Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20](=[O:37])[C:19]=1[CH3:38]>O1CCOCC1.[Pd]>[CH3:36][C:26]([S:32]([CH3:35])(=[O:34])=[O:33])([CH2:25][CH2:24][N:21]1[CH:22]=[CH:23][C:18]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:19]([CH3:38])[C:20]1=[O:37])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(C)(CCn1ccc(I)c(C)c1=O)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C)(CCn1ccc(-c2ccccc2)c(C)c1=O)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Water (1 mL) was added to a suspension of potassium carbonate (392 mg, 2.84 mg), phenylboronic acid (76.1 mg, 0.624 mmol), and ethyl 4-(4-iodo-3-methyl-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (250 mg, 0.567 mmol) in 1,4-dioxane (5 mL) at ambient temperature. To this mixture was added Pd EnCat™ (154 mg, 0.06 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, filtered, diluted with ethyl acetate and washed with water. To the organic extract was added silica gel and the mixture was concentrated to dryness. The material was purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanoate as an oil. 118.3 mg
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (2.7 g, 6.7 mmol), 2,6-dibromopyridine (2.3 g, 10.0 mmol), cesium carbonate (3.04 g, 9.4 mmol), and BINAP (0.187 g, 0.3 mmol) were stirred in THF (100 mL) at room temperature and bubbled with nitrogen for 1 hr. Palladium(II) acetate (0.068 g, 0.20 mmol) was added, and the mixture was warmed to 70° C., stirred for 72 hrs, then cooled to room temperature. The resulting mixture was diluted with EtOAc (300 mL) and extracted with H2O (2×100 mL). The organic layer was dried over MgSO4, filtered and concentrated, and the crude residue was purified on silica gel (0% to 80% EtOAc in hexane gradient) to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][NH:31][CH2:32][CH3:33]>>[CH2:32]([N:31]([CH3:30])[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6])[CH3:33]
Reactant: CCNC
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Product: CCN(C)c1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)ccn1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and N-methylethylamine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.25 (m, 2 H), 7.84 (m, 1H), 7.56 (m, 2H), 7.45 (d, 1H), 7.17 (s, 1H), 7.10 (d, 1H), 7.05 (d, 1H), 4.31 (t, 2 H), 3.62 (m, 4H), 3.06 (s, 3H), 2.88 (t, 2H), 2.57 (t, 4H), 1.10 (t, 3H). MS: 435.2 (M+1).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[C:13]([CH3:19])([CH3:18])[CH2:12]1)C1C=CC=CC=1.C(Cl)Cl>[Pd].CO>[NH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[C:13]([CH3:19])([CH3:18])[CH2:12]1
Reactant: CC1(C)CC(NC(=O)OCc2ccccc2)CCC1O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC(N)CCC1O
Yield: 95 %

Procedure:
Benzyl-4-hydroxy-3,3-dimethylcyclohexylcarbamate (peak 1) (1.0 equiv.) and palladium on carbon (10%) in MeOH (0.37 M) was stirred at room temperature under hydrogen balloon overnight. TLC (DCM:MeOH=10:1) showed that the reaction was completed. The mixture was filtered through a celite pad and evaporation of the solvents under reduced pressure provided 4-amino-2,2-dimethylcyclohexanol (95% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 3.70 (s, 2H), 3.16 (s, 1H), 2.65-2.71 (m, 1H), 1.18-1.65 (m, 6H), 0.83 (m, 6H).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][OH:18])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]2[CH:34]=[C:35]([O:38][C@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C@@H:42]([NH2:49])[CH2:41][CH2:40]3)[CH:36]=[CH:37][C:32]2=[N:31][N:30]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:49][C@@H:42]2[C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:39]([O:38][C:35]3[CH:36]=[CH:37][C:32]4[N:33]([C:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[Cl:22])=[N:30][N:31]=4)[CH:34]=3)[CH2:40][CH2:41]2)=[O:19])[N:8]([CH2:16][CH2:17][OH:18])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4ccccc4Cl)n3c2)c2ccccc21
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(-c5ccccc5Cl)n4c3)c3ccccc32)n(CCO)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A mixture of Intermediate 26a (340 mg, 0.95 mmol), Intermediate 31c (372 mg, 0.95 mmol), and DIPEA (248 μL, 1.43 mmol) in dioxane (5 mL) was stirred at 70° C. for 18 h. After cooling to RT, the reaction mixture was partitioned between DCM and water. The organic layer was dried through a phase separator and then concentrated in vacuo. The resultant residue was purified by FCC, using 0-10% MeOH in DCM to afford the title compound (536 mg, 94%) as a brown solid. An aliquot of the compound thus obtained (100 mg) was further purified by MDAP (Method 7) to afford the title compound (45 mg). LCMS (Method 5): Rt 4.08 min, m/z 600 [MH+]. 1H NMR (400 MHz, DMSO): 1.20 (9H, s), 1.81-2.19 (4H, m), 3.66 (2H, d, J=6.1 Hz), 3.93 (2H, t, J=6.0 Hz), 4.78-4.84 (1H, m), 4.98 (1H, br s), 5.51 (1H, t, J=4.3 Hz), 6.05 (1H, s), 7.06 (1H, d, J=8.6 Hz), 7.23-7.30 (1H, m), 7.32-7.38 (4H, m), 7.60 (1H, td, J=7.5, 1.3 Hz), 7.68 (1H, td, J=7.7, 1.9 Hz), 7.73 (2H, td, J=7.5, 1.3 Hz), 7.82-7.92 (2H, m), 8.17 (1H, s).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)[CH:16]=1)[CH:11]=2.[NH:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1>>[N:26]1([CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:19]([CH:20]=2)=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:26]4[CH:30]=[CH:29][CH:28]=[CH:27]4)[CH:16]=2)[CH:11]=3)[CH:30]=[CH:29][CH:28]=[CH:27]1
Reactant: c1cc[nH]c1
Reactant: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Agent: Cl
Product: c1ccn(CCCOc2ccc3cc4ccc(OCCCn5cccc5)cc4nc3c2)c1

Procedure:
The compound is prepared from 3,6-bis(3-chloropropoxy)acridine hydrochloride and pyrrole as described in Example 44.
Reaction SMILES: O1CC1COC1C(C)=CC=C2C=1C=NN2.O1CC1COC1C=CC(C)=C2C=1C=NN2.[O:31]1[CH2:46][CH:32]1[CH2:33][O:34][C:35]1[CH:43]=[C:42]([CH2:44]C)[CH:41]=[C:40]2[C:36]=1[CH:37]=[N:38][NH:39]2>>[O:31]1[CH2:46][CH:32]1[CH2:33][O:34][C:35]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]2[C:36]=1[CH:37]=[N:38][NH:39]2
Reactant: CCc1cc(OCC2CO2)c2cn[nH]c2c1
Agent: Cc1ccc(OCC2CO2)c2cn[nH]c12
Agent: Cc1ccc2[nH]ncc2c1OCC1CO1
Product: Cc1cc(OCC2CO2)c2cn[nH]c2c1

Procedure:
The following compounds are obtained in an analogous manner: 4-(2,3-epoxypropoxy)-5-methyl-indazole (m.p. 76°-78° C.), 4-(2,3-epoxypropoxy)-7-methyl-indazole and 4-(2,3-epoxypropoxy)-6-ethyl-indazole.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][C:8]([CH3:10])=[O:9].Cl>C1COCC1>[OH:9][C:8]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)([CH3:10])[CH3:7]
Reactant: CC(C)=O
Reactant: Cn1ccnc1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1ccnc1C(C)(C)O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
The 1-methylimidazole was dissolved in dry THF and the solution cooled to 5° C. A 10% excess n-butylithium was added over one hour period with the reaction vessel being maintained at a temperature range of 5°-20° C. under nitrogen. The solution at the end of the addition was homogenous and purplish in color. After stirring two hours at room temperature, the reaction flask was then cooled to ~10° C. and the acetone in dry THF was added slowly with stirring. After the addition the solution was allowed to stir at ambient temperature one hour then poured onto ice-water. The aqueous layer was acidified with dilute HCl and extracted with ether. The aqueous layer was then basified with K2CO3 then extracted with CH2Cl2 several times. The combined and dried CH2Cl2 extracts were concentrated to yield a white solid which was recrystallized from ethyl acetate; mp 128°-129° C. Structure was confirmed by IR and NMR.
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][O:5][C:6]([O:11][CH3:12])([CH3:10])[CH:7]([NH2:9])[CH3:8]>O.CO>[CH3:4][O:5][C:6]([O:11][CH3:12])([CH3:10])[CH:7]([NH:9][C:2]#[N:1])[CH3:8]
Reactant: N#CBr
Reactant: COC(C)(OC)C(C)N
Solvent: O
Solvent: CO
Product: COC(C)(OC)C(C)NC#N

Procedure:
Cyanogen bromide (424 mg., 4 m moles) was added to a solution of 2,2-dimethoxy-1-methylpropylamine (266 mg., 2 m moles) and KHCO3 (400 mg., 4 m moles) in a mixture of water (2 ml.) and methanol (4 ml.). After 15 minutes the mixture was poured in to water (150 ml.) and the mixture extracted with CH2Cl2. The extract was washed with water and brine, dried (MgSO4) and evaporated to dryness to give 2,2-dimethoxy-1-methylpropylcyanamide as a pale yellow oil (280 mg., 88%) having the following n.m.r. spectrum in CDCl3 : 1.15 (s, 3H); 1.18 (d, 3H); 3.15 (s, 6H); 3.0-3.6 (m, 1H); 4.0 (m, 1H).
Reaction SMILES: BrC1N=C([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])C=CC=1.COC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.Br[C:52]1[CH:53]=[CH:54][C:55]([Cl:58])=[N:56][CH:57]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[Cl:58][C:55]1[N:56]=[CH:57][C:52]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])=[CH:53][CH:54]=1
Reactant: Clc1ccc(Br)cn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Agent: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(Cl)nc1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (100 mg, 0.29 mmol) was reacted with 5-bromo-2-chloropyridine (55 mg, 0.29 mmol) and Na2CO3 (90 mg, 0.86 mmol) in DME (2 mL), and H2O (2 mL) to afford the desired 2-[4-(6-chloropyridin-3-yl)-3-methoxyphenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.59 (d, 1H), 7.85–7.66 (m, 3H), 7.44–7.78 (m, 1H), 7.56–7.60 (m, 1H), 7.48–7.45 (d, 1H), 7.42–7.38 (m, 3H), 3.98 (s, 3H). MS (ESI) 337 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OCc2ccccc2)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 81.4 %

Procedure:
A mixture of 6.06 g (0.02 mol) of product of Example 3, 16 g of benzyl bromide, 3 g of potassium carbonate and 50 ml of acetone was held at reflux for 2 hours and concentrated. The residue was treated with water and extracted with ether. The ether solution was dried and concentrated. The residue was kugelrohr distilled at 13 Pa (pot temperature 50° C.) to remove excess benzyl bromide. The residue was crystallized from hexane to give 6.4 g (81%) of product; mp 56°-58.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=1)[O:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]1[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=1[CH2:44][NH2:45].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=1)[O:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C:22](=[O:28])[CH2:23][CH2:24][C:25]([NH:45][CH2:44][C:43]1[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=1[F:41])=[O:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1F
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(Cl)c(Cl)c2)C(=O)CCC(=O)O)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(Cl)c(Cl)c2)C(=O)CCC(=O)NCc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A mixture of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(3,4-dichlorobenzyl)succinamic acid (0.91 g, 1.5 mmols), 2-fluorobenzylamine (0.23 g, 1.8 mmols), diethyl cyanophosphate (0.25 ml, 1.8 mmols), triethylamine (0.25 ml, 1.8 mmols) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an amorphous solid of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(3,4-dichlorobenzyl)-N′-(2-fluorobenzyl)succinamide (0.61 g, 57%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([NH2:22])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6]C=CC=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[S:31][C:30]([S:32](Cl)(=[O:34])=[O:33])=[C:29]([CH3:36])[C:28]=2[CH:37]=1>CC(C)=O>[CH:2]1([CH2:1][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[C:16]([NH:22][S:32]([C:30]4[S:31][C:27]5[CH:26]=[CH:25][C:24]([Cl:23])=[CH:37][C:28]=5[C:29]=4[CH3:36])(=[O:34])=[O:33])[CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[CH2:12][CH2:13]2)[CH2:7][CH2:6]1
Reactant: COc1ccc(N)cc1N1CCN(Cc2ccccc2)CC1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: CC(C)=O
Product: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1N1CCN(CC2CC2)CC1
Reaction time: 14 h
Yield: 42 %

Procedure:
To a solution of 3-(4-benzyl-piperazin-1-yl)-4-methoxy-phenylamine (D22) (1 mmol) in acetone (5 ml) was added 5-chloro-3-methylbenzothiophene-2-sulphonyl chloride (1 mmol). Stirring was continued at room temperature for 14 hrs. The hydrochloride salt of the sulphonamide was collected by filtration, triturated with diethyl ether and dried in vacuo in 42% yield. Found MH+ 506/508.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[NH2:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8])=[CH:5][CH:4]=1.C(#N)C.C(Cl)(Cl)Cl.C(N(CC)CC)C.[C:37]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>C(#N)C>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[NH:20][C:45](=[O:46])[C:44]2[CH:48]=[CH:49][C:41]([C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:42][CH:43]=2)[C:13]([O:15][CH3:16])=[O:14])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)c(NC(=O)c2ccc(OC)cc2)c1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c(NC(=O)c2ccc(OC)cc2)c1
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of methyl 3-[(4-methoxybenzoyl)amino]-4-aminobenzoate (0.800 g, 2.67 mmol) in 1:1 acetonitrile/chloroform (100 mL) was cooled to 0° C. and treated with triethylamine (0.41 mL, 2.9 mmol), and a solution of 4-tert-butylbenzoyl chloride (0.58 mL) in acetonitrile (25 μL). The reaction mixture was allowed to warm to room temperature over 16 h, concentrated in vacuo, diluted with ethyl acetate, washed with cold dilute aqueous hydrochloric acid and cold saturated aqueous sodium bicarbonate solution. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Crystallization of the residue from methylene chloride/hexane provided 1.0 g (81%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:21])[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:22]([OH:24])=[O:23].O.O.O.C[C:30]1([CH3:53])S[C@@H]2[C@H](NC([C@H](N)C3C=CC(O)=CC=3)=O)C(=O)N2[C@H:31]1[C:50](O)=[O:51].O1CCCC1O.[OH-].[Na+:61]>O>[Na+:61].[O:51]1[CH2:50][CH2:31][CH2:30][CH:53]1[NH:21][CH:13]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:11]([NH:10][CH:7]1[C:8](=[O:9])[N:4]2[CH:5]1[S:6][C:2]([CH3:25])([CH3:1])[CH:3]2[C:22]([O-:24])=[O:23])=[O:12]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Agent: OC1CCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)SC2C(NC(=O)C(NC3CCCO3)c3ccc(O)cc3)C(=O)N2C1C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a stirred suspension of 6.28 g (0.015) mol) of amoxicillin trihydrate in 150 ml of distilled water was added in one portion 15 ml of 1 N aqueous sodium hydroxide solution. The amoxicillin quickly dissolved and after two minutes 2.25 g (0.025 mol) of tetrahydro-2-furanol was added. After stirring at 25° C. for two minutes the solution was quickly frozen by means of a dry ice-acetone bath and then lyophilized for 22 hr. The resulting product {2S-[2α, 5α, 6β(S*)]}-6-{[2-tetrahydrofuranylamino(4-hydroxyphenyl)acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt (6.55 g) was obtained as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:25])[N:11]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:10]2=[O:39])[O:5][N:4]=1)[CH3:2].[ClH:40]>O1CCOCC1>[ClH:40].[CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[S:17][C:13]=3[C:12](=[O:25])[N:11]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:10]2=[O:39])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 4-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(4-fluorophenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (360 mg, compound B65) in 1,4 dioxane (13 ml) is added a solution of hydrogen chloride in 1,4-dioxane (3 ml, 4.0 M) and the reaction mixture is stirred for 48 h at RT. Subsequently the suspension is filtered to give title compound as a solid.
Reaction SMILES: 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.[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH:43](O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[C:47]([OH:50])(=[S:49])[CH3:48]>C1COCC1>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH:43]([S:49][C:47](=[O:50])[CH3:48])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CC(O)=S
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.9 %

Procedure:
To a 0° C. solution of triphenylphosphine (2.1 g, 8 mmol) in THF (14 ml) was added dropwise (15 minutes) diisopropylazodicarboxylate (1.55 ml, 8 mmol). After 30 minutes stirring at 0° C., a solution containing (RS)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 5.34 mmol) and thioacetic acid (0.57 ml, 8 mmol) in THF (7 ml) was added dropwise. The reaction mixture was stirred 30 minutes at 0° C., 45 minutes at room temperature and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1 then 8:2 then 1:1) to provide (RS)-3-acetylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.4 g, 100%) as a slightly yellow oil, MS: m/e=246.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:35]([C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccc(Cl)cc3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccc(Cl)cc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-bromo-4-[4-(4-chloro-benzyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.051 g, 0.12 mmol) and EtOH (3 ml) was added 4-methoxybenzaldehyde (0.026 g, 0.18 mmol) with the aid of EtOH (1 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.50 ml, 0.50 mmol). The reaction mixture was stirred at 70° C. for 18 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 3%) in ethyl acetate/dichloromethane (v:v; 2:3) afforded a pale yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.026 g, 42%). 1H-NMR (500 MHz, DMSO-d6) 2.60 (br s, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2—C6H4Cl), 3.66 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.1 Hz, 2H) and 8.13 (d, J=8.1 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4OMe), 7.41 (m, 4H, C6H4Cl), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.37 (br s, 1H, imidazo[4,5-b]pyridine N—H);