Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19]=[CH2:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[N:22]1(C=CCCC)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:24]([CH2:25][CH2:26][CH3:27])=[CH:23][N:22]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=CC(=O)c1ccc(-c2ccc(CCCCC)cc2)cc1
Reactant: CCCC=CN1CCCCC1
Product: CCCCCc1ccc(-c2ccc(-c3ccc(CCC)cn3)cc2)cc1

Procedure:
Example 11 is repeated by reacting 1-(4'-pentylbiphenyl-4-yl)-prop-2-en-1-one and 1-piperidinopentene to give the corresponding 2-(4'-pentylbiphenyl-4-yl)-5-propylpyridine having C 171° N 198° I.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:20][CH2:21][Mg+].[Br-].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[CH2:20]([C:5]1[C:6]2[N:10]=[CH:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:7]=2[CH:18]=[CH:19][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:21]
Reactant: CC[Mg+]
Reactant: CC(C)(C)OC(=O)n1cnc2cc([N+](=O)[O-])ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCc1c([N+](=O)[O-])ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
To a solution of tert-butyl 5-nitro-1H-benzo[d]imidazole-1-carboxylate (150 g, 0.56 mol) in dry THF (1500 mL) was added EtMgBr (3.0 Min THF, 1.12 mol, 2 equiv.) dropwise at −15° C. The reaction mixture was stirred at −15° C. for 2 h. A solution of DDQ (129 g, 1.12 mol, 2 equiv.) in THF (120 mL) was added at −15° C., then the reaction mixture was warmed to RT and the stirring was continued for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and then (Na2SO4), filtered, and concentrated. The crude material was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford tert-butyl 4-ethyl-5-nitro-1H-benzo[d]imidazole-1-carboxylate (20 g, 12% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28]([O:31][CH2:32][C:33](Cl)=[O:34])(=[O:30])[CH3:29]>>[C:28]([O:31][CH2:32][C:33](=[O:34])[NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:30])[CH3:29]
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC(=O)OCC(=O)Cl
Product: CC(=O)OCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and 2-chloro-2-oxoethyl acetate (20 mg, 150 μmol). Yield 16 mg (70%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:4]1[CH3:19])[CH3:2].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:3]([CH2:1][CH3:2])[C:4]([CH3:19])=[C:5]2[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCn1c(C)c(-c2ccncc2)c2cc(O)ccc21
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c(C)n2CC

Procedure:
The above compound was prepared from 1-ethyl-2-methyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methylpropanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:35]([NH:38][CH2:39][CH2:40][CH2:41][OH:42])(=[O:37])=[O:36])[CH:5]=[C:6]([F:34])[C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)([CH3:17])[CH3:16])=[CH:13][N:14]=1.C(N(C(C)C)CC)(C)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>C(Cl)Cl>[CH3:52][S:53]([O:42][CH2:41][CH2:40][CH2:39][NH:38][S:35]([C:4]1[CH:5]=[C:6]([F:34])[C:7]([CH2:8][S:9][C:10]2[N:11]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:12]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=3)([CH3:16])[CH3:17])=[CH:13][N:14]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:37])=[O:36])(=[O:55])=[O:54]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCO)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCOS(C)(=O)=O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of 3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-N-(3-hydroxypropyl)benzenesulfonamide (910 mg, 1.42 mmol) and diisopropylethylamine (0.74 mL, 0.74 mmol) in DCM (6 mL) was added methanesulfonyl chloride (0.13 mL, 1.706 mmol) at −10° C. After the reaction was slowly warmed to ambient temperature over 30 min, it was extracted with DCM (10 mL). The combined extracts were washed with water (10 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex:EA=1:2) to give 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenylsulfonamido)propyl methanesulfonate (0.80 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.39 (dd, J=8.27, 1.73 Hz, 1H), 7.27 (d, J=2.32 Hz, 2H), 6.89 (dd, J=10.97, 8.54 Hz, 1H), 6.84-6.74 (m, 2H), 6.58 (dd, J=8.09, 2.16 Hz, 1H), 6.53-6.45 (m, 1H), 6.41-6.33 (m, 2H), 5.26 (s, 1H), 4.42-4.29 (m, 2H), 4.23-4.08 (m, 3H), 3.78 (d, J=2.18 Hz, 4H), 3.21-3.10 (m, 2H), 3.10-2.99 (m, 4H), 2.00 (dd, J=11.78, 6.04 Hz, 2H), 1.65 (s, 7H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[F:29][C:30]1([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[N:34]=2)[CH2:32][CH2:31]1>>[F:29][C:30]1([C:33]2[N:34]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]5)[N:8]4[CH3:11])=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:3]=3)[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:31][CH2:32]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: FC1(c2nc3ccccc3[nH]2)CC1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4(F)CC4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(1-fluorocyclopropyl)-1H-benzimidazole were reacted to give 307. LCMS m/z: 549.3 (MH+)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([F:17])[F:16])[CH:9]=O)[C:2]#[C:3][CH3:4].C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].Cl>N1CCCCC1.N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:9]=[CH:19]/[C:20]([OH:22])=[O:21])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([F:17])[F:16])[C:2]#[C:3][CH3:4]
Reactant: O=C(O)CC(=O)O
Reactant: CC#CCOc1cc(C=O)ccc1OC(F)F
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC#CCOc1cc(/C=C/C(=O)O)ccc1OC(F)F
Temperature: 120 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
A solution of 3-(but-2-ynyloxy)-4-difluoromethoxybenzaldehyde (0.53 g, 2.2 mmol) and malonic acid (0.34 g, 3.3 mmol) in a mixture of piperidine (0.2 mL) and pyridine (5.0 mL) was heated to 120° C. and stirred for 16 h. The mixture was cooled to rt and acidified with 1 M HCl. The crude product was collected by filtration and recrystallised from acetonitrile to give (E)-3-(3-(but-2-ynyloxy)-4-difluoromethoxyphenyl)-2-propenoic acid (0.38 g, 61%) as a colourless crystalline solid; mp 206-208° C.; δH (500 MHz, DMSO-d6) 1.84 (t, J=2.2 Hz, 3H, C≡CH3), 4.87 (q, J=2.2 Hz, 2H, OCH2), 6.55 (d, J=16.0 Hz, 1H, CH═CHCO2H), 7.13 (t, J=72.0 Hz, 1H, CHF2), 7.19 (d, J5,6=8.0 Hz, 1H, H5), 7.30 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.52 (d, J2,6=2.0 Hz, 1H, H2), 7.54 (d, J=16.0 Hz, 1H, CH═CHCO2H), 12.41 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 3.1, 56.8, 74.1, 84.1, 113.6, 116.4 (t, J=256 Hz), 119.7, 120.6, 122.0, 132.4, 141.2, 142.9, 148.6, 167.4; νmax 1011, 1113, 1267, 1516, 1629, 1686, 2578, 2924 cm−1.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@H:10]3[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]3)=[CH:6][C:5]=2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]3[O:26][CH2:27][CH2:28][O:29][C:24]=3[CH:23]=2)[CH2:3][CH2:2]1.Cl[C:33]([O:35][CH3:36])=[O:34]>N1C(C)=CC(C)=CC=1C.C(Cl)Cl>[CH3:36][O:35][C:33](=[O:34])[O:20][CH2:19][C@@H:12]1[C@@H:13]([OH:18])[C@H:14]([OH:17])[C@@H:15]([OH:16])[C@H:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:5]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)[CH:6]=2)[O:11]1
Reactant: OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 3, 890 mg, 2.1 mmol) in collidine (7 ml) was added a solution of methyl chloroformate (0.21 ml, 2.5 mmol) in DCM (0.5 ml) at −40° C. After stirring for 1 h at same temperature, it was stirred at room temperature for 1.5 h. Reaction mixture was poured into ice cold 10% HCl solution and extracted with ethyl acetate (2×10 ml). Combined organic layers were washed with brine (10 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 1.1 g of carbonic acid (2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester methyl ester as a white solid.
Reaction SMILES: [N:1]([CH2:4][CH:5]([S:60][S:61][C:62]([CH3:65])([CH3:64])[CH3:63])[CH2:6][C@@H:7]([NH:52]C(OC(C)(C)C)=O)[C:8]([O:10][C@H:11]1[C@@H:15]([OH:16])[C@H:14]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH2:26])[O:13][C@H:12]1[CH2:27][O:28][P:29]([O:32][C@H:33]1[CH2:37][C@H:36]([N:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[N:40][C:39]2=[O:45])[O:35][C@@H:34]1[CH2:46][O:47][P:48]([OH:51])([OH:50])=[O:49])([OH:31])=[O:30])=[O:9])=[N+:2]=[N-:3].FC(F)(F)C(O)=O>ClCCl>[NH2:52][C@H:7]([CH2:6][CH:5]([S:60][S:61][C:62]([CH3:65])([CH3:64])[CH3:63])[CH2:4][N:1]=[N+:2]=[N-:3])[C:8]([O:10][C@H:11]1[C@@H:15]([OH:16])[C@H:14]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH2:26])[O:13][C@H:12]1[CH2:27][O:28][P:29]([O:32][C@H:33]1[CH2:37][C@H:36]([N:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[N:40][C:39]2=[O:45])[O:35][C@@H:34]1[CH2:46][O:47][P:48]([OH:51])([OH:50])=[O:49])([OH:31])=[O:30])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)SSC(CN=[N+]=[N-])C[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
The aforementioned crude product of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy) (hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azide-2-((tert-butoxycarbonyl)amino)-4-(tert-butyldisulfanyl)pentanoate (Compound 42) (53 mg) was suspended by adding dichloromethane (2 ml) thereto, after which trifluoroacetic acid (0.5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-5-azido-4-(tert-butyldisulfanyl)pentanoate (Orn(N3) (4-SStBu)-pdCpA) (Compound 43) (24 mg, 31% in two steps).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([NH:9][CH:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[CH:12](O)[CH2:11]1)[CH:7]=[CH2:8]>O1CCOCC1>[CH2:6]([NH:9][CH:10]1[CH:11]=[CH:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][CH2:16]1)[CH:7]=[CH2:8]
Reactant: C=CCNC1CCc2ccccc2C(O)C1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=CCNC1C=Cc2ccccc2CC1
Yield: 79.1 %

Procedure:
12.4 ml of 18 N sulfuric acid were added to a refluxing solution of 6.2 g of 7-allylamino-5-ξ-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene in 124 ml of dioxane and the mixture was refluxed for 30 minutes and was cooled. The mixture was concentrated to 40 ml and 100 ml of ice water were added. The aqueous phase was washed with ethyl acetate and made alkaline with concentrated ammonium hydroxide. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness to obtain 4.5 g of 7-allylamino-6,7-dihydro [5H] benzocycloheptene.
Reaction SMILES: [C:1](Cl)([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.[NH:21]1[CH:25]=[C:24]([CH2:26][OH:27])[N:23]=[CH:22]1.C(N(CC)CC)C>CN(C=O)C>[C:1]([N:21]1[CH:25]=[C:24]([CH2:26][OH:27])[N:23]=[CH:22]1)([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
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Trityl chloride (45.57 g, 0.163 mol), (1H-imidazol-4-yl)-methanol (20.00 g, 0.148 mol) and triethylamine (37.46 g, 0.370 mol) in DMF (150 mL) are stirred at r.t. for 16 h, whereupon the mixture is poured into ice-cold water. The precipitate is filtered off and dried under high vacuum to give (1-trityl-1H-imidazol-4-yl)-methanol as a solid. Crude (1-trityl-1H-imidazol-4-yl)-methanol (26.4 g, 0.077 mol), imidazole (15.88 g, 0.233 mol), DMAP (0.950 g, 7.7 mmol) and TBSCl (12.89 g, 0.085 mol) in DMF (0.1 L) are stirred at r.t. for 2 h, whereupon water is added. The mixture is extracted three times with dichloromethane. The organic layer is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel flash chromatography (elution with hexanes-ethyl acetate, 7:3) to yield 4-(tert-butyl-dimethyl-silanyloxymethyl)-1-trityl-1H-imidazole as a white solid; MS (ESI) m/z 243, 455 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:18][NH2:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Temperature: 25 °C

Procedure:
100 g piperidine-1,4-dicarboxylic acid 1-tert-butyl ester was dissolved in 100 mL methanol and 100 mL hydrazine monohydrate was added. The mixture was reflux overnight. The reaction was cooled to RT and then the solvent was removed under vacuum to give 95 g of the desired product. Rf: 0.2 (DCM/MeOH=20/1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](=[O:43])[NH:34][O:35]CC3C=CC=CC=3)=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:44])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33](=[O:43])[NH:34][OH:35])=[CH:29][CH:30]=2)=[CH:20][CH:19]=1)[C:9]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)NOCc3ccccc3)cc2)cc1)C(=O)N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1)C(=O)N1CCOCC1
Yield: 80.8 %

Procedure:
Palladium on BaSO4 (5%, 0.5 g) was added to a degassed solution of the benzyl hydroxamate 15 (1.6 g) in MeOH (50 mL) and the suspension was treated with hydrogen at atmospheric pressure for 6 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 16 (1.1 g, 81%). 1H NMR (400 MHz, DMSO-d6): 10.35 (s, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.13-7.17 (m, 3H), 6.85 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 4.52 (m, 1H), 3.21-3.49 (m, 8H), 2.69-2.83 (m, 4H), 2.20 (t, J=8.0 Hz, 2H), 1.28 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2].CO.[BH4-].[Na+]>O>[N:19]1[CH:20]=[CH:21][C:16]([C:5]2[S:6][C:7]([C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[C:8]([CH3:9])[C:4]=2[CH:1]([OH:3])[CH3:2])=[CH:17][CH:18]=1
Reactant: CC(=O)c1c(-c2ccncc2)sc(-c2ccncc2)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1C(C)O
Reaction time: 2 h

Procedure:
To a stirred solution of 3-acetyl-4-methyl-2,5-di(4-pyridyl)thiophene (200 mg, 0.68 mmol) in MeOH (5 mmol) was added sodium borohydride (30 mg, 0.79 mmol) at 0° C., and the mixture was stirred for 2 hours. Water (5 mL) was added to the mixture. The whole was extracted with ethyl acetate (50 mL), the organic layer washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with CH2Cl2 -MeOH (20:1) to provide the title product as a solid. Recrystallized from ethyl acetate gave the title product (130 mg, 75% yield).
Reaction SMILES: CN(C)[CH2:3][CH2:4]CN=C=NCC.C(O)C.[C:15]([CH:17]([C:30]1[CH:31]=[N:32][CH:33]=[C:34]([Br:36])[CH:35]=1)[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21])#[N:16]>CN(C)C1C=CN=CC=1.ClCCl>[C:15]([CH:17]([C:30]1[CH:31]=[N:32][CH:33]=[C:34]([Br:36])[CH:35]=1)[CH:18]([C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:19][C:20]([O:22][CH2:3][CH3:4])=[O:21])#[N:16]
Reactant: N#CC(c1cncc(Br)c1)C(CC(=O)O)c1ccc(Cl)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccc(Cl)cc1)C(C#N)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under protective gas (Ar), 0.121 g (0.632 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), a spatula tip of 4-dimethylaminopyridine (DMAP) and 0.061 g (1.317 mmol) of ethanol were added to 0.200 g (0.527 mmol) of 4-cyano-4-(5-bromopyridin-3-yl)-3-(4-chlorophenyl)butanoic acid (Example A4) in 4 ml of dichloromethane, and the mixture was stirred at 25° C. for 8 h. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane and washed twice with in each case 15 ml of water. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel (gradient: starting with ethyl acetate/heptane=5:95 over the course of 20 minutes increased to ethyl acetate/heptane=20:80) gave 0.143 g (67% of theory) of the title compound (erythro:threo=58:42). 1H-NMR in CDCl3 see Table 2.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2)[CH2:3][CH2:2]1>Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Product: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A suspension of 4.1 g (13.3 mmol) of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 150 ml of 6N hydrochloric acid was refluxed for six hours, then cooled to room temperature. The solids were filtered, washed with water and ether, and dried to give 3.2 g of the title compound, mp >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=[O:11])[NH:6]2.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:14][NH2:15])[C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN=C1C(=O)Nc2cccc(Cl)c21

Procedure:
To a stirred slurry of 43.3 g of 4-chloroisatin in 350 ml of ethanol was added 17.3 ml of hydrazine hydrate, and then the reaction mixture was cooled, and the precipitate was recovered by filtration to give 43.5 g of 4-chloro-3-hydrazono-2-oxindole, m.p. 235°-236° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[Br:11]Br>O1CCOCC1>[Br:11][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(O)cc1
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(O)cc1
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To a solution of 4-hydroxyacetophenone (2.5 g, 18.3 mmol) (Aldrich) in dioxane (10 mL) was added dropwise a solution of bromine (3.22 g, 20.1 mmol) in dioxane (20 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo and the residue was recrystalized from methanol to provide 2-bromo-1-(4-hydroxyphenyl)ethanone (1.73 g, 44% yield).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:4]=2[CH:3]=1.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:15][N:16]([C:17]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9]([NH2:10])(=[O:11])=[O:12])=[CH:8][C:4]=2[CH:3]=1)=[O:18])[CH3:20]
Reactant: NS(=O)(=O)c1cc2cc(O)ccc2s1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Oc1ccc2sc(S(N)(=O)=O)cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A solution of 2.3 g (10 mmoles) of 5-hydroxy-2-sulfamoylbenzo[b]thiophene in 50 ml of pyridine was treated with 200 mg of 4-dimethylaminopyridine and finally 2.5 ml (2.9 g, 27 mmoles) of dimethylcarbamyl chloride. The resultant clear solution was stirred at room temperature for 48 hours, when it was poured into a mixture of 200 g of chopped ice and 100 ml of concentrated HCl. The precipitated solid was collected and washed with cold H2O until the washings were neutral. Drying gave 2.25 g (75%) of tan powder which was crystallized from isopropyl alcohol to give 1.6 g of product, m.p. 192°-194° C.