Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.S(Cl)(Cl)=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:26]2[C:31]([CH3:32])=[C:30]([CH3:33])[CH:29]=[C:28]([CH3:34])[C:27]=2[OH:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[CH:13][CH:12]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>ClCCl.C(N(CC)CC)C>[CH:36]([NH:39][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1)[C:26]1[C:31]([CH3:32])=[C:30]([CH3:33])[CH:29]=[C:28]([CH3:34])[C:27]=1[OH:35])([CH3:38])[CH3:37]
Reactant: CC(C)N
Reactant: Cc1cc(C)c(O)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(O)c(C(CCCCCC(=O)NC(C)C)c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of dichloromethane (10 ml) and dimethylformamide (0.43 ml) was added thionyl chloride (0.24 ml) at -10° C. and the mixture was stirred at the same temperature for 20 minutes. To this solution was added a solution of 7-(4-fluorophenyl)-7-(2-hydroxy-3,5,6-trimethylphenyl)heptanoic acid (1.0 g) in dichloromethane (5 ml) and the mixture was stirred at the same temperature for 1 hour. Isopropylamine (0.48 ml) and triethylamine (1.1 ml) were added and the temperature was raised slowly to room temperature. The reaction mixture was stirred at room temperature for 1 hour and washed in turn with 1N hydrochloric acid, water, aqueous sodium hydrogen carbonate, water and saturated saline and dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and the resulting crystals were recrystallized from isopropyl ether to obtain N-isopropyl-7-(4-fluorophenyl)-7-(2-hydroxy-3,5,6-trimethylphenyl)heptane amide (0.64 g) (Compound 7). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:28]=[CH:27][C:13]3[N:14]([CH:20]4[CH2:25][CH2:24][N:23](C)[CH2:22][CH2:21]4)[CH2:15][C:16]([CH3:19])([CH3:18])[O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OC(Cl)C)=O.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>ClC(Cl)C>[C:1]1([S:7]([C:10]2[CH:28]=[CH:27][C:13]3[N:14]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH2:15][C:16]([CH3:18])([CH3:19])[O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCC(N2CC(C)(C)Oc3cc(S(=O)(=O)c4ccccc4)ccc32)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC1(C)CN(C2CCNCC2)c2ccc(S(=O)(=O)c3ccccc3)cc2O1
Reaction time: 0.02 h
Yield: 75.5 %

Procedure:
A solution of 7-benzenesulfonyl-2,2-dimethyl-4-(1-methyl-piperidin-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine (0.119 g., 0.298 mmol) in 3 mL dichloroethane was cooled to 0° C. and α-chloroethyl chloroformate (0.033 mL, 0.312 mmol) was added dropwise with stirring over 1 minute. The reaction mixture was refluxed for 18 hours, concentrated in vacuo, and the residue dissolved in 20 mL methanol and refluxed for 1 hour. The reaction mixture was concentrated in vacuo and a vacuum of 0.5 Torr was applied for 30 minutes. The resulting residue was dissolved in 35 mL THF, to which was added di-tert-butyldicarbonate (0.065 g., 0.300 mmol) and the reaction mixture was stirred for 72 hours at room temperature. The reaction mixture was then concentrated in vacuo and purified by flash chromatography (15% ethyl acetate in hexanes) to afford 0.087 g (75%) of 7-benzenesulfonyl-2,2-dimethyl-4-piperidin-4-yl-3,4-dihydro-2H-benzo[1,4]oxazine as a waxy solid. MS: 387, mp: 284.9-296.3° C. (as hydrochloride salt).
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19][CH:18]3[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[OH-].[Na+].Cl>C(O)C>[ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH:18]3[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:15][CH2:16]2)=[CH:7][CH:6]=1)(=[NH:3])[NH2:4]
Reactant: CCOC(=O)CCC1CN(CC(=O)OCC)CCC1N1CCN(c2ccc(C(=N)N)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)c1ccc(N2CCN(C3CCN(CC(=O)O)CC3CCC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.8 %

Procedure:
350 mg of ethyl 4-[4-(4-amidinophenyl)-1-piperazinyl]-1-ethoxycarbonylmethyl-3-piperidinepropionate hydrochloride was dissolved in 20 ml of ethanol, and 2.5 ml of an aqueous solution of 1N-sodium hydroxide was added thereto and stirred at room temperature for 5 hours. 2.5 ml of 1N-hydrochloric acid was added to the reaction liquid, from which the solvent was removed by distillation. The resulting residue was purified by HP-20 column chromatography (using a gradient eluent of water to water/ethanol=50/1) to obtain 180 mg of 4-[4-(4-amidinophenyl)-1-piperazinyl)-1-carboxymethyl-3-piperidinepropionic acid hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1)=[C:5]2[OH:20].Cl[C:22]([F:28])([F:27])C(OC)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[N:16][CH:15]=1)=[C:5]2[O:20][CH:22]([F:28])[F:27]
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1Cc1cncnc1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1nc2ccc(Br)cc2c(OC(F)F)c1Cc1cncnc1
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-4-hydroxy-3-(pyrimidin-5-ylmethyl)quinolin-2(1H)-one (0.5 g, 1.51 mmol, Intermediate 49: step a) methyl 2-chloro-2,2-difluoroacetate (0.24 mL, 2.26 mmol) and K2CO3 (0.52 mg, 3.76 mmol) in DMF (0.6 mL) was stirred at 80° C. for 2 hours, cooled to room temperature, diluted with H2O and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried, filtered, evaporated in-vacuo and purified by chromatography (0-10% MeOH in DCM, gradient) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([OH:20])=O)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][N:28](C=O)C.CN>C1COCC1.ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([NH:28][CH3:27])=[O:20])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Reaction time: 0.08 h
Yield: 76 %

Procedure:
6-Bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxylic acid (250 mg, 0.746 mmol) was slurried into DCE (8 mL) and then oxalyl chloride (0.30 mL, 3.4 mmol) was added and the slurry was stirred for 5 min. Then DMF (50 μL, 0.65 mmol) was added (foaming) and the slurry was stirred 1 h before methanamine (5 mL, 10 mmol) 2M in THF (exothermic) and TEA (˜3 mL) (exothermic) were added. The reaction was stirred at rt overnight. The reaction was partitioned between water (˜30 mL) and DCM/MeOH (9/1, 3×30 mL). The combined organics were concentrated to dryness and the residue was slurried in MeOH/EtOAc (1:1˜40 mL) and filtered to collect 6-bromo-2-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (172 mg, 0.494 mmol, 66% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.92 (s, 1H), 8.25 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 2.79 (d, J=4.0 Hz, 3H). LC-MS retention time 1.73 min; ink 348, 350 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[C:13]([CH2:14][O:15][CH2:16][O:17][CH3:18])=[CH:12][C:11]([F:19])=[C:10]([CH3:20])[N:9]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O.C(O)=O.C(N(CC)CC)C.CN(C)C=O>[F:19][C:11]1[C:10]([CH3:20])=[N:9][CH:8]=[C:13]([CH2:14][O:15][CH2:16][O:17][CH3:18])[CH:12]=1
Reactant: COCOCc1cc(F)c(C)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COCOCc1cnc(C)c(F)c1
Reaction time: 2 h

Procedure:
To 30 mL of a 1,4-dioxane solution containing 2.4 g of 2-chloro-5-fluoro-3-((methoxymethoxy)methyl)-6-methylpyridine, 2.3 mL of triethylamine, 0.61 mL of formic acid and 0.63 g of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was stirred for 2 hours with reflux by heating under a nitrogen atmosphere. Thereto was added 30 mL of N,N-dimethylformamide, and the mixture was stirred at 90 to 100° C. for 1 hour. Thereto were added 2.3 mL of triethylamine, 0.61 mL of formic acid and 0.63 g of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 90 to 100° C. for 1 hour. Water and ethyl acetate were added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [hexane:gradient elution of ethyl acetate=95:5 to 80:20] to obtain 1.8 g of a yellow oily substance, 3-fluoro-5-((methoxymethoxy)methyl)-2-methylpyridine.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:9]([O:11]C)Cl>>[SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]=[O:11])=[CH:4][CH:3]=1
Reactant: COC(Cl)Cl
Reactant: Sc1ccccc1
Product: O=Cc1ccc(S)cc1

Procedure:
The above reaction of Example 6A is repeated except that the starting materials are mercaptobenzene and dichloromethyl methylether. Using the same reaction conditions and techniques, there is obtained 4-mercaptobenzaldehyde.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][C:15](OCC)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCC/C=C/CCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCCCCC/C=C/CCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of (E)-ethyl 9-phenylnon-6-enoate (1.45 g, 5.53 mmol) in methylene chloride (35 ml) under argon at 0° was added diisobutylaluminum hydride (15.0 ml of a 1.0M solution). This mixture was warmed to room temperature and quenched with 10% aqueous hydrochloric acid. The organic portion was washed with saturated sodium bicarbonate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. Purification by flash chromatography (silica, 20% ethyl acetate/hexane) gave the desired alcohol.
Reaction SMILES: [Mg].II.[C:4]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)Cl)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24](=[O:26])=[O:25].Cl>CCOCC>[C:4]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]([OH:26])=[O:25])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To 400 ml of ether were added 15 g of magnesium (flaked) and 3.2 g of iodine. 27.9 g of triphenylchloromethane was carefully added thereto and the mixture was refluxed by heating for 3 hours. To the reaction solution was gradually added a large excess of dry ice. The reaction solution was acidified with hydrochloric acid and then extracted with ethyl acetate. After distilling off the solvent, the crystals thus obtained were recrystallized from ethanol to obtain 16.5 g of triphenylacetic acid. The melting point was 258° to 260° C. (decomposed).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[C:11]([N:16]=1)=[N:12][CH:13]=[CH:14][CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:18].[K+].S(=O)(=O)(O)O.S(=O)(O)[O-].[Na+]>[OH-].[Na+].O>[C:1]([C:8]1[O:9][C:10]2[C:11]([N:16]=1)=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: c1ccc(Cc2nc3ncccc3o2)cc1
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Product: O=C(c1ccccc1)c1nc2ncccc2o1

Procedure:
A mixture of 800 mg. of 2-benzyloxazolo[ 4,5-b]pyridine, 2.5 g. of potassium permanganate, 35 ml. of water and 6 drops of 2.5 N sodium hydroxide solution was heated at 50°-55° C. for 3 hours. After cooling, sulfuric acid was added to about pH 6 and sufficient sodium bisulfite was added to remove the manganese dioxide. The crystalline precipitate remaining was collected and recrystallized from ethylacetate to give 2-benzoyloxazolo[ 4,5-b]pyridine, m.p. 151°-153° C.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[NH:13][CH:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[Cl:16].Cl.[NH2:19][CH2:20][C:21]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:16][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[C:14](=[O:15])[NH:13][CH:12]=[N:11]2)=[CH:9][C:4]=1[C:3]([NH:19][CH2:20][C:21]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17]
Reactant: COC(=O)c1cc(-n2nc[nH]c2=O)ccc1Cl
Reactant: NCC1(O)CCCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC1(O)CCCCCC1)c1cc(-n2nc[nH]c2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2-chloro-5-(5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-benzoic acid methyl ester (48.0 mg, 0.2 mmol) in DMF (3 mL) was added 1-aminomethyl-cycloheptanol HCl (54.0 mg, 0.3 mmol), polymer-supported CDI (660 mg, 0.6 mmol), polymer-supported DMAP (280 mg, 0.20 mmol), and HOBt (40.0 mg, 0.3 mmol). The resulting reaction was shaken for 3 hours at ambient temperature. The reaction was filtered, washed with methanol, and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC using a (5–100% gradient of 0.1% formic acid in acetonitrile and 0.1% formic acid in water) to yield 20 mg of the above named compound.
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH:3]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[C:16]([N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]1[C:2]([Cl:1])([Cl:14])[Cl:15])(=[O:18])[CH3:17]
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1C(=O)c2ccccc2OC1C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4-Dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (prepared as described in Example 3--4.0 g.) was stirred with acetic anhydride (40 ml.) on a steam-bath for 10 hours. The reaction mixture was cooled to room temperature, poured into water (400 ml.) and stirred for 3 hours, and the oil which separated was extracted into diethyl ether. The extract was dried and the solvent was evaporated to leave an oil, which was purified by column chromatography on "Kieselgel 60" (trade mark) silica, and the column was eluted with 10% v/v ethyl acetate in toluene. 25 Ml. fractions were collected, fractions 1-7 were combined, and the solvent was evaporated to give 3-acetyl-3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one as an oil. The n.m.r. spectrum in hexadeuterio-dimethylsulphoxide showed the following characteristic peaks (δ values):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[NH:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:49]2[CH2:48][CH2:47][CH:46]([NH:45][C:37]3[NH:36][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)[CH2:51][CH2:50]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid to give, after purifying by chromatography on silica gel eluting with 25% methanol/ethyl acetate, the title compound: Rf=0.20 (silica gel, 40% methanol/ethyl acetate).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([C:13]([OH:15])=O)=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][NH2:45]>O.CN(C=O)C>[O:1]=[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([C:13]([NH:45][O:44][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][O:38]3)=[O:15])=[CH:7][CH:8]=2)[NH:3]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1ccc2c(=O)[nH]c(=O)[nH]c2c1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1ccc2c(=O)[nH]c(=O)[nH]c2c1
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
A mixture of 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (0.15 g, 0.73 mmol), DMF (2.80 mL), triethylamine (0.30 mL, 2.2 mmol) and fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (0.25 g, 0.95 mmol) was stirred for 15 min and O-(tetrahydropyran-2-yl)hydroxylamine (0.10 g, 0.87 mmol) was added. The reaction mixture was stirred at rt for 1 d. Water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (50% to 100% EtOAc/hexanes) to afford 2,4-dioxo-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (0.15 g, 68%). LC-MS: (FA) ES+ 306.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[CH2:15][C:16]([OH:18])=[O:17])([O-:3])=[O:2].Cl.[CH3:20]O>>[N+:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]([F:14])([F:12])[F:13])[C:5]=1[CH2:15][C:16]([O:18][CH3:20])=[O:17])([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Agent: Cl
Product: COC(=O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Yield: 92 %

Procedure:
[2-Nitro-4-iodo-6-(trifluoromethyl)phenyl]acetic acid (34.7 g, 96.2 mmol) was dissolved in HCl/MeOH (300 mL) and the solution was heated at reflux for 4.5 hours. The solvent was removed in vacuo and the resulting oil was dissolved in EtOAc (400 mL). The solution was washed with saturated aqueous NaHCO3 (60 mL, 100 mL and 80 mL) and then dried (anhydrous MgSO4). After filtration, the solvent was removed in vacuo to yield the title compound (33.11 g, 92%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]=[CH:6]1)#[N:2].[H][H]>CO.[Pt]=O>[C:1]([CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6]1)#[N:2]
Reactant: N#CCCn1cnc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: N#CCCn1cnc(N)c1
Yield: 84.8 %

Procedure:
1-(2-Cyanoethyl)-4-nitroimidazole (3.32 g, 20 mmol) was dissolved in methanol (100 ml), and platinum oxide (50 mg) was added to the solution. The mixture was stirred for 12 hours in a hydrogen atmosphere. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (chloroform:methanol=10:1 to 5:1) to obtain 2.31 g of the title compound (oil).
Reaction SMILES: [CH:1]([N-:3][CH:4]=[O:5])=[O:2].[Na+].[Na+].[I-].Br[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(#N)C>[CH:1]([N:3]([CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=[O:5])=[O:2]
Reactant: CCOC(=O)/C=C/CBr
Reactant: O=C[N-]C=O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)/C=C/CN(C=O)C=O
Yield: 84.8 %

Procedure:
Prepared according to WO 2010/031816. In a 250 mL RBF, sodium diformylamide (Fluka; 2.66 g, 28.0 mmol) and NaI (3.49 g, 23.31 mmol) were treated with ACN (60 mL) and (E)-ethyl 4-bromobut-2-enoate (Aldrich; 4.28 mL, 23.31 mmol) and the flask was fitted with a reflux condenser and heated at reflux overnight (16 h). The mixture was concentrated in vacuo and the crude residue was treated with water and extracted with EtOAc (100 mL). The organic extract was washed with brine, then dried over MgSO4, filtered, and concentrated. The resulting light-brown solid was suspended in Et2O (ca. 10 mL), filtered, and washed with Et2O (5 mL), then dried by drawing air through the filtercake for 2 min to afford (E)-ethyl 4-(N-formylformamido)but-2-enoate (3.66 g, 19.76 mmol, 85% yield) as a brown amorphous solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.91 (2H, br. s.), 6.74-6.84 (1H, m), 5.90 (1H, dt, J=15.8, 1.6 Hz), 4.40 (2H, d, J=4.5 Hz), 4.13-4.24 (2H, m), 1.20-1.33 (3H, m). m/z (ESI, +ve ion) 186.1 (M+H)+. The crude material was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4](Cl)[CH2:5][S:6][CH3:7].[N-:10]=[N+:11]=[N-:12].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH3:1][O:2][C:3](=[O:9])[CH:4]([N:10]=[N+:11]=[N-:12])[CH2:5][S:6][CH3:7]
Reactant: COC(=O)C(Cl)CSC
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(CSC)N=[N+]=[N-]
Yield: 87.5 %

Procedure:
6.0 grams (35.5 mmoles) of the 2-chloro-3-methylmercapto-propionic acid methyl ester produced in Example 5 were stirred with 3.47 grams (53.4 mmoles) of sodium azide and 0.82 grams of Aliquat 336 in 15 ml of water for 7 hours at 45° C. After working up according to Example 2 there were obtained 5.44 grams (87% of theory) of 2-azido-3-methylmercapto-propionic acid methyl ester as an analytically pure material.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:31])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23]CC2C=CC=CC=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:31])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[OH:23])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c(O)c1
Reaction time: 6 h
Yield: 94.4 %

Procedure:
To a solution of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate (42.84 g, 0.097 mol) in ethanol (600 mL) was added palladium on carbon (10 wt. %, 5.81 g) and the reaction mixture was shaken under an H2 atmosphere (50 psi) for 6 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide 32.27 g (95%) of (±)-2-hydroxy-3-(2-hydroxy-4-methoxyphenyl)propyl 4-methylbenzenesulfonate as a colorless oil. Rf=0.34 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C17H18O5S: C, 61.06; H, 5.43. Found: C, 60.70; H, 5.37.