Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:26]2[C:27](=[O:47])[N:28]([CH2:33][O:34][P:35](=[O:46])([O:41]C(C)(C)C)[O:36]C(C)(C)C)[CH:29]=[C:30]([F:32])[CH:31]=2)[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:26]2[C:27](=[O:47])[N:28]([CH2:33][O:34][P:35](=[O:36])([OH:41])[OH:46])[CH:29]=[C:30]([F:32])[CH:31]=2)[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[CH:17][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:19][CH:20]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-c2cc(F)cn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c2=O)cc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-c2cc(F)cn(COP(=O)(O)O)c2=O)cc1C(C)(C)C
Reaction time: 3 h

Procedure:
step 3—To a solution of 346 and DCM (10 mL) at RT under an Ar atmosphere was added TFA (0.523 mL, 6.78 mmol). The resulting solution was stirred for 3 h. The solution was concentrated in vacuo and the residue twice taken up in benzene and re-evaporated to afford 0.346 g of I-8: MS (M+H)=581.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:26]([O:28][C:29]([CH:31]1[CH:36]2[CH:32]1[C:33](=[O:45])[N:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:35]2=[O:37])=[O:30])[CH3:27].Cl>C1COCC1>[CH2:26]([O:28][C:29]([CH:31]1[CH:36]([C:35](=[O:37])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:4][C:3]=2[F:15])[CH:32]1[C:33](=[O:45])[NH:34][C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1C2C(=O)N(c3ccc(Cl)cc3)C(=O)C12
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A solution of 7 g (34 mmol) of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C. F. Bigge et al., patent application WO 2003045912) in 25 ml of THF was cooled to −78° C. and treated dropwise with 41 ml of a 1M lithium bis(trimethylsilyl)amide-solution in THF and stirred for 30 min. To this solution 9.5 g (32 mmol) of (1RS, 5SR, 6R)-3-(4-chloro-phenyl)-2,4-dioxo-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester were added portionwise and the mixture was allowed to reach room temperature within a few hours. The mixture was then poured into a diluted aqueous HCl-solution (ca. 0.2 M) and extracted with AcOEt. The combined organic phases were dried with Na2SO4. Evaporation of the solvent and chromatography on silica gel with dichloromethane and then with a gradient of dichloromethane/MeOH from 98:2 to 95:5 gave 4.1 g (24%) of the title compound. Light brown solid. MS: 496 (M−H)−.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][CH:26]=[O:27])[C:5]1=[O:30])[CH:2]=[CH2:3].[CH:32]1([Mg]Br)[CH2:34][CH2:33]1>C1COCC1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][CH:26]([CH:32]2[CH2:34][CH2:33]2)[OH:27])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC=O)C1=O
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal (160 mg, 0.349 mmol; Example 130, Step A) in THF (3.5 mL) was added 0.5 M cyclopropylmagnesium bromide in THF (2.09 mL, 1.05 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 3.5 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a mixture of two diastereomers. The crude product was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:26])[CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O>ClCCl>[C:33]([O:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10](=[O:26])[CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:15])=[O:16])[CH2:8][CH2:9]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])N1CCN(CCO)CC1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCN1CCN(C(=O)CCNS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-hydroxyethyl)-1-[3-(2-nitrobenzenesulfonylamino)propionyl]piperazine (1.15 g) and pyridine (1.47 mL) in dichloromethane (10 mL) was added acetic anhydride (1.72 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2-dichloromethane/methanol=10/1) to give the title compound (0.38 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[Cl:9])[N:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ncn1
Temperature: 160 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
4-Amino-6-chloropyrimidine (648 mg) was dissolved in N,N-dimethylformamide (5 ml), and 2-chloro-4-nitrophenol (1.736 g) and N,N-diisopropylethylamine (3.48 ml) were added thereto, followed by stirring at 160° C. overnight. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a 1 N aqueous solution of sodium hydroxide. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reducer pressure to give a residue, to which ethyl acetate (10 ml) was then added to precipitate crystals. The crystals were filtered and dried under aeration to provide the titled compound (230 mg, 17%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([C:28](Cl)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1cccc2ccccc12
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccc5ccccc45)cc3c2C1
Yield: 78.2 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.2 μL (0.051 mMol) 1-naphthoyl chloride, 13.8 mg (78%) of the title compound were recovered as a dark brown solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:34]=[CH:33][C:23]2[N:24]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:26][C:22]=2[CH:21]=1>O1CCCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:26][C:22]3[CH:21]=[C:20]([O:19][CH3:18])[CH:34]=[CH:33][C:23]=3[N:24]=2)[CH2:28][CH2:29]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1ccc2nc(N3CCNCC3)sc2c1
Solvent: C1CCOC1
Product: COc1ccc2nc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)sc2c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-Isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 6-Methoxy-2-piperazin-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white foam.
Reaction SMILES: Br[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.[C:16]1(B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19][CH2:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[C:16]1([C:2]2[C:3]([N+:13]([O-:15])=[O:14])=[N:4][N:5]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[CH:6]=2)[CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nn(C2CCCCO2)cc1C1=CCCC1
Yield: 89.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 33a by using 4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (WO 2010/079443; 1.20 g, 4.35 mmol), 2-cyclopent-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.20 g, 6.18 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (250 mg, 0.342 mmol), potassium carbonate (2.00 g, 14.5 mmol) and DMF (13 mL), to yield the title compound (1.02 g, 89%) as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N12CCN(CC1)C[CH2:13]2.CCOC(C)=O.O>C(=O)(OC)OC>[CH3:13][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: C1CN2CCN1CC2
Solvent: COC(=O)OC
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ccc2cc(C=O)ccc21
Temperature: 90 °C
Yield: 46 %

Procedure:
A solution of indole-5-carbaldehyde (0.5 g) in dimethyl carbonate (5 mL) was treated with 1,4-diaza-bicyclo[2.2.2]octane (38 mg). The resulting mixture was heated to 90° C. for 5 h and cooled to room temperature (rt). EtOAc (10 mL) and water (10 mL) were added, and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (1×20 mL), dried (MgSO4), and concentrated. Chromatography of the residue (0-50% EtOAc-hexanes) gave the title compound as a white solid (46%).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[O:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[O:11][C:10]2[C:5](=[N+:6]([O-:22])[CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[Si](C)(C)c1cc2ncccc2o1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc2c(ccc[n+]2[O-])o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Trimethylsilyl)furo[3,2-b]pyridine (14.68 g, 76.7 mmol) was dissolved in 80 mL DCM and cooled to 0° C. m-CPBA (33.1 g, 192 mmol) was dissolved in 160 mL DCM and slowly added to the reaction vessel. Upon complete addition, the reaction was warmed to RT and stirred for three hours. Reaction was diluted with DCM and washed twice with saturated sodium bicarbonate solution. 30 g of carbonate scavenger beads (—30 mmol) were added to the organic layer and the solution was stirred for 30 minutes. The reaction was filtered, washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-10% MeOH:DCM) to afford 2-(trimethylsilyl)furo[3,2-b]pyridine N-oxide as a light brown oil that solidified under high vacuum. MS: M+H+=208.2
Reaction SMILES: [C:1]([C:6]1[S:20][C:9]2[O:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[NH:13][C:14](=[O:15])[C:8]=2[CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C:6]1[S:20][C:9]2[O:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[NH:13][C:14](=[O:15])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.3 %

Procedure:
2-Butyrylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.1 g) was dissolved in trifluoroacetic acid (20 ml) and triethylsilane (1.3 g) was added. The mixture was stirred at room temperature for 72 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform. The mixture was washed with water and saturated aqueous sodium hydrogencarbonate solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure. To the residue were added chloroform and ethyl acetate and the precipitated crystals were collected by filtration. The obtained crystals were washed with diisopropyl ether to give 2-butylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (600 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:35]=[CH:34][C:28]([CH2:29][C:30]2([NH2:33])[CH2:32][CH2:31]2)=[CH:27][CH:26]=1>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:21])[CH2:22][NH:33][C:30]2([CH2:29][C:28]3[CH:34]=[CH:35][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH2:32][CH2:31]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]1
Reactant: COc1ccc(CC2(N)CC2)cc1
Solvent: CCCCO
Product: COc1ccc(CC2(NCC(O)c3ccc(OCc4ccccc4)c4[nH]c(=O)ccc34)CC2)cc1

Procedure:
587 mg (2.0 mmol) 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 480 mg (2.7 mmol) 1-(4-methoxy-benzyl)-cyclopropylamine are refluxed in 10 mL n-butanol for 10 hours. Then the solvent is distilled off and the residue is purified by chromatography (reverse phase, water/acetonitrile gradient). Yield: 259 mg (27%); mass spectroscopy: [M+H]+=471.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:3]([O:8][CH:7]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:2][CH2:9][CH3:6]
Reactant: CCCCO
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOC(OCCCC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 192 %

Procedure:
Heat a solution of 5-fluoro-2-nitro-benzaldehyde (10 g, 59.17 mmol), butanol (20 mL, 219 mmol) and p-toluenesulfonic acid (600 mg, 3.15 mmol) in toluene (200 mL) at reflux for 2 hours in a flask equipped with a Dean-Stark trap. Cool the reaction mixture to room temperature, dilute with ethyl acetate (400 mL), and wash sequentially with saturated aqueous sodium bicarbonate (300 mL×3) and saturated aqueous sodium chloride (300 mL×2). Dry the organic phase over sodium sulfate and concentrate under reduced pressure to provide the desired compound as a pale yellow oil (17 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][CH:6]([CH2:16][O:17][CH3:18])[C:7]([NH:9][C:10]([CH3:15])([CH3:14])[C:11]#[C:12]C)=[O:8].NC(C)(C)C#C.NC(C)(C)C#CC>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[O:5][CH:6]([CH2:16][O:17][CH3:18])[C:7]([NH:9][C:10]([CH3:14])([CH3:15])[C:11]#[CH:12])=[O:8]
Reactant: CC#CC(C)(C)NC(=O)C(COC)Oc1cc(Cl)cc(Cl)c1
Agent: C#CC(C)(C)N
Agent: CC#CC(C)(C)N
Product: C#CC(C)(C)NC(=O)C(COC)Oc1cc(Cl)cc(Cl)c1

Procedure:
2-(3,5-Dichlorophenoxy)-3-methoxy-N-(3-methylbut-1-yn-3-yl)propionamide was prepared in a similar way to 2-(3,5-dichlorophenoxy)-3-methoxy-N-(4-methylpent-2-yn-4-yl)propionamide as described in Example 1 except that 3-amino-3-methylbut-1-yne (commercially available as 90% aqueous solution) was used in place of 4-amino-4-methyl pent-2-yne in Stage 4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.[CH2:33]([NH2:40])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(=O)(O)[O-].[Na+]>C(#N)C>[C:13]1([C:11]2[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:40][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCCCN
Reactant: C[Si](C)(C)CCOCn1c(CCCCCCBr)nc(-c2ccccc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCNCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Yield: 96.9 %

Procedure:
Part B. A solution of 6-bromo-1-(4,5-diphenyl-1-[(trimethylsilyl)ethoxymethyl]-1H-imidazol-2-yl)hexane (1.0 g, 0.00195 mol) and n-heptylamine (0.45 g, 0.00389 mol) in acetonitrile (25 mL) was heated to 60° for 8 hours. The reaction mixture was poured into 10% aqueous sodium bicarbonate and extracted with ethyl acetate (2×50 mL). The combined organic extract was washed with water, brine, dried over magnesium sulfate and concentrated to give N-[6-(4,5-diphenyl-1-[(trimethylsilyl)ethoxymethyl]-1H-imidazol-2-yl)hexyl]-N-heptylamine as a colorless viscous oil (1.04 g, 0.00189 mol). 1H NMR (CDCl3) δ7.52-7.2(m,10H), 5.11(s,2H), 4.7-4.2(bs,1H), 3.3(t,2H), 2.93-2.70(m,6H), 1.95-1.34(m,18H), 0.93(t,3H), 0.86(t,2H), 0.005(s,9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:14]=2[CH3:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28].[BH4-].[Na+].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][NH:30][CH:27]([CH3:29])[CH3:28])[CH:18]=2)[N:6]=1
Reactant: CC(C)N
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)NCc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Yield: 92.8 %

Procedure:
A small vial (2 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (27.9 mg, 77.6 □mol). To this was added half of a solution of isopropylamine (10 mg, 0.169 mmol) in methanol (1 ml). After stirring for two hours sodium borohydride (7.4 mg) was added, then after another 20 minutes 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 29 mg (93%) 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.26 Hz, 6H) 1.63-1.68 (m, 1H) 2.59-2.63 (m, 1H) 2.93 (s, 3H) 3.57 (d, J=7.2 Hz, 2H) 6.60 (br. s., 2H) 7.05 (d, J=8.8 Hz, 2H) 7.12 (t, J=74.18 Hz, 1H) 7.15-7.18 (m, 2H) 7.22 (t, J=4.2 Hz, 1H) 7.35 (s, 1H) 7.42 (d, J=8.8 Hz, 2H); MS (ES) m/z 401.2 [M−H]−
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([O:10][CH3:18])=[O:9])=[N:6][CH:7]=1
Reactant: CO
Reactant: COc1cc(Cl)cnc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncc(Cl)cc1OC
Temperature: 0 °C
Yield: 67 %

Procedure:
In a 350-mL resealable vessel, 5-chloro-3-methoxypicolinic acid (intermediate 14, 7.51 g, 40.0 mmol) was dissolved in MeOH (120 mL). The solution was cooled to 0° C., and concentrated sulfuric acid (7.57 mL, 140 mmol) was added. The vessel was sealed and heated to 95° C. for 1.5 h. The reaction mixture was cooled to 0° C., and quenched with Na2CO3 (1M, 140 mL). The reaction mixture was concentrated under reduced pressure and the residue was extracted with EtOAc (3×100 mL). The combined organics extracts were dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient 20%-33% EtOAc/hexane) to afford the title compound as a yellow solid (5.59 g, 27.7 mmol, 67%). MS m/z=202 [M+H]+. Calculated for C8H8ClNO3: 201. 1H NMR in CDCl3 δ: 8.24 (d, 1H, J=1.9), 7.37 (d, 1H, J=1.9), 3.97 (s, 3H), 3.94 (s, 3H).