Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[CH3:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[C:17]([CH3:21])[C:18]=1[O:19][CH3:20].C1COCC1>>[OH:5][C:4]1([C:15]2[CH:16]=[C:17]([CH3:21])[C:18]([O:19][CH3:20])=[C:13]([CH3:12])[CH:14]=2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: COc1c(C)cc([Mg]Br)cc1C
Solvent: C1CCOC1
Product: COc1c(C)cc(C2(O)C(=O)Nc3ccccc32)cc1C
Yield: 84 %

Procedure:
Using a method similar to Preparation 18 with isatin (1.77 g, 12 mmol) a 0.5M solution of 3,5-dimethyl-4-methoxyphenylmagnesium bromide in THF (50 mL, 25 mmol) gives 2.70 g (84%) of a yellow solid. MS (ES): m/z=266 (M+1−H2O), 282 (M−1); 1H NMR(DMSO-d6): δ10.35 (s, 1H), 7.24 (dt, J=1.3 Hz, J=7.6 Hz, 1H), 7.10 (d, J=6.4 Hz, 1H), 6.98 (dd, J=0.9 Hz, J=7.5 Hz, 1H), 6.90 (m, 3H), 6.50 (s, 1H), 3.62 (s, 3H), 2.17 (s, 6H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+].O>C(Cl)(Cl)Cl>[CH2:26]([NH:33][CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: c1ccc(CNCC2CCn3c(nc4ccccc43)S2)cc1
Yield: 31.3 %

Procedure:
To a solution of 1.12 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in chloroform (20 ml) was added with 0.41 g of benzylamine and a catalytic amount of sodium hydride, and refluxed for 11 hours. The reaction mixture was cooled and then condensed under reduced pressure. Theresidue was added with water, extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.29 g (Yield: 31%) of theintended product, m.p. 155°-156° C.; IR νmaxKBr cm-1 : 3260, 3100-2800, 1600, 1420; Anal. Calcd. for C18H19N3S: C, 69.87; H, 6.19; N, 13.58; S, 10.36; Found: C, 70.00; H, 6.21; N, 13.69; S, 10.10.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:33])[NH:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:29]([O:28][C:26](=[O:27])[NH:25][CH2:24][CH2:23][NH:22][C:21](=[O:33])[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:16][CH:17]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CCCCN)cc1
Yield: 62.9 %

Procedure:
A suspension of 32 (0.9 g, 1.92 mmol) with 10% palladium on carbon (0.30 g, wet) in methanol (50 mL) was stirred for 2 h at room temperature under atmospheric pressure of hydrogen. The mixture was then filtered through a silica gel pad. The solvent was evaporated and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 33 (0.405 g, 63%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.08 (m, 2H), 1.37 (s, 9H), 1.58 (m, 2H), 2.52 (m, 2H), 3.28 (m, 2H), 6.91 (m, 1H), 7.27 (d, 2H), 7.74 (d, 2H), 8.39 (m, 1H).
Reaction SMILES: [Na].[P:2]([OH:7])([O:5][CH3:6])[O:3][CH3:4].[CH:8]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=O.CS(O)(=O)=O>CO>[O:13]=[C:12]1[C:11]2[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]([P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[O:14]1
Reactant: COP(O)OC
Reactant: O=Cc1ccccc1C(=O)O
Agent: CS(=O)(=O)O
Agent: [Na]
Solvent: CO
Product: COP(=O)(OC)C1OC(=O)c2ccccc21
Yield: 67.3 %

Procedure:
To dry methanol (40 ml) was slowly added sodium (1.15 g, 50 mmol) at 0 under N2 atmosphere while stirring, then added dimethyl hydrogen phosphite (5.5 g, 50 mmol), and 2-formylbenzoic acid (5.25 g, 35 mmol). The ice bath was removed and the reaction mixture was stirred for 30 min at room temperature, and then the reaction mixture was slowly added methanesulfonic acid (5.5 g, 55 mmol) and concentrated at reduced pressure to give the crude residue. The crude residue was partitioned between DCM and cold water (100 ml each), and the organic phase was washed with water and brine, dried over sodium sulphate, filtered, and concentrated to give the crude product (5.7 g, 67%) as an off white solid, used in next step without further purification.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[S:25][C:18]=34)=[C:12]([F:32])[CH:11]=2)=[O:8])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH3:39][S:40]([O-])(=[O:42])=[O:41]>CN(C=O)C.O>[CH:3]1([NH:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:30][CH:31]=5)[S:25][C:18]=34)=[C:12]([F:32])[CH:11]=2)=[O:8])[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)[O-]
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1)NC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 23.2 %

Procedure:
To a stirred suspension of compound 271 (150 mg, 0.302 mmol) and K2CO3 (180 mg, 1.302 mmol) in DMF (10 mL) was added 2,5,8,11-tetraoxamidecan-13-yl methanesulfonate (112 mg, 0.39 mmol, K. Fukase, et al., SynLett., 2005, 2342-2346). The reaction mixture was stirred at RT for 2.5 days, diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; MeOH/DCM: 0/100 to 15/85 over 20 CV) tp produce a material that upon trituration with Et2O/hexane afforded an unexpected compound 275 (35 mg, 0.07 mmol, 21% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.45 (d, J-5.6 Hz, 1H), 7.71 (dd, J=2.8 and 13.6 Hz, 1H), 7.57 (s, 1H), 7.35 (t, J=8.8 Hz, 1H), 7.22-7.16 (m, 1H), 6.02-5.95 (m, 2H), 6.44 (t, J=3.2 Hz, 1H), 3.95-3.90 (m, 2H), 3.42 (t, J=6.4 Hz, 2H), 2.96 (s, 3H), 2.58-2.50 (m, 1H), 0.68-0.62 (m, 2H), 0.44-0.41 (m, 2H). MS (m/z): 503.3 (M+H).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH2:23]>O1CCOCC1>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH3:15])[CH2:23][CH2:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccccn1
Solvent: C1COCCO1
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccccn1

Procedure:
A solution containing 2,2-diphenyl-5-methylaminopentanamide (2.0 g-see Preparation 3) and 2-vinylpyridine (1.1 ml) in dioxan (15 ml) was heated under reflux for 48 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (50 ml) and water (50 ml). The dichloromethane layer was dried (MgSO4) and concentrated in vacuo to give a solid which was purified by column chromatography eluting with hexane containing dichloromethane (50% up to 100%) and then with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil which was crystallised from acetonitrile, yield 0.5 g, m.p. 134°-136°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]([CH3:35])[C:29]2=[O:34].[BH4-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:17])([F:18])[F:19])[CH2:14][NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][N:28]([CH3:35])[C:29]3=[O:34])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cn1ccc2c(N)cccc2c1=O
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: [BH4-]
Agent: [Na+]
Product: Cn1ccc2c(NCC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cccc2c1=O

Procedure:
Analogously to Example 1, 4-(2,3-dihydro-5-fluoro-7-benzofuranyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-amino-2-methylisoquinol-1(2H)-one into the corresponding imine. After reaction with sodium borohydride, the title compound is obtained.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:22]([N:23]1[CH2:28][CH2:27][N:26]([CH2:14][CH2:13][CH2:12][CH:10]2[O:9][N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11]2)[CH2:25][CH2:24]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CCCC1CC(c2ccccc2)=NO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(C2=NOC(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)cc1
Yield: 106.8 %

Procedure:
3-(3-Phenyl-4,5-dihydroisoxazol-5-yl)propanal (19.1 mg, 0.087 mmol), 1-(diphenylmethyl)piperazine (20.0 mg, 0.079 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (50.4 mg, 0.237 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 37.1 mg (96.8%) of the target compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:13][CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)Cc1cccc(OCCCBr)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of methyl 3-hydroxyphenylacetate (11.3 g, 0.068 mole) in 300 mL of anhydrous toluene was treated with 3-bromopropanol (12.2 g, 0.088 mole). Polymer bound triphenylphosphine (36.0 g, 0.108 mole, 3 mmol/g, Fluka Chemie) was then added, and the mixture reacted for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (16.9 g, 0.084 mol) was added in a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered and the solid washed with 100 mL toluene. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford 15.8 g (81% yield) of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.23–7.19 (m, 1 H), 6.85–6.7 (m, 3), 4.09–4.06 (t, 2 H, J=5.8), 3.67 (s, 3 H), 3.67–3.56 (m, 4 H), 2.32–2.26 (p, 2 H, J=6.0); MS (ESP+) m/e 288 (MH+); TLC (hexanes:EtOAc/3:1) Rf=0.68. Anal. (C12H15O3Br) C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].C([O-])([O-])=O.[K+].[K+].P(=O)([O-])O[C:22](CC)(CC)[C:23]#[N:24]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6](/[CH:7]=[CH:22]/[C:23]#[N:24])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1cc(/C=C/C#N)ccc1OC
Yield: 59.6 %

Procedure:
3-Ethoxy-4-methoxybenzaldehyde (4.5 g, 25 mmol), K2CO3 (5.2 g, 37.5 mmol), and diethylcyanomethyl phosphonate (4.2 mL, 26.3 mmol) were combined in ethanol (75 mL). The mixture was stirred at reflux for 1.5 h. After all benzaldehyde had been consumed, the reaction mixture was concentrated to about 15 mL, and diluted with CH2Cl2 (150 mL) and H2O (150 mL). The mixture was shaken in a separatory funnel and the layers separated. The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was then titurated from ether to afford >99% of the (E)-3-(3-ethoxy-4-methoxyphenyl)-acrylonitrile 3.03 g as a light tan powder, 60%: 1H NMR (400 M Hz, CDCl3) δ 7.32 (d, 1H, J=16.4 Hz), 7.03 (dd, 1H, J=8.4, 2.0 Hz), 6.94 (d, 1H, J=2.0 Hz), 6.87 (d, 1H, J=8.4 Hz), 6.51 (d, 1H, J=16.8 Hz), 4.11 (q, 2H, J=6.8 Hz), 3.91 (s, 3H), 1.49 (t, 3H, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:18])=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2c(Cl)cccc2Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccc(CBr)cc1)c1c(Cl)cccc1Cl
Yield: 48.2 %

Procedure:
A refluxing mixture of 4-(2,6-dichlorobenzoyl)toluene (12.0 g, 45.2 mmol) and dibenzoylperoxide (90 mg, 0.37 mmol) in benzene (450 ml) was treated in portions with N-bromosuccinimide (8.83 g, 49.6 mmol), refluxed 1.5 hours, cooled, and evaporated to dryness under vacuum. The residue was triturated with diethyl ether (300 ml), filtered, and the filtrate was evaporated to dryness under vacuum. The crude product was chromatographed on a column of silica gel (700 g) eluted with 97:3 (v/v) hexaneethyl acetate to provide 7.49 g (48%) 4-(2,6-dichlorobenzoyl)benzyl bromide, m.p. 126°-130° C.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[Cs+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 85 °C

Procedure:
A stirred mixture of 4-bromobenzoic acid, ethyl ester (23.6 g, 103 mmol), 4-methoxyphenylboronic acid (15.6 g, 103 mmol), tetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol) and powdered caesium fluoride (30.0 g, 200 mmol) in 1,2-dimethoxyethane (300 mL) is heated at 85° C. for 3 h. The mixture is then treated with water (500 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 5% ethyl acetate/95% cyclohexane) to 4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester as a colourless crystalline solid. m.p. 103-104° C.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>>[N+:1]([C:4]1[N:5]([CH2:18][CH:17]([OH:19])[CH2:15][Cl:16])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1nccn1CC(O)CCl

Procedure:
Epichlorohydrin (100 mL) was added to a mixture of 2-nitroimidazole (11.3 g, 0.1 mol) and 1 g of potassium carbonate and the solution refluxed for 15-20 min until all 2-nitroimidazole was dissolved. The hot solution was filtered and the yellow crystal was collected to give compound (5, 17 g, 83%). 1H NMR (DMSO-d6, δppm): 3.61 (m, 2H, Cl—CH2—), 4.06 (m, 1H, HO—CH—), 4.32 (dd, 1H, N—CHa—, J=13.8 Hz, 8.4 Hz), 4.63 (dd, 1H, N—CHb—, J=13.8 Hz, 3.6 Hz), 5.67 (d, 1H, OH, J=5.7 Hz), 7.15 (s, 1H, —CH═), 7.56 (s, 1H, —CH═). 13C NMR (DMSO-d6, δppm):46.81, 52.27, 68.75, 127.40, 128.45, 144.98.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[N:20]1([C:24](=[O:30])[C:25]([OH:29])([CH3:28])[C:26]#[CH:27])[CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:24](=[O:30])[C:25]([OH:29])([CH3:28])[C:26]#[C:27][C:2]2[C:3]([F:19])=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)C(=O)N1CCC1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(=O)N1CCC1
Yield: 22 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 1-(azetidin-1-yl)-2-hydroxy-2-methylbut-3-yn-1-one to give the titled compound as a yellow solid (40 mg, 22%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].O[CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>Cl>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[CH2:7][S:5][CH2:4][CH2:3][NH2:2]
Reactant: NCCS
Reactant: OCc1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCSCc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(b)(i) Cysteamine hydrochloride (9.95 g) was dissolved in concentrated hydrochloric acid (50 ml) and the solution was cooled to 0°. 2-Hydroxymethylthiophene (10 g) was added dropwise to the stirred solution which was maintained at below 5°. The mixture was stirred overnight at room temperature, adjusted to pH 10 with concentrated aqueous sodium hydroxide and extracted with ethyl acetate. The extracts were evaporated and the residue was distilled at 158°-164°/760 mm Hg to give 2-(2-thienylmethylthio)ethylamine which was converted into the hydrochloride, m.p. 108°-111°, by treatment with ethanolic HCl and ether.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[C:26]1([C:32]2([CH2:36]O)[CH2:35][O:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13]2)=[O:25])=[CH:17][C:18]=1[O:24][CH2:36][C:32]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33][O:34][CH2:35]1
Reactant: OCC1(c2ccccc2)COC1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCC1(c2ccccc2)COC1

Procedure:
The compound of step 2 of example 15 and (3-phenyl-oxetan-3-yl)-methanol (S. Kanoh et al., Tetrahedron 58 (2002), 7065-7074) were reacted in analogy to step 3 of example 15, and the obtained methyl ester was hydrolyzed in analogy to example 16.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1>>[O:21]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[N:11][N:2]1[NH:1][C:31](=[O:32])[CH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:34])([F:22])[F:35])[CH:25]=1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 68B and 2-(3-(trifluoromethyl)phenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93-11.95 (bs, 1H), 8.55-8.57 (m, 1H), 8.37-8.40 (m, 1H), 8.09-8.13 (m, 1H), 7.98-8.03 (m, 3H), 7.77-7.82 (m, 1H), 7.59-7.71 (m, 6H), 3.83 (s, 2H); MS (ESI−) M/Z 486 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[N:25]1([CH2:30][CH2:31][NH2:32])[CH:29]=[CH:28][N:27]=[CH:26]1.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:32][CH2:31][CH2:30][N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Reactant: NCCn1ccnc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCCn4ccnc4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), 2-imidazol-1-yl-ethylamine and DIEA to give 4-ethoxy-6-[2-(2-imidazol-1-yl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 417 (MH+).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([N:8]1[CH2:11][C@H:10]([NH:12]C(OCC2C=CC=CC=2)=O)[C:9]1=[O:23])=[O:7])(=[O:4])=[O:3].[ClH:24]>CO.[Pd].O>[ClH:24].[CH3:1][S:2]([NH:5][C:6]([N:8]1[CH2:11][C@H:10]([NH2:12])[C:9]1=[O:23])=[O:7])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CS(=O)(=O)NC(=O)N1C[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 300 mg of (S)-N-(methylsulfonyl)-2-oxo-3-[[(phenylmethoxy)carbonyl]-amino-1-azetidinecarboxamide (see example 5) in 8 ml of dry methanol was added 150 mg of 10% palladium on charcoal. The mixture was hydrogenated at room temperature and 1 atmosphere for 30 minutes, and then 2 ml of water was added followed by dilute hydrochloric acid to adjust the pH to 1.8. The catalyst was filtered using water/methanol. Evaporation of the filtrate gave 65 mg of crude product. The catalyst was suspended in water, adjusted to pH 1.8 and stirred at room temperature for 15 minutes. Removal of the catalyst and evaporation of the filtrate provided additional crude product (124 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:20][CH3:21]>C1COCC1>[CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH2:20][CH3:21])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: c1ccc(CN2CC3CCCNC3C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCCC2CN(Cc3ccccc3)CC21
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a solution of 6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine (5.00 g) in THF was added 80% NaH (3.00 g) at room temperature. The reaction mixture was stirred for 30 min, and 5.3 mL of iodoethane was added dropwise. The reaction mixture was stirred for another 5 h, and then quenched with ice-water. The resulted mixture was extracted with CH2Cl2 (70 mL×5). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (2.58 g, 45.60%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 245.2 (M+1).