Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:15]=[C:14]([O:16][CH3:17])[C:7]2[O:8][CH:9]([CH2:12][NH2:13])[CH2:10][O:11][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29](=[O:33])[O:30]2)=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.CO.C(O)(C)C>[CH3:2][O:3][C:4]1[CH:15]=[C:14]([O:16][CH3:17])[C:7]2[O:8][CH:9]([CH2:12][NH:13][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]4[CH:27]=[CH:28][C:29](=[O:33])[O:30][C:31]=4[CH:32]=3)[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: COc1cc(OC)c2c(c1)OCC(CN)O2
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c2c(c1)OCC(CNCCCOc1ccc3ccc(=O)oc3c1)O2
Temperature: 96 °C

Procedure:
2,3-Dihydro-6,8-dimethoxy-1,4-benzodioxin-2-methanamine hydrochloride (3.58 g, 13.7 mmole), 7-(3-bromopropoxy)coumarin (3.35 g, 11.8 mmole), and diisopropylethylamine (3.25 ml, 18.7 mmole) were combined in 200 ml of DMF and heated at 96° C. for 2 days under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on 300 g of silica gel using first dichloromethane and then 1% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the free base thus obtained redissolved in methanol and 7 ml of 4N isopropanolic HCl added. The mixture was brought to a boil on a hot plate and the solvent gradually replaced with isopropanol. Upon cooling, 0.87 g of the title compound (m.p. 184°-187° C.) precipitated as a white solid, monohydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([NH:14]C(OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC(N)CC1
Yield: 100.3 %

Procedure:
To a solution of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid tert-butyl ester (3.0 g, 9.009 mmol) in THF (80 mL) is added TEA (0.24 mL, 1.724 mmol) and 10% Pd/C (wet) (420 mg). The mixture stirs under a blanket of hydrogen gas at atmospheric pressure for 12 h. The mixture is then filtered though celite. The celite is washed with MeOH (50 mL). The filtrated is concentrated to afford 1.8 g of 4-amino-cyclohexanecarboxylic acid tert-butyl ester. LC/MS: [M+H]+ 200, Rt=0.39 min (method 6).
Reaction SMILES: [F:1][C:2]1[C:3]([F:21])=[C:4]2[O:8][C:7]([CH3:9])=[CH:6][C:5]2=[C:10]([CH:19]=[O:20])[C:11]=1[O:12]COCCOC.Cl>C1COCC1.CC(OC)(C)C>[F:1][C:2]1[C:3]([F:21])=[C:4]2[O:8][C:7]([CH3:9])=[CH:6][C:5]2=[C:10]([CH:19]=[O:20])[C:11]=1[OH:12]
Reactant: COCCOCOc1c(F)c(F)c2oc(C)cc2c1C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc2c(C=O)c(O)c(F)c(F)c2o1

Procedure:
18.0 g (60.0 mmol) of 6,7-difluoro-5-(2-methoxyethoxymethoxy)-2-methylbenzofuran-4-carbaldehyde are stirred for 17 h at 20° C. together with 11.0 ml of conc. HCl in 100 ml of THF. The reaction soln. is diluted with MTBE and washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed successively with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, 1-chlorobutane), giving 6,7-difluoro-5-hydroxy-2-methylbenzofuran-4-carbaldehyde as a yellow crystalline solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([N+:21]([O-])=O)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]>C1COCC1.[Pd]>[NH2:21][C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:12][C:13]=2[CH:20]=1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N)ccc21

Procedure:
2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-5-nitro-benzimidazole (5.5 g, 18 mmol) in 150 mL THF/75 mL methanol is hydrogenated in the presence of 1.0 g of 5% Pd/C at ambient temperature and normal pressure. The catalyst is filtered off, the filtrate is evaporated not quite to dryness, diluted with 100 mL acetonitrile and evaporated down to a residual volume of 30 mL. The crystal slurry is cooled and filtered. The crystals are washed with cold acetonitrile and ether.
Reaction SMILES: [Cl-].[CH2:2]([O:4][P:5](=O)([OH:9])[O:6][CH2:7][CH3:8])[CH3:3].[OH-].[Na+].[CH2:13]([OH:16])[C:14]#[CH:15]>O>[CH2:13]([O:16][P:5](=[O:9])([O:6][CH2:7][CH3:8])[O:4][CH2:2][CH3:3])[C:14]#[CH:15]
Reactant: C#CCO
Reactant: CCOP(=O)(O)OCC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCOP(=O)(OCC)OCC
Reaction time: 0.25 h
Yield: 70 %

Procedure:
1 mol of phosphoric acid diethyl ester chloride and 1.07 mols of 50% strength sodium hydroxide solution were added dropwise to 3.33 mols of propargyl alcohol (233% excess) at 15°-20° C. The mixture was stirred for 15 minutes, water was added to dissolve the salt and the mixture was extracted with 800 ml of chloroform. On distillation, 70% of phosphoric acid diethyl propargyl ester was obtained.
Reaction SMILES: [CH2:1]([O:8][O:9]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].S(=O)(=O)(O)[OH:19]>C(Cl)(Cl)Cl.CO>[CH:7]1[C:2]([C:1]([O:8][OH:9])=[O:19])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(COOCc2ccccc2)cc1
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(OO)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
19 g (78 mmol) of dibenzyl peroxide is dissolved in 125 ml of chloroform at −5° C. 2.2 g (94 mmol) of sodium dissolved in 50 ml of methanol under a nitrogen stream, is added dropwise. After stirring for 30 minutes at −5° C., ice water is added and the medium is acidified with an aqueous solution of 2N sulphuric acid. It is extracted with dichloromethane, then the organic phase is dried over magnesium sulphate, filtered and concentrated. 9 g of perbenzoic acid is obtained in the form of white solid at a yield of 83%.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:20])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][CH2:18][OH:19])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[N:35]2[CH:36]=[C:37]([O:40][C@H:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C@@H:44]([NH2:51])[CH2:43][CH2:42]3)[CH:38]=[CH:39][C:34]2=[N:33][N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:51][C@@H:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@H:41]([O:40][C:37]3[CH:38]=[CH:39][C:34]4[N:35]([C:31]([C:25]5[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][C:26]=5[Cl:30])=[N:32][N:33]=4)[CH:36]=3)[CH2:42][CH2:43]2)=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][OH:19])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCCO)n1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4c(Cl)cccc4Cl)n3c2)c2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(-c5c(Cl)cccc5Cl)n4c3)c3ccccc32)n(CCCO)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
A mixture of Intermediate 35b (200 mg, 0.54 mmol), Intermediate 26d (228 mg, 0.54 mmol), and DIPEA (140 μL, 0.80 mmol) in dioxane (2 mL) was stirred at 70° C. for 18 h. The reaction mixture was cooled to RT, diluted with DCM (10 mL), and washed with water (2×10 mL). The aqueous layer was extracted with DCM, and the combined organics were passed through a phase separator and concentrated in vacuo and the resultant residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM to afford the title compound (270 mg, 76%). A 50 mg sample of this was purified by MDAP (Method 7) to afford the title compound as a glassy solid (17 mg). LCMS (Method 5): Rt 4.24 min, m/z 648.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.20 (9H, s), 1.79-1.87 (2H, m), 1.88-2.14 (4H, m), 3.41 (2H, t, J=5.9 Hz), 3.91 (2H, t, J=7.2 Hz), 4.58 (1H, br s), 4.79-4.87 (1H, m), 5.55 (1H, t, J=4.2 Hz), 6.03 (1H, s), 6.93 (1H, d, J=8.8 Hz), 7.23-7.29 (1H, m), 7.32-7.38 (4H, m), 7.69-7.79 (3H, m), 7.91 (1H, dd, J=9.6 Hz, 0.9 Hz), 7.98 (1H, d, J=1.7 Hz), 8.17 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][C:9](OC)=[O:10])[CH:7]=1.[CH3:14][NH2:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][C:9]([NH:15][CH3:14])=[O:10])[CH:7]=1
Reactant: COC(=O)Cn1cc(Br)ccc1=O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1cc(Br)ccc1=O

Procedure:
A solution of methyl 2-(5-bromo-2-oxopyridin-1(2H)-yl)acetate (0.5 g, 1.92 mmol, WO 2009134400) in 2M solution of Methyl amine in THF (5 mL) was stirred at RT for 16 h. The separated solid is collected by filtration and dried under vacuum to afford 2-(5-bromo-2-oxopyridin-1(2H)-yl)-N-methylacetamide as off-white solid, 0.35 g (74%), 1H NMR (400 MHz, DMSO): 8.09 (1H, d, J=4.4 Hz), 7.93 (1H, d, J=2.4 Hz), 7.54 (1H, dd, J=3.0, 9.8 Hz), 6.36 (1H, d, J=9.8 Hz), 4.47 (2H, s), 2.61 (3H, d, J=4.9 Hz). ES-MS: 247.1 (M+2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([NH2:12])[CH:10]=[CH2:11]>>[CH2:9]([N:12]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH:10]=[CH2:11]
Reactant: O=Cc1ccncc1
Reactant: C=CCN
Product: C=CCN=Cc1ccncc1

Procedure:
Pyridine-4-carboxaldehyde and 2-propenyl amine were reacted by the procedure of example 1(c) to afford the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][CH2:8][C:9]1(OS(C)(=O)=O)[CH2:12][CH:11](CO[Si](C(C)(C)C)(C)C)[CH2:10]1)([CH3:4])[CH3:3].[N-:29]=[N+:30]=[N-:31].[Li+]>CN(C=O)C>[CH3:4][C:2]([Si:5]([CH3:27])([CH3:28])[O:6][CH2:7][CH2:8][CH:9]1[CH:10]([CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:28])[CH3:27])[CH2:11][CH:12]1[N:29]=[N+:30]=[N-:31])([CH3:1])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCCC1(OS(C)(=O)=O)CC(CO[Si](C)(C)C(C)(C)C)C1
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC1C(CO[Si](C)(C)C(C)(C)C)CC1N=[N+]=[N-]
Temperature: 80 °C
Yield: 146.4 %

Procedure:
2-(2-(((1,1-Dimethylethyl)dimethylsilyl)oxy)ethyl-3-(((1,1-dimethylethyl)dimethyl-silyl)oxymethyl)-1-O-methanesulfonylcyclobutanol (180 mg, 0.41 mmol) was mixed with 200 mg (4.1 mmol) of lithium azide in 4 mL of DMF. The reaction mixture was heated at 80° C. for 2 h then concentrated in vacuo. The residue was purified on a silica gel column eluted with 5% ethyl acetate in hexane to give 120 mg (73% yield) of the title compound; MS DCI-NH3M/Z: 400 (M+H)+, 417 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[O:14]=[C:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[C:16]([C:15](=[O:14])[CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CC(=O)CCCCCCC(=O)O
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: CC(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)CCCCCC(=O)O

Procedure:
The procedure described in Example 9 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.72 g of 8-ketononanoic acid. Yield 1.85 g (55%), yellow viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([Cl:18])[N:6]=2.[CH3:20][O:21][P:22]([O:25]C)[O:23][CH3:24]>>[Cl:18][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([CH2:2][P:22](=[O:25])([O:23][CH3:24])[O:21][CH3:20])[N:4]2[CH3:19])=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: COP(OC)OC
Product: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Reaction time: 1.25 h
Yield: 76.5 %

Procedure:
A mixture of 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (0.25 g, 0.72 mmol) and trimethylphosphite (4.0 mL, 34 mmol) was stirred at 120 degree for 1.25 hours. The resulting suspension was partitioned between water and dichloromethane. The aqueous layer was neutralized and extracted again with dichloromethane. The organic extracts were washed with water, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (0-5% methanol in DCM) to give the title compound (207 mg, 76%).
Reaction SMILES: [C:1]([C:3]1([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1)#N.C[Mg]Br.C1(C)C=CC=CC=1.C1COCC1>O1CCCC1>[OH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:3]2([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)N1CCC(C#N)(N2CCC(O)CC2)C1
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C)(N2CCC(O)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
To a stirred solution of ethyl 3-cyano-3-(4-hydroxy-1-piperidyl)pyrrolidine-1-carboxylate (1.0 gm, 3.74 mmol) in tetrahydrofuran (25 mL) was added a 1.4 M solution of methyl magnesium bromide in toluene/THF (5.35 mL, 7.48 mmol) at 0° C., and the mixture was allowed to warm to room temperature. The mixture was stirred for another 12 h at room temperature, the reaction was quenched with saturated ammonium chloride solution (5 mL) at 0° C. and diluted with ethyl acetate (25 mL). The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound as a pale solid (830 mg), which was used for the subsequent step without further purification. MS (M+1): 257.16.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:15]3[N:16]([C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=3)[N:17]=[C:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23][C:24](OCC)=[O:25])[CH:11]=[CH:12][CH:13]=1>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:15]3[N:16]([C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=3)[N:17]=[C:18]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCCc1c(-c2ccccc2)nn2c(CC)ccc2c1-c1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCO)c(-c3ccccc3)nn12
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a suspension of lithium aluminum hydride (98.8 mg) in tetrahydrofuran (10 mL) was added ethyl 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (600 mg) in tetrahydrofuran (10 mL) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. The reaction was quenched with saturated potassium sodium tartrate solution and the insolubles were filtered off and washed with ethyl acetate. The filtrates were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1-2:1) to give 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol as an yellow oil (478 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=O)=[C:22]([CH3:33])[C:21]=1[CH3:34]>O1CCCC1>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=[C:8]([CH3:9])[C:6]([O:5][CH2:4][CH3:3])=[O:7])=[C:22]([CH3:33])[C:21]=1[CH3:34]
Reactant: COc1cc(C)c(C=CC=CC=O)c(C)c1C
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=CC=CC=Cc1c(C)cc(OC)c(C)c1C
Temperature: 0 °C

Procedure:
To a suspension of NaH (2g of 50% reagent) in 100 ml of tetrahydrofuran (THF), stirred under an atmosphere of nitrogen at 0° C., (ice bath), was added dropwise 8.8 g (37 mmol) of triethyl 2-phosphonopropionate. The resulting mixture was stirred in the ice bath for additional 2.5 hrs and a solution of 5-(4-methoxy-2,3,6-trimethylphenyl)-penta-2,4-dien-1-al (8.4 g, 37 mmol) in 20 ml of THF was added. The mixture was stirred at room temperature for 4 hrs.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.ClC1C=C(B(O)O)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Agent: OB(O)c1cccc(Cl)c1
Product: COc1ccc(-c2cccc(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 17 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 3-chlorophenylboronic acid (41 mg, 0.2625 mmol) to produce the title compound (20 mg, 17% yield).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=1)(=[O:18])=[O:19]
Reactant: COC(=O)c1ccc(Oc2cccc(S(C)(=O)=O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(Oc2ccc(C(=O)O)cc2)c1

Procedure:
A stirred solution of 4-(3-methanesulfonyl-phenoxy)-benzoic acid methyl ester (1.0 mmol) (see Intermediate 12) in 1:1 methanol/tetrahydrofuran (0.15 M), is treated with 2 N sodium hydroxide (3.0 mmol) and heated to reflux for one hour. The reaction is concentrated in vacuo. 1 N Hydrochloric acid and water are added and the mixture extracted with 10% isopropanol/dichloromethane. The organic portion is concentrated in vacuo to yield the desired product. MS (m/e): 291.0 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:20])([CH3:19])[C:10]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:28][O:29][C:30](=[O:44])[C:31]([CH3:43])([CH3:42])[NH:32][C:33](=[O:41])[C@H:34]([CH2:36][O:37][C:38]#[C:39][CH3:40])[NH2:35].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:28][O:29][C:30](=[O:44])[C:31]([CH3:43])([CH3:42])[NH:32][C:33](=[O:41])[C@H:34]([CH2:36][O:37][C:38]#[C:39][CH3:40])[NH:35][C:14](=[O:16])[C:13]([CH3:18])([CH3:17])[NH:12][C:10](=[O:11])[C:9]([CH3:20])([CH3:19])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC#COC[C@H](N)C(=O)NC(C)(C)C(=O)OC
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC#COC[C@H](NC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)OC
Temperature: 0 °C
Reaction time: 44 h
Yield: 86.4 %

Procedure:
N-tert-butoxycarbonyl α,α-dimethylglycyl α,α-dimethylglycine 4 (3.37 g, 11.7 mmol) and O-propynyl L-seryl α,α-dimethylglycine methyl ester trifluoroacetate 15 (4.16 g, 11.7 mmol) were dissolved in DMF (30 mL). A solution of N,N-diisopropylethylamine (1.51 g, 11.7 mmol) in DMF (20 mL) was added and the solution cooled to 0° C. (ice bath). HOBt hydrate (1.79 g, 11.7 mmol) and then EDC hydrochloride (2.46 g, 12.8 mmol) were added in portions together with more DMF (10 mL). The reaction mixture was stirred for 5 min at 0° C. after which the ice bath was removed and stirring continued for 44 h at room temperature. The solvent was evaporated and the residue taken up in EtOAc (300 mL). The solution was washed with 1 M HCl (3×120 mL), 7.5% (w/w) K2CO3 solution (3×120 mL) and saturated brine (120 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a slightly yellowish solid (5.18 g). The solid was purified by flash column chromatography (eluent: CH2Cl2/acetone (4:1)) affording the title compound as a white solid (4.58 g, 77%); 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H, NH(Aib)), 7.73 (s, 1H, NH(Aib)), 7.66 (d, J=8.1 Hz, 1H, NH(propSer)), 7.31 (s, 1H, NH(Aib1)), 4.33 (td, J=8.6, 3.8 Hz, 1H, CαH), 4.03 (t, J=2.8 Hz, 1H, CH2CCH), 3.81 (dd, J=9.9, 3.6 Hz, 1H, CHH), 3.59 (dd, J=9.3, 9.3 Hz, 1H, CHH), 3.54 (s, 3H, OCH3), 3.41 (t, J=2.3 Hz, 1H, CCH), 1.41 (s, 9H, (CH3)3), 1.37 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.29 (s, 3H, CH3), 1.28 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 175.2, 174.2, 174.0, 168.7, 155.5, 79.8, 79.0, 77.2, 68.5, 57.3, 55.9, 55.8, 55.0, 52.9, 51.7, 28.1, 26.7, 25.4, 24.6, 24.6, 24.1, 23.2; HRMS (m/z): [M+Na]+ calcd. for C24H40N4O8Na, 535.2743. found, 535.2728; Anal. Calcd. for C24H40N4O8: C, 56.23; H, 7.87; N, 10.93. Found: C, 56.0; H, 7.8; N, 10.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)=[C:6]([NH2:23])[CH:5]=1.CO[C:27](=N)[C:28]([Cl:31])([Cl:30])[Cl:29]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][C:12]3[CH:16]=[C:15]([C:17]4[S:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[O:14][N:13]=3)[C:27]([C:28]([Cl:31])([Cl:30])[Cl:29])=[N:23][C:6]=2[CH:5]=1)=[O:24]
Reactant: COC(=O)c1ccc(NCc2cc(-c3ccc(Cl)s3)on2)c(N)c1
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)nc(C(Cl)(Cl)Cl)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
36.0 mg (0.098 mmol) 3-Amino-4-{[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-amino}-benzoic acid methyl ester were dissolved in 3 mL acetic acid. 17.4 μl (0.14 mmol) 2,2,2-trichloro-acetimidic acid methyl ester were added and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was co-distilled twice with 15 mL toluene to give crude 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester as a brown solid. Yield: 49 mg MS (ES+): m/e=491, chloro pattern.
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8](=O)[CH:9]([CH:16]=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])C.[NH2:19][C:20]([NH2:22])=[S:21].C(O)(=O)C>C(O)C>[O:7]=[C:8]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][NH:22][C:20](=[S:21])[NH:19]1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(C=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1c[nH]c(=S)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
Sodium ethoxide (6.105 g, 89.71 mmol) was added to absolute ethanol (150 mL) under an atmosphere of nitrogen followed by diethyl-2-formylsuccinate (1105) (crude, 16.5 g) in absolute ethanol (30 mL) and thiourea (6.829 g, 89.71 mmol). The reaction mixture was heated at reflux for 1 hour then cooled to room temperature at which stirring was continued for 16 hours. The volatiles were evaporated under reduced pressure to give a brown oily solid. Cold aqueous acetic acid solution (15%; 120 mL) was added and the resulting mixture was sonicated and then stirred at 0° C. until all the residue was in suspension. The resulting precipitate was collected by filtration. The filter cake was washed with water (100 mL) and dried to give the title compound (I106) (6.31 g, 19% yield over 2 steps) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 7.44 (s, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.28 (s, 2H), 1.17 (t, J=7.1 Hz, 3H). LCMS Method C: rt 2.92 min; m/z 213.0 [M−H]−.