Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH:18]=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:18]=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1ccc2cc(-c3ccc4ccc(Cl)cc4n3)oc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCOc1ccc2cc(-c3ccc4ccc(Cl)cc4n3)oc2c1
Yield: 55.4 %

Procedure:
A mixture of 7-chloro-2-[6-[3-(ethoxycarbonyl)-propoxy]benzofuran-2-yl]quinoline (1.26 g) and potassium hydroxide (1.51 g) in a mixture of ethanol (12 ml) and water (6 ml) was stirred under reflux for one hour. After being cooled, the resulting precipitates were collected by filtration, washed with ethanol and added to water. The mixture was adjusted to pH 7 with diluted aqueous hydrochloric acid. The resulting crystals were collected by filtration, washed with water, and recrystallized from a mixture of acetic acid and methanol to give 7-chloro-2-[6-(3-carboxypropoxy)benzofuran-2-yl]quinoline (0.65 g).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[CH2:2].[Cl:8][CH2:9][C:10](Cl)=[O:11].CN1CCOCC1.O>COC(C)(C)C>[Cl:8][CH:9]1[CH:1]([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][C:10]1=[O:11]
Reactant: C=COCC(C)C
Reactant: O=C(Cl)CCl
Solvent: COC(C)(C)C
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)COC1CC(=O)C1Cl
Yield: 75.8 %

Procedure:
A solution formed by dissolving 30.0 g of isobutyl vinyl ether (0.3 mol) as the compound (V) and 34.9 g of chloroacetyl chloride (0.3 mol) as the compound (VI) in 135 ml of tert-butyl methyl ether was heated to 50˜55° C. with stirring. Subsequently, a solution formed by dissolving 30.3 g of N-methylmorpholine (with a pKa value of 7.4) (0.3 mol) in 45 ml of tert-butyl methyl ether was added dropwise to the aforementioned solution over two hours. Four hours after the completion of the dropwise addition, 40 ml of water was added thereto in order to separate the solution, followed by removal of the water layer. Analysis of the organic layer using gas chromatography under the following analysis conditions, revealed a yield of 75.8% for the compound (IV), 2-chloro-3-isobutoxycyclobutanone. Furthermore, after concentration of the aforementioned organic layer, a sample for analysis was obtained by means of distillation, and analyzed by means of elemental analysis and nuclear magnetic resonance analysis (NMR).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][N:5]2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:12])[N:22]([CH3:21])[O:23][CH3:24])=[CH:6][N:5]2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNOC
Reactant: Nc1nc2ccc(C(=O)O)cn2c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2nc(N)c(-c3ccccc3)n2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
The 2-amino-3-phenyl-6-(carboxy)imidazo-[1,2-a]-pyridine (80.4 g, 0.317 mol) and N,O-dimethylhydroxylamine hydrochloride (92.8 g, 0.951 mol) were dissolved in 500 ml DMF under N2. The diisopropylethylamine (123 g, 0.951 mol) was added and the mixture stirred for 30 minutes at RT. The 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 g, 0.634 mol) was added and allowed to stir for 19 hours at RT. The DMF was removed in vacuo and the residue was poured onto 4 L of H2O. The aqueous layer was extracted with CH2Cl2 (3×500 ml) and the organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in 400 ml of EtOAc and stirred for 1 hour at RT to form the precipitate. The precipitate was filtered and washed with cold EtOAc. The filter cake was dried in vacuo at 40° C. to yield 55.5 g of product. (59.2%). MS(FD), NMR.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](/[CH:7]=[CH:8]/[C:9]2[O:10][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][N:13]=2)=[CH:5][N:6]=1.CN(C=O)C.C(N(CC)C(C)C)(C)C.[C:32]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:14]([C:11]1[O:10][C:9]([CH:8]=[CH:7][C:4]2[S:3][C:2]([NH:1][C:39](=[O:40])[CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:6][CH:5]=2)=[N:13][CH:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cnc(/C=C/c2cnc(N)s2)o1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cnc(C=Cc2cnc(NC(=O)Cc3ccccc3)s2)o1
Temperature: 0 °C

Procedure:
To a solution of 2-amino-5-[(E)-2-(5-t-butyl-oxazol-2-yl)-vinyl]-thiazole (20 mg, 0.08 mmol) in dry CH2Cl2 (1 mL) was added dry DMF (0.1 mL) and N,N-diisopropylethylamine (28 μL, 0.16 mmol). The resulting solution was cooled to 0° C. and phenyl acetyl chloride (21 μL, 0.16 mmol) was added via syringe. The reaction mixture was allowed to warm to room temperature over two hours and then concentrated. Chromatography (SiO2, 5% MeOH/CH2Cl2) provided a N-[5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazol-2-yl]-phenylacetamide as a mixture of Z and E isomers which were separated by reverse-phase HPLC to give the Z isomer (3 mg, 10%, MS m/e 368 (M+H)+) as a light yellow solid, and the E isomer (3 mg, 10%, C20H21N3O2S, MS m/e 368 (M+H)+) as a yellow solid. (Z)-isomer: HPLC-HI 86% at 4.05 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm). (E)-isomer: HPLC-HI 84% at 4.18 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm).
Reaction SMILES: C(O[CH:5]1[S:9][C@H:8]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)(=O)C.[Cl:29][C:30]1[N:38]=[C:37]2[C:33]([NH:34][CH:35]=[N:36]2)=[C:32]([Cl:39])[N:31]=1.C1(C)C=CC=CC=1.[Cl-].C([Al+]CC)C>C(#N)C>[Si:12]([O:11][CH2:10][C@H:8]1[S:9][CH:5]([N:36]2[CH:35]=[N:34][C:33]3[C:37]2=[N:38][C:30]([Cl:29])=[N:31][C:32]=3[Cl:39])[CH2:6][CH2:7]1)([C:25]([CH3:27])([CH3:26])[CH3:28])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)OC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(Cl)nc(Cl)nc32)S1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A mixture of 10 (0.25 g, 0.6 mmol), 2,6-dichloropurine (0.142 g, 0.75 mmol) in 10 mL acetonitrile was cooled to 0° C. and a 1.8M toluene solution of diethyl aluminum chloride (0.345 mL, 0.62 mmol) was added over 1 min. Stirring was continued at 0° C. for 5 minutes and at 25° C. for 10 minutes. The reaction mixture was quenched by pouring into a mixture of 20 mL dichloromethane and 10 mL saturated NaHCO3. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was flash chromatographed with 15:1 toluene/ethyl acetate. Solvent removal gave 98 mg (30%) of 12. FAB MS 543 (M+H)+ ; 1H NMR (CDCl3) δ 8.47 (s, 1, H-8), 7.7 (m, 4, ArH), 7.45 (m, 6, ArH), 6.22 (m, 1, 1'-H), 3.96 (m, 1, 5'-H), 3.85 (m, 2, 4'-H, 5'-H), 2.45 (m, 2, 2'-H's), 2.25 (m, 1, 3'-H), 1.82 (m, 1, 3'-H), 1.1 (s, 9, t-butyl).
Reaction SMILES: FC1C(=O)NC(=O)NC=1.[C:10](Br)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:19]([N:27]1[C:32](=[O:33])[C:31]([F:34])=[CH:30][NH:29][C:28]1=[O:35])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:10]([N:29]1[CH:30]=[C:31]([F:34])[C:32](=[O:33])[N:27]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:28]1=[O:35])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(F)c1=O
Reactant: O=C(Br)c1ccccc1
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1cc(F)c(=O)n(C(=O)c2ccccc2)c1=O
Yield: 11.7 %

Procedure:
In the same manner as described in Example 1 but using 2.6 g (0.02 mole) of 5-fluorouracil, 10 ml of absolute pyridine and 7.4 g (0.04 mole) of benzoyl bromide, 1.6 g of 3-N-benzoyl-5-fluorouracil (yield, 34%) and 270 mg of 1,3-di-N-benzoyl-5-fluorouracil (yield, 4%) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6](OC)=[CH:7][CH:8]=2)[N:3]=1.N1CCCC1.CCN(C(C)C)C(C)C.[O:29]1CCOC[CH2:30]1>O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:29][CH3:30])[N:3]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
Reactant: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCNC1
Product: COc1cccc2nc(Cl)cc(Cl)c12
Temperature: 140 °C
Yield: 43.4 %

Procedure:
To a solution of 2,4-dichloro-7-methoxyquinoline (0.1 g, 0.43 mmol) in 1,4-Dioxane (10 ml) was added pyrrolidine (0.3 g, 0.43 mmol) followed by DIPEA (0.11 g, 0.87 mmol) at room temperature. The reaction mass was heated at 140° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (50 mg, 43.4%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.86-7.83 (d, J=12 Hz, 1H), 7.06 (s, 1H), 6.88-6.85 (d, J=12 Hz, 1H), 6.67 (s, 1H), 3.91 (s, 3H), 3.58 (t, J=8 Hz, 4H), 2.03 (t, J=6 Hz, 1H); MS: MS m/z 263.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C=CC=1OC)C=O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCCC(O)c2ccc(OC)c(OC)c2)cc1OC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CCCC(=O)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C

Procedure:
When a substituted benzaldehyde, preferably 3,4-dimethoxybenzaldehyde, is reacted with the grignard reagent, an alcohol is produced by the well-known grignard synthesis reaction. Preferably, the alcohol formed is 1,4-bis(3,4-dimethoxyphenyl)butane-1-ol. Preferably the grignard reagent is cooled to about 0° C. and 3,4-dimethoxybenzaldehyde in a suitable solvent such as tetrahydrofuran is added over a period of about one hour at a temperature of between about 0° C. and about 3° C. The starting materials should be of high purity; and the reaction should be carried out in a dry, inert atmosphere. The mixture is allowed to warm to room temperature and stirred for a period of between about 8 and about 12 hours. The mixture is then cooled to about 0° C. and treated with saturated ammonium chloride solution at about this temperature. After several more hours at room temperature, product is obtained by filtration and evaporation of the filtrate. Additional product is extracted from the solids with methylene chloride. Some 1,4-bis(3,4-dimethoxyphenyl) 1-butanone may be formed along with the expected alcohol, and this may be converted to the alcohol with a suitable reducing agent such as sodium borohydride. An additional impurity, wherein one of the phenolic methoxy groups has been converted to a hydroxy, may also be present, but where the final product calls for replacement of all phenolic alkoxy groups with hydroxy groups, this impurity may be carried along through ensuing steps and will be converted to the desired end product. Based on these considerations, a maximum yield for the grignard synthesis reaction is obtained by this method.
Reaction SMILES: CN1CCOCC1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][S:16]2(=[O:21])=[O:20])=[CH:11][CH:10]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:39]=[CH:40][CH:41]=2)[O:31][CH:32]([CH2:36][CH2:37][CH3:38])[C:33](O)=[O:34])[N:24]=1.Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.O>[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:39]=[CH:40][CH:41]=2)[O:31][CH:32]([CH2:36][CH2:37][CH3:38])[C:33]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:19][CH2:18][CH2:17][S:16]3(=[O:21])=[O:20])=[CH:13][CH:14]=2)=[O:34])[N:24]=1
Reactant: Nc1ccc(N2CCCS2(=O)=O)cc1
Reactant: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)Nc1ccc(N2CCCS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
101 μl (1.00 mmol) of 4-methylmorpholine are added to a solution of 212 mg (1.00 mmol) of 2-(4-aminophenyl)isothiazolidine 1,1-dioxide, 276 mg (1.00 mmol) of 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-pentanoic acid, 192 mg (1.00 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 135 mg (1.00 mmol) of hydroxybenzotriazole hydrate (HOBt) in 1 ml of DMF, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is introduced into water, and the precipitate is filtered off, giving 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-N-[4-(1,1-dioxoisothiazolidin-2-yl)phenyl]valeramide as a colourless solid; ESI 471.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]#[N:14])=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)[N:10]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27](C(OCC(Cl)(Cl)Cl)=O)[CH:26]=2)[C:9]1=[O:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.O.C(OCC)(=O)C>CN(C=O)C.[Zn].[Cl-].[Cd+2].[Cl-]>[C:1]([O:5][C:6]([N:8]1[C:12]([C:13]#[N:14])=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)[N:10]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[C:9]1=[O:42])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2c(C#N)n(C(=O)OC(C)(C)C)c(=O)n2-c2cn(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)c2ccccc21
Agent: [Cd+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(-c2c(C#N)n(C(=O)OC(C)(C)C)c(=O)n2-c2c[nH]c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.26 g (0.41 mmol) of the product from step b) in 5 ml of DMF was added 0.27 g (4.1 mmol) zinc powder, 0.028 g (0.12 mmol) of cadmium chloride and 5 ml of acetic acid. The mixture was sonicated for 2 minutes and stirred at room temperature for 30 minutes. Water and ethyl acetate were added, the phases were separated and the organic phase washed with saturated NaHCO3(aq), dried over Na2SO4 and evaporated. The residue was purified by chromatography on SiO2 (toluene:ethyl acetate) fuishing the sub-title compound (150 mg, 80%).
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[C:3]1[CH3:18].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C([O-])(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:25]([O:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:15])[Cl:16])=[O:11])=[C:3]1[CH3:18])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C[C@H]2C1O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1C(C)=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C[C@@H]12

Procedure:
To a freshly prepared solution of 2,2,2-trichloroethyl 1-hydroxy-2-methylcarbapen-2-em-3-carboxylate in methylene chloride, prepared from 100 mg. (0.317 mmole) of the 1-beta-oxide by Examples 11 and 12) was added 24 microl. (0.317 mmole) of pyridine, 29 microl. (0.317 mmole) of acetic anhydride and 4 mg. of 4-dimethylaminopyridine. Infrared spectral analysis indicated clean conversion to the desired acetate. Following water wash and drying, evaporation to dryness gave 2,2,2-trichloroethyl 1-acetoxy-2-methylcarbapen-2-em-3-carboxylate [ir (CH2Cl2) 1780, 1725, 1700 cm-1 ; Rf 0.7-0.75 (4:1 chloroform:ethyl acetate].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.FC1C=C([N+]([O-])=O)C=CC=1OC1C=CN=C2C=C(C(N(C)C)=O)SC=12.[Cl:43][C:44]1[CH:49]=[C:48]([N+:50]([O-:52])=[O:51])[CH:47]=[C:46]([Cl:53])[C:45]=1[OH:54]>>[Cl:43][C:44]1[CH:49]=[C:48]([N+:50]([O-:52])=[O:51])[CH:47]=[C:46]([Cl:53])[C:45]=1[O:54][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Agent: CN(C)C(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Product: O=C(c1cc2nccc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)c2s1)N1CCCC1
Yield: 69 %

Procedure:
Starting from the compound 139 and following the procedure described above for the synthesis of compound 6 (scheme 1, example 1) but replacing 2-fluoro-4-nitrophenol with 2,6-dichloro-4-nitrophenol, title compound 140 was obtained in 69% yield. LRMS (M+1) 438.0 (100%), 439.1 (20%), 440.1 (70%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[F:17][CH:15]([F:16])[C:8]1([C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[F:18])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C1COCC(c2cc(Br)ccc2F)(C(F)F)N1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1COCC(c2ccccc2F)(C(F)F)N1
Yield: 99.7 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholin-3-one (190 g, 586 mmol) [example 42 step e)] and sodium acetate (57.7 g, 703 mmol) were suspended in 1850 mL methanol. 10% Pd on charcoal (18.7 g) was then added and the reaction mixture was shaken in a Parr apparatus in an atmosphere of hydrogen at rt. After 60 minutes the reaction mixture was filtered over celite and evaporated. The residue was dissolved in 2 L TBME and washed with aqueous NaHCO3 and brine. The organic layer was dried over MgSO4.H2O and evaporated to give 143.2 g of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:5])C.O1CCCC1.[OH-].[Li+]>O>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]2[N:13]=[CH:12][N:11]([C:9]3[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[N:8]=3)[C:15]=2[CH:16]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Yield: 100.1 %

Procedure:
A mixture of 3.5 g (7.14 mmole) of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (I.25a), 50 mL of tetrahydrofuran, 50 mL of water and 0.857 g (35.7 mmole) of lithium hydroxide was heated at 60 degrees for 3 hours. The mixture was concentrated under reduced pressure, and then 100 mL of water was added. The pH was adjusted to ca. 3-4 by the addition of hydrochloric acid. The resulting precipitate was collected by filtration to give 3.3 g of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid (I.25b) as a white solid.
Reaction SMILES: Cl.[C:2]([O:10][CH2:11][CH:12]1C[C:13]1([CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH2:15][O:16][Si](C(C)(C)C)(C)C)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:33]O>>[CH3:33][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:2]([O:10][CH:11]1[CH2:12][C:13]1([CH2:15][OH:16])[CH2:24][OH:25])=[O:9]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO[Si](C)(C)C(C)(C)C)CC1COC(=O)c1ccccc1
Reactant: CO
Agent: Cl
Product: Cc1ccccc1C(=O)OC1CC1(CO)CO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
137 ml (137 mmol) of 1N hydrochloric acid, and 683 ml of methanol were added to 21.15 g (45.5 mmol) of 2,2-bis[(tert-butyldimethylsilyloxy)methyl]cyclopropylmethyl benzoate, and the solution was stirred for 40 minutes at room temperature. The solvent was distilled off, and the resulting oily product was purified by silica gel column chromatography (4% methanol/dichloromethane) to obtain 10.91 g (45.5 mmol, 100%) of 2,2-bis(hydroxymethyl)cyclopropyl methylbenzoate. This was a colorless oil; 1H-NMR (CDCl3) δ: 0.52 (dd, J=5.4, 5.4 Hz, 1H), 0.82 (dd, J=5.1, 8.7 Hz, 1H), 1.41 (m, 1H), 2.95 (broad s, 2H), 3.55 (d, J=11.4 Hz, 1H), 3.66 (d, J=11.4 Hz, 1H), 3.69 (d, J=12.0 Hz, 1H), 4.03 (d, J=12.0 Hz, 1H), 4.29 (dd, J= 8.7, 12.0 Hz, 1H), 4.57 (dd J=6.3, 12.0 Hz, 1H), 7.44 (m, 2H), 7.56 (m, 1H), 8.04 (m, 2H); FD MASS, M/z 236 (M+).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[NH2:19][CH2:20][CH2:21][CH2:22][C:23]1[C:24]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25][C:26]([NH2:30])=[N:27][C:28]=1[CH3:29].[C:37]1([CH2:47][C:48](O)=[O:49])[CH:42]=[CH:41][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:39][CH:38]=1>C1COCC1.CCOC(C)=O>[NH2:30][C:26]1[N:27]=[C:28]([CH3:29])[C:23]([CH2:22][CH2:21][CH2:20][NH:19][C:48](=[O:49])[CH2:47][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:39][CH:38]=2)=[C:24]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[N:25]=1
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCNc1nc(N)nc(C)c1CCCNC(=O)Cc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of T3P (1.591 ml, 1.57M in THF) was added to a mixture of the product from example 1 step (v) (0.2 g), TEA (0.333 ml) and 2,2′-(1,4-phenylene)diacetic acid (0.463 g) in THF (15 mL) and the mixture stirred at rt overnight. The reaction was diluted with EtOAc, washed with water, dried and evaporated under reduced pressure. Used crude in next step.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH3:15])[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)=O.C([O-])(=O)C.[NH4+:22].CC(O)=O.[OH-].[Na+]>O>[CH3:15][N:5]1[CH:4]=[CH:3][N:22]=[C:6]1[C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1
Reactant: [NH4+]
Reactant: COC(CN(C)C(=O)[C@H]1CC[C@H](O)CC1)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cn1ccnc1[C@H]1CC[C@H](O)CC1
Temperature: 125 °C

Procedure:
A mixture of trans-N-(2,2-Dimethoxyethyl)-4-hydroxy-N-methylcyclohexanecarboxamide (265 mg, 1.08 mmol) and Ammonium acetate (2.2 g, 29 mmol) in AcOH (3.0 mL, 53 mmol) was heated to reflux (oil bath temperature 125° C.) for 16.5 h. To the cooled solution were added 10 N NaOH (≈10 mL) and water (≈10 mL), and the mixture was extracted with DCM (3×20 mL). The combined DCM extracts were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound as light orange solid. Additional material was obtained by saturating the aqueous layer from the previous extractions with NaCl and extracting with more DCM (4×25 mL). The light orange solid was chromatographed on silica gel [Isco Combiflash, 2.5 g loading column/4 g Gold column, eluting with DCM→10% 7N NH3 in MeOH] to give the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ=6.92 (d, J=1.4 Hz, 1H), 6.77 (d, J=1.4 Hz, 1H), 3.73 (tt, J=10.8, 4.2 Hz, 1H), 3.60 (s, 3H), 2.60 (tt, J=12.0, 3.6 Hz, 1H), 2.18-2.08 (m, 2H), 1.99-1.91 (m, 2H), 1.88 (brs, 1H), 1.83-1.71 (m, 2H), 1.46-1.35 (m, 2H). MS (ES+): m/z=181.13 (100) [MH+]. HPLC: tR=0.69 min (very polar—5 min, ZQ3). UV: λmax=216 nm.