C1CCCC1=O
Reactant: NC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1nc(S)nc2c1CCC2
Yield: 26.4 %

Procedure:
To a solution of the methyl 2-oxocyclopentanecarboxylate (40 g, 281 mmol) and thiourea (21 g, 281 mmol) in ethanol (200 ml) was added KOH (20 g, 356 mmol) in water (120 ml). The mixture was refluxed for 12 hour. The solvent was removed and the residue was quenched with concentrated HCl (25 mL). The precipitate was filtered, washed with water and dried to afford the 2-mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12.5 g, 26%). MS (APCI+) [M+H] +168.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[N:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[N:23]=[N:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][CH:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: O=C(c1ccc(Cl)nn1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nn1)N1CCOCC1
Temperature: 140 °C

Procedure:
A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol (E3) (84 mg, 0.385 mmol), 4-[(6-chloro-3-pyridazinyl)carbonyl]morpholine (E280, Step 1) (70 mg, 0.308 mmol) and potassium carbonate (85 mg, 0.616 mmol) in dry acetone (3 ml) was heated at 140° C. for 2×15 mins. (300 W) in a microwave reactor. The cooled reaction mixture was filtered, concentrated in vacuo. and Purified by column chromatography on silica gel, eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:190) to afford the title compound; MS (ES+) m/e 409 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2([OH:15])[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCOCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,4-Dibromobenzene (1 17.96 g, Aldrich) in tetrahydrofuran (THF) (700 ml) was cooled to -7020 C. under nitrogen and butylithium (175 ml) was added dropwise. After stirring the mixture for 15 minutes, tetrahydro-4H-pyran4-one (25 g, Aldrich) in the THF (300 ml) was added. The reaction was left for 2 hours before being allowed to warm to room temperature. The reaction mixture was shaken with 5% citric acid (800 ml), then extracted with diethyl ether (3×600 ml). The combined organic layers were washed with water (500 ml), and dried over MgSO4. Removal of the solvent from the filtrate gave the crude tide product as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[OH:14][CH:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(C2CCC(O)CC2)cc1
Yield: 87 %

Procedure:
10 g (0.052 mol) of 4-(4-Hydroxy-phenyl)-cyclohexanone is dissolved in 300 mL of methanol. 2.13 g (0.058 mol) of NaBH4 is added at room temperature by small portion for 2 hours. After stirring over night, the mixture is cooled using an ice-water bath, then hydrolysed with a solution of 10% HCl aqueous solution. The solution is extracted several times with ethyl acetate. The resulting organic phase is washed with water, dried over magnesium sulfate, then concentrated under reduced pressure. The residue recrystallised from ethanol gives pure white crystals (8.7 g, 87% yield).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=[CH:10][CH:11]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:13]1[CH:17]=[CH:16][N:15]2[CH:18]=[C:19]([C:21]([NH:23][NH2:24])=[O:22])[N:20]=[C:14]12>CO>[N+:1]([C:4]1[O:8][C:7]([CH:9]=[CH:10][CH:11]=[N:24][NH:23][C:21]([C:19]2[N:20]=[C:14]3[N:15]([CH:18]=2)[CH:16]=[CH:17][S:13]3)=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NNC(=O)c1cn2ccsc2n1
Reactant: O=CC=Cc1ccc([N+](=O)[O-])o1
Solvent: CO
Product: O=C(NN=CC=Cc1ccc([N+](=O)[O-])o1)c1cn2ccsc2n1

Procedure:
According to the same procedure as in Example 1.2., 1.1 g (0.065 mole) of 3-(5-nitro-2-furyl)-2-propenal and 1.2 g of imidazo[2,1-b]-thiazole-6-carbohydrazide are reacted in methanol. The compound, melting point 332° C., is obtained.