Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.O.O.O.C([O-])(=[O:22])C.[Na+].[Cl-].[OH-].[Na+]>C(O)C.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:22]
Reactant: BrCCCCCCOCCc1ccccn1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCCCCOCCc1ccccn1
Yield: 70.3 %

Procedure:
A mixture of 2-[2[(6-bromohexyl)oxy]ethyl]pyridine (9.0 g), sodium acetate trihydrate (34.24 g), trictylpropylammonium chloride (1.9 g) and water (25 ml) was stirred under reflux for 2 h. 2N sodium hydroxide solution (50 ml) and ethanol (50 ml) were added to the cooled mixture which was further stirred for 10 min at room temperature. The ethanol was evaporated in vacuo and the residue diluted with brine (150 ml) and extracted with ether (2×100 ml). The combined organic extracts were washed successively with water (150 ml), brine (100 ml), dried and evaporated in vacuo to give a yellow oil. Purification by FCC eluting with ether gave the title compound as a colourless oil (4.94 g), t.l.c. (ether) Rf 0.31.
Reaction SMILES: [Li][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:8]1([P:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH4+].[Cl-]>C1COCC1>[C:25]1([P:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][CH:22]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:21]=[CH:20]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(P(c2ccccc2)c2cccc3cccnc23)cc1
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C1=CC(c2ccccc2)Nc2c1cccc2P(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
PhLi (0.56 mL, 1.8M in di-n-butyl ether, 1 mmol) was added to a stirred solution of 8-diphenylphoshinoquinoline (1) (156 mg, 0.5 mmol) in dry THF (5 mL) at −78° C. and the solution was stirred at 0° C. for 10 minutes. The solution was then cooled to −78° C., saturated aqueous NH4Cl solution (10 mL) was added and the mixture was warmed to room temperature. Products were extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give 4 (196 mg) quantitatively as a yellow oil. 1H NMR (400.13 MHz, CDCl3) δ 7.4-7.3 (m, 15H, Ph-H), 6.92 (d, 1H, J=7.2 Hz, C5—H), 6.69 (ddd, 1H, J=7.2, 6.0, 1.2 Hz, C7—H), 6.54 (t, 1H, J=7.2 Hz, C6—H), 6.38 (d, 1H, J=9.6 Hz, C4—H), 5.64 (dd, 1H, J=10.0, 4.0 Hz, C3—H), 5.44 (bs, 1H, N1—H), 5.15 (d, 1H, J=7.2 Hz, C2—H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 146.5 (d, J=19.2 Hz), 145.1, 135.4 (d, J=8.1 Hz), 135.3 (d, J=7.1 Hz), 134.5, 133.7 (d, J=18.2 Hz), 133.6 (d, J=19.2 Hz), 133.4 (d, J=19.2 Hz), 127.3, 128.7-128.3 (m), 127.1, 126.0, 125.2, 124.5, 119.1, 117.1, 116.1 (d, J=8.1 Hz), 57.6 ppm; 31P NMR (161.97 MHz, CDCl3) δ-23.8 ppm.
Reaction SMILES: O1C2C=CC=CC=2C=C1C1(C(O)=O)CCC=CCN1[S:17]([C:20]1[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=1)(=O)=O.[OH:31][NH:32][C:33]([CH:35]1[CH:41]([CH2:42]OC(=O)C)[CH2:40][CH:39]=[CH:38][CH2:37][N:36]1[S:47]([C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)(=[O:49])=[O:48])=[O:34]>>[OH:31][NH:32][C:33]([CH:35]1[CH:41]([CH2:42][S:17][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:40][CH:39]=[CH:38][CH2:37][N:36]1[S:47]([C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)(=[O:48])=[O:49])=[O:34]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)NO)cc1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCCC2(C(=O)O)c2cc3ccccc3o2)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(CSc3ccccc3)C2C(=O)NO)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-phenylsulfanylmethyl-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid hydroxyamide was synthesized from 3-Benzofuran-2-yl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid in the same manner as the procedures used for the preparation of Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepin-3-ylmethyl ester: MS (M-H)+ =441.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)([O-])=O>CO.[Pd]>[O:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[O:7][C:6]1[CH:5]=[C:4]([CH:16]=[CH:15][CH:14]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cccc(OC2CCCCO2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 2-(3-nitrophenoxy)tetrahydro-2H-pyran (1.0 g, 4.5 mmol) in methanol (13 mL) was degassed with nitrogen (3×) and treated with 10% Pd/C (wet Degussa type) (12 mg). The reaction mixture was degassed and stirred under an atmosphere of hydrogen at 25° C. for 2 h. The reaction mixture was filtered to give the desired product (0.87 g, quantitative) as a tan oil. LCMS for C11H16NO2 (M+H)+: m/z=194.0.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][C@@:6]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH2:23]O)([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[OH:7].C([O-])([O-])=O.[K+].[K+].ClC1C=CC(Cl)=CC=1[N+]([O-])=O.O.O.[C:45]([OH:50])(=[O:49])[C:46]([OH:48])=[O:47]>CS(C)=O.CC(C)=O.O>[CH3:25][N:2]([CH2:3][CH2:4][CH2:5][C@@:6]1([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[O:7][CH2:23][C:16]2[CH:17]=[C:18]([C:19]#[N:20])[CH:21]=[CH:22][C:15]1=2)[CH3:1].[C:46]([OH:48])([C:45]([OH:50])=[O:49])=[O:47]
Reactant: CN(C)CCC[C@](O)(c1ccc(F)cc1)c1ccc(C#N)cc1CO
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCC[C@@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 6.0 gm of (S)-(−)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile in 30 ml of DMSO at room temperature was added 7.3 gm of anhydrous K2CO3 and 4.04 gm of 2,5-dichloronitrobenzene was added to the above reaction mixture at room temperature and stirred at 100° C. for 15.0 hours. To the above reaction mixture, 120 ml of water was added, and extracted with toluene. The toluene layer was washed with water and 5% sodium hydroxide solution and after acid base treatment yielded an oily product. The oil was dissolved in 16 ml of acetone at 30° C. and 1.9 gm of oxalic acid dihydrate in 8 ml of acetone was added to it, stirred, cooled, filtered and dried at 60° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:14][Mg+].[Br-]>CCOCC.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Mg+]
Reactant: FC(F)(F)COc1cccnc1Cl
Agent: Cl[Ni]Cl
Agent: [Br-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1ncccc1OCC(F)(F)F
Temperature: 25 °C

Procedure:
2-Chloro-3-(2,2,2-trifluoro-ethoxy)-pyridine (1.21 g, 5.73 mmol) (Hoglen, D. K. PCT Int. Appl. (2000), WO 2000005212) and 1,3-bis(diphenylphosphino)propane nickel (II) chloride (217 mg, 0.40 mmol) were taken up in Et2O (40 mL) at room temperature. MeMgBr (3.0M in Et2O, 2.25 ml, 5.73 mmol) was added dropwise via syringe over 3 minutes to give a tan slurry. The mixture was refluxed for 16 h, cooled to room temperature, quenched with water (60 mL) and extracted with CH2Cl2 (8×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford 2-methyl-3-(2,2,2-trifluoro-ethoxy)-pyridine as an orange oil. Purification via column chromatography on silica gel (CH2Cl2) afforded 2-methyl-3-(2,2,2-trifluoro-ethoxy)-pyridine as a yellow solid (0.46 g, 42%). 1H NMR (CDCl3) δ 2.52 (s, 3H), 4.36 (q, 2H, J=7.5 Hz), 7.06-7.14 (m, 2H), 8.19 (d, 1H, J=3.0 Hz). 19F NMR (CDCl3) δ 2.03 (s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:42][OH:43]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14]([NH:42][OH:43])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(O)c3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(O)c3C2=O)ccc1OC
Yield: 80.5 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-hydroxyphthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(3-hydroxyphthalimido)propanoic acid (0.70 g, 1.8 mmol), carbonyldiimidazole (690 mg, 4.25 mmol) and hydroxylamine hydrochloride (380 mg, 5.47 mmol) in tetrahydrofuran (10 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-hydroxyphthalimido)propionamide as a yellow solid (580 mg, 80% yield): mp, 209.0-210.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 3.08 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.62 (t, J=7.9 Hz, 1H, NCH), 6.88 (br s, 2H, Ar), 6.99 (br s, 1H, Ar), 7.18 (d, J=8.3 Hz, 1H, Ar), 7.22 (d, J=7.1 Hz, 1H, Ar), 7.58 (dd, J=7.4, 8.2 Hz, 1H, Ar), 8.88 (br s, 1H, OH), 10.58 (br s, 1H, NH); 13C NMR (DMSO-d6) δ24.73, 44.31, 59.77, 65.49, 73.77, 121.76, 122.40, 123.84, 124.29, 129.66, 133.41, 141.53, 143.24, 146.04, 157.66, 158.49, 165.49, 176.14, 176.39, 177.51; Anal Calcd for C20H20N2O7: C, 60.00; H, 5.03; N, 7.00. Found: C, 59.99; H, 5.08; N, 7.03.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.CC(C)(C)C(=O)CN1C2C=CC=CC=2C(C2C=CC=CN=2)=NN([CH2:61][C:62](O)=[O:63])C1=O.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:62]([O:63][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:61]
Reactant: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccn2)c2ccccc21
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 5, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.63 (1H, m), 8.36 (1H, m), 8.02 (1H, m), 7.81 (1H, t), 7.36 (2H, m), 7.23 (3H, m), 7.11 (4H, m), 5.05 (1H, br s), 4.72 (2H, m), 4.36 (2H, m), 3.61 (2H, s), 1.27 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:12]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2cc(F)c(F)cc2NC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CNc2cc(F)c(F)cc2N(CC(F)(F)F)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 200 mg of ((S)-7,8-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 7 ml of tetrahydrofurane was cooled to −78° C. under an argon atmosphere. Thereafter, the solution was treated with 0.62 ml of lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofurane), stirred for 30 min at −78° C., then warmed to room temperature before 0.13 ml of 2,2,2-trifluoroethyl trifluoromethanesulphonate were added to the reaction mixture. After stirring overnight in a sealed flask, another 0.05 ml of 2,2,2-trifluoroethyl trifluoromethanesulphonate were added and stirring continued for 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure and the residue was directly submitted to chromatography on a Si—NH2 phase using a gradient of heptane/ethyl acetate=100/0 to 60/30 as the eluent. There were obtained 193 mg (77% of theory) of the title compound as a white foam; MS 418 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[C:10]([CH2:19]Br)[N:9]=2)=[CH:4][CH:3]=1.[CH3:21][O-:22].[Na+].[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH2:19][O:22][CH3:21])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2)nc1CBr
Reactant: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Ethyl 6-(4-fluorophenyl)-2-(bromomethyl)nicotinate (D85) (38 mg, 0.11 mmol) was treated with sodium methoxide (18 mg, 0.34 mmol) in methanol (1 ml) at room temperature for 1 h. 2M Sodium hydroxide solution was then added and the solution stirred for 1 h. The mixture was diluted with water and extracted with EtOAc which was dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (19 mg). MS(ES): MH+ 262, M-H+ 260.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C[Si]([N:23]=[N+:24]=[N-:25])(C)C>COCCOC>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:16]3[NH:25][N:24]=[N:23][N:17]=3)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C2(C#N)CCOCC2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: COCCOC
Product: COC(=O)c1ccc(C2(c3nnn[nH]3)CCOCC2)cc1

Procedure:
A solution of 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (400 mg, 1.63 mmol), trimethylsilyl azide (TMSN3) (40 mg, 2.1 eq), and Bu2Sn(O) (40 mg, 1.0 eq) in DME was heated in the microwave at 150° C. for 4 hours. After the reaction was done the mixture was washed with water and extracted with EtOAc. The organic phase was dried and evaporated to give 4-[4-(1H-tetrazol-5-yl)-tetrahydro-pyran-4-yl]-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:17]=1[C:18]([O:20]CC)=[O:19].[OH-].[Li+].C(O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.6 %

Procedure:
Ethyl 2-(6,7-dimethoxyquinolin-4-yloxy)-5-methoxybenzoate (143 mg) and lithium hydroxide (78 mg) were suspended in a mixed solvent composed of ethanol (10 ml) and water (1 ml), and the suspension was stirred at room temperature overnight. The solvent was then removed therefrom by distillation under the reduced pressure. Water was added to the residue, and the resultant solution was neutralized with 12N hydrochloric acid. The mixture was then extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure to give the title compound (140 mg, yield 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O[C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:22][CH:21]=1>>[CH2:27]([O:26][C:24](=[O:25])[C:23]1[CH:34]=[CH:35][C:20]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([C:14]([OH:16])=[O:15])[O:17][CH3:18])=[CH:8][CH:7]=2)=[CH:21][CH:22]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: COC(Cc1ccc(OCCCOc2ccc(C(=O)OCc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with benzyl 4-hydroxybenzoate and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [C:1]([S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:38]1([CH3:57])[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]O)=[CH:40][CH:39]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([S:20][CH2:21][CH2:22][C:23]([O:25][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH3:57])=[CH:39][CH:40]=1)=[O:24])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCCCCCCCCCCCO)cc1
Reactant: O=C(O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(OCCCCCCCCCCCOC(=O)CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound 14 (1.86 g), 0.896 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), and 0.029 g of 4-dimethylaminopyridine (DMAP) were dissolved in 300 ml of methylene chloride. After the compound 16 (3.04 g) was then added and stirred at room temperature for 24 hours, the reaction solution was moved into a separating funnel, and was washed twice with 100 ml of 10% aqueous potassium hydrogen sulfate solution, twice with 100 ml of aqueous saturated sodium hydrogen carbonate solution, twice with 100 ml of ion-exchange water, and twice with 100 ml of saturated brine. After the methylene chloride phase collected was dehydrated with magnesium sulfate, the desiccant agent was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. The reaction mixture was purified by chromatography, and 2.63 g of 11-(p-tolyloxy)undecyl 3-(tritylthio)propioate 17, which was a white solid, was obtained.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:9]([OH:12])[C:10]#[CH:11]>N1(C2CCCCCCC2)CCCCCCN1>[CH2:1]([NH:6][C:7](=[O:8])[O:12][CH2:9][C:10]#[CH:11])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C#CCO
Reactant: CC(C)(C)CN=C=O
Agent: C1CCCC(N2CCCCCCN2)CCC1
Product: C#CCOC(=O)NCC(C)(C)C
Yield: 94.5 %

Procedure:
4520 g (40 moles) of neopentylisocyanate and 1 g of diazabicyclooctane (Dabco) are heated to 80° C. (10 l flask) and 2240 g (40 moles) of propargyl alcohol are then added in the course of 1.5 hours. When the addition of the alcohol has ended, IR spectra are used to monitor whether the reaction is complete. When the NCO band has disappeared, the mixture is distilled under a high vacuum. 6395 g (95% of theory) of 2-propinyl N-neopentylcarbamate of boiling point: 85° C./40 mbar are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][CH3:13])[CH:6]=[CH:5]2.[Cu][C:15]#[N:16]>N1C=CC=CC=1>[CH3:13][NH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:15]#[N:16])[CH:11]=[CH:10]2
Reactant: N#C[Cu]
Reactant: CNc1ccc2cc(Br)ccc2c1
Solvent: c1ccncc1
Product: CNc1ccc2cc(C#N)ccc2c1
Temperature: 220 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A solution of 6-bromo-N-methyl-2-naphthylamine (2.0 g, 8.5 mmol) in pyridine (50 ml) was added to copper (I) cyanide (1.1 g, 12.3 mmol). The mixture was stirred at 220° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, extracted with dichloromethane, washed with an aqueous solution of hethylene diamine (10 vol %), and purified by column chromatography using hexane/ethyl acetate (4:1) as an eluting solvent to give the title compound (1.1 g, yield: 71%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][NH:3]1.S(=O)(=O)(O)[OH:17]>>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([NH2:9])=[O:17])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][NH:3]1
Reactant: N#Cc1cc(=O)[nH]nc1-c1ccccc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc(=O)[nH]nc1-c1ccccc1
Reaction time: 24 h

Procedure:
2,3-Dihydro-3-oxo-6-phenyl-5-pyridazinecarbonitrile (10.0 g) is added to cold (0°-5° C.) concentrated sulfuric acid (50 ml) and the resulting solution is kept at 0°-5° C. for 24 hours and then poured onto crushed ice and the solid product is collected and recrystallized from aqueous ethanol to give 2,3-dihydro-3-oxo-6-phenyl-5-pyridazinecarboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][C:25]([O:27]C)=O)([O-:3])=[O:2].[NH3:29]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][C:25]([NH2:29])=[O:27])([O-:3])=[O:2]
Reactant: N
Reactant: COC(=O)CCNc1cc(Oc2ccc(S(C)(=O)=O)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(NCCC(N)=O)c2)c(Cl)c1
Reaction time: 48 h

Procedure:
The ester (7), obtained according to Example III, in an amount of 1.6 g was suspended in 40 ml of methanol. Ammonia was introduced until saturation and then the reaction mixture was stirred for two days. The solid material was sucked off and recrystallized from ethylacetate. The desired product was obtained in a yield of 0.9 g; melting point 196° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][S:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH2:20](N(CC)CC)[CH3:21].ICC>O>[C:1]([NH:4][C@@H:5]([CH2:9][S:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:20][CH3:21])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CSC(=O)c1ccc(C)cc1)C(=O)O
Reactant: CCN(CC)CC
Solvent: O
Solvent: CCI
Product: CCOC(=O)[C@H](CSC(=O)c1ccc(C)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To a solution of 2-acetylamino-3-(4-methyl-benzoylsulfanyl)-propionic acid (1.1 g, 3.91 mmol) and triethylamine (0.68 mL, 4.89 mmol) N,N-dimethylformamide (5 mL) was added iodoethane (0.39 mL, 4.89 mmol) and the resulting solution was stirred at ambient temperature for 18 hours. The reaction mixture was added slowly to water (50 mL) with rapid stirring. After stirring for 2 hours, the resulting slurry was filtered and the solid was rinsed with water and dried under vacuum to give the product as a white solid (780 mg, 60%). 1H NMR (300 MHz, DMSO) δ=8.47 (d, J=7.9 Hz, 1H), 7.81 (s, 1H), 7.80-7.78 (m, 1H), 7.35 (d, J=7.6 Hz, 2H), 4.46 (dt, J=5.3, 8.1 Hz, 1H), 4.09 (q, J=6.8 Hz, 2H), 3.50 (dd, J=5.4, 13.6 Hz, 1H), 3.24 (dd, J=8.2, 13.8 Hz, 1H), 2.37 (s, 3H), 1.83 (s, 3H), 1.16 (t, J=7.0 Hz, 3H). MS (ESI) m/z 310 (M+1)+.