Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1(C)[CH2:13][O:12][CH2:11]1.[OH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.[C:27](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:27][CH:11]1[CH:10]([CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)[CH2:13][O:12]1
Reactant: CC1(COCCCCCCBr)COC1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCCCCOCC2COC2C)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
A mixture of 3-[(6-bromohexyloxy)methyl]-3-methyloxetane (84 g), ethyl 4-hydroxybenzoate (50 g), potassium carbonate (50 g) and dimethyl formamide (600 mL) was stirred at 90° C. for 4 hours. Water was added to the reaction mixture to terminate the reaction and, after extraction with ethyl acetate, the liquid extract was washed with an aqueous solution of 2N-sodium hydroxide and water successively, and the organic layer was dried over anhydrous magnesium sulfate. The residues obtained by distilling off the solvent were purified on silica gel chromatography (toluene/ethyl acetate=8/2), to obtain ethyl 4-[6-(2-methyloxetane-3-ylmetoxy)hexyloxy)benzoate (85 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:19]=3)=[N:11][C:12]([C:15](O)=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.Cl.[NH2:42][C:43]1([C:49]([O:51][CH3:52])=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[ClH:1].[Cl:1][C:2]1[C:3]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH:19]=3)=[N:11][C:12]([C:15]([NH:42][C:43]3([C:49]([O:51][CH3:52])=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)C1(N)CCCCC1
Reactant: Cc1cnc(-c2ccc(C(=O)O)nc2-c2ccc(Cl)c(OCCCN(C)C)c2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NC(=O)c2ccc(-c3ncc(C)cc3Cl)c(-c3ccc(Cl)c(OCCCN(C)C)c3)n2)CCCCC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a suspension of 134 mg (0.29 mmol) of 3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-methyl-2,3′-bipyridine-6′-carboxylic acid in 5 mL of anhydrous acetonitrile are successively added 0.18 mL (1.02 mmol) of DIEA and 56 mg (0.29 mmol) of methyl 1-aminocyclohexanecarboxylate hydrochloride. The mixture is cooled to 0° C. and 112 mg (0.35 mmol) of TBTU are added. After stirring for 18 hours between 0 and 10° C., the reaction medium is concentrated under reduced pressure and then taken up in 20 mL of a 1/1 EtOAc/ether mixture. After washing with 10 mL of water and 10 mL of saturated aqueous NaHCO3 solution, the organic phase is dried over Na2SO4 and concentrated under reduced pressure. 0.2 mL (0.1 mmol) of a 2N solution of HCl in ether and then 20 mL of anhydrous ether are added to the residue, taken up in 5 mL of DCM, which allows precipitation of 139 mg of methyl 1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-methyl-2,3′-bipyridin-6′-yl)-carbonyl]amino}cyclohexanecarboxylate hydrochloride in the form of a white powder.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([Mg]Cl)[CH2:22][CH2:21]1>O1CCCC1.C(#N)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]2[CH:6]=[CH:5][C:18]3[CH:17]=[CH:16][CH:15]=[CH:4][C:3]=3[CH:2]([CH:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:8]=2[CH:9]=1
Reactant: COc1ccc2c(c1)C(Cl)c1ccccc1C=C2
Reactant: CN1CCC([Mg]Cl)CC1
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc2c(c1)C(C1CCN(C)CC1)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A cooled solution of 5.4 grams (0.021 mole) of 5-chloro-3-methoxy-5H-dibenzo[a,d]cycloheptene in 60 milliliters of tetrahydrofuran was added dropwise under an atmosphere of nitrogen to 50 milliliters of a cooled solution of 0.49M 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran (Grignard solution) over a period of about 40 minutes. After completion of the addition, the mixture was stirred at room temperature for 2 hours and then at reflux temperature for fifteen minutes. The reaction mixture was then cooled and the product recovered from the reaction mixture by concentrating the mixture in vacuo to dryness, adding toluene to dissolve the organic product, filtering off the magnesium, and then separating, washing and drying the toluene solution in a manner similar to that described in Example I. The toluene was vaporized from the dried solution to obtain a residue which was dissolved in acetonitrile, recrystallized therefrom and the crystals dried at 78° C./0.2 mm. Hg over phosphorus pentoxide for four hours to obtain the desired 4-(3-methoxy-5H-dibenzo[a,d]cyclohepten-5 -yl)-1-methylpiperidine product, m.p. 122°-23° C. Elemental analyses were as follows:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19](Cl)(Cl)=[O:20].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:20])[S:3][C:4]=2[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: C1COCCN1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCOCC3)nc12
Yield: 25 %

Procedure:
Conversion of 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.377 mg) with phosgene (20% in toluene, 0.2 ml) and morpholine (0.041 ml, 0.47 mmol) using the general procedure D affords the product as white solid in 25% yield. MS: m/e=379 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH2:30][OH:31]>O.C(O)C>[OH:31][CH2:30][CH2:29][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)[CH2:2]1
Reactant: OCCBr
Reactant: c1ccc2c(c1)CCc1ccccc1N2CC1CNCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OCCN1CCOC(CN2c3ccccc3CCc3ccccc32)C1

Procedure:
A mixture of 5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.2 g), potassium carbonate (0.1 g) and ethylenebromohydrin (0.1 g) in water and ethanol was stirred under reflux for 10 hours. The reaction mixture was concentrated and extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-hydroxyethyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 186°-188° C (oxalate).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].CC1(C)[O:24][CH:23]([CH2:25][NH2:26])[CH2:22][O:21]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH:26][CH2:25][CH:23]([OH:24])[CH2:22][OH:21])=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)OCC(CN)O1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)NCC(O)CO)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (160 mg; 0.53 mmol; 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 2,2-Dimethyl-1,3-dioxolane-4-methanamine (Aldrich) (0.07 ml; 0.53 mmol; 1 eq.) and triethylamine (0.15 ml; 1.06 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC. As some TFA is used for the mobile phase of the preparative HPLC, the diol protecting group is removed during the concentration of the chromatography fractions, affording directly Compound (39) as a white-off solid (26.6 mg; 14%). 1H NMR (DMSO-d6, 300 MHz) δ 2.15 (s, 3H), 2.49 (s, 3H), 3.17-3.52 (m, 4H), 3.67 (m, 1H), 4.65 (br s, 1H), 4.93 (br s, 1H), 7.99 (s, 1H), 8.46 (t, J=4.5 Hz, 1H), 12.15 (s, 1H). M− (ESI): 355.04; M+ (ESI): 356.99. HPLC (method A), Rt: 1.87 min (purity: 100%).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28][CH3:29])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28][CH3:29])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCCOc1ccnc(N(CCCCCCC(=O)OCC)c2ccccn2)c1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: CCCOc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 22.5 h
Yield: 50 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (16 mg, 0.045 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22.5 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:5 to 100:8) to furnish IV as a colourless oil (14 mg, 50%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
2-Fluoronitrobenzene (1.5 g) and 4-chlorophenol (1.3 g) were dissolved in dimethylformamide (20 ml) and potassium carbonate (1.4 g) was added thereto. The mixture was stirred overnight at 80° C. After the mixture was cooled, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate (50 ml×2). The mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was re-crystallized from methanol, to thereby yield the target compound (2.2 g) as pale-yellow crystals.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Br.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>CN(C)C=O>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:12][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COC(CBr)OC
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(CNc1ccc(Oc2ccccc2)cc1)OC
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 4-phenoxyaniline (915 mg) in dimethylformamide (5 ml) was mixed with bromoacetaldehyde dimethyl acetal (1.1 ml) and BEMP (1.9 ml). The reaction mixture was shaken at 100° C. for 16 hours. Volatiles were removed and the residue was purified by chromatography on silica gel (eluent: dichloromethane/hexane 1:2, later 1:1 with in each case 1% v/v 7N ammonia solution in methanol). The product with the molecular weight of 273.33 (C16H19NO3); MS (ESI): 274 ([M+H]+), was obtained in this way.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][S:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.C(O)(=[O:33])C.OO>O>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][S:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:33])=[O:24])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: NN=Cc1ccc(CCCCC(=O)NC(CC(=O)O)CS(=O)c2ccccc2)cc1
Agent: OO
Solvent: O
Product: NN=Cc1ccc(CCCCC(=O)NC(CC(=O)O)CS(=O)(=O)c2ccccc2)cc1
Reaction time: 24 h

Procedure:
(±)-3-[[5-[4-(Aminoiminomethyl)phenyl]-1-oxopentyl]amino]-4-[(phenylsulfinyl)]butanoic acid (2.5 g) was dissolved in 10 ml water and 5 ml acetic acid followed by the addition of 5 ml 30% H2O2. The oxidation was allowed to proceed for 24 h. after which the reaction mixture was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to give 1.6 g of the title compound as a white solid: 1H NMR (d6 -DMSO) δ1.48 (m, 2H), 1.56 (m, 2H), 1.75 (m, 2H), 2.10 (m, 2H), 2.41 (m, 2H), 2.68 (m, 2H), 3.9 (m, 1H), 4.02 (m, 2H), 7.35 (m, 9H), 7.7 (bd, 1H, J=7.9 Hz), 9.05 (bs, 2H), 9.3 (bs, 2H); MS (FAB) m/e 446.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1(O)[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].C([O:20]CC)C>>[C:13]([O:16][C:3]12[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]([CH2:8]3)[CH:2]1[CH3:1])[CH2:4]2)(=[O:20])[CH:14]=[CH2:15]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)Cl
Reactant: CCOCC
Product: C=CC(=O)OC12CC3CC(CC(C3)C1C)C2
Yield: 55 %

Procedure:
200 mL of diethyl ether was put into a round-neck flask, 41.5 g of 2-methyl-2-adamantanol and 27.6 g of tetraethyl amine were added thereto and then 22.6 g of acryloyl chloride was dropped. The reactant was reacted at room temperature for about 12 hours and then filtered using diethyl ether. Subsequently, the solvent was removed by an evaporator and then the reactant product was obtained using vacuum distillation (yield: 55%).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:9]2[N:8]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[C:7](=[O:22])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH3:4].C([O:40]C(=O)C(C)C[N+]#N)C.[C:48]1([CH3:54])[CH:53]=CC=[CH:50][CH:49]=1>C([O-])(=O)C.[Rh+]>[CH2:1]([C:5]1[N:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:9]2[N:8]([C@H:15]2[CH2:20][CH2:19][C@H:18]([O:21][CH:49]([CH3:50])[C:48]([OH:40])([CH3:54])[CH3:53])[CH2:17][CH2:16]2)[C:7](=[O:22])[C:6]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Reactant: CCOC(=O)C(C)C[N+]#N
Reactant: Cc1ccccc1
Agent: [Rh+]
Agent: CC(=O)[O-]
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.45 g), rhodium(I) acetate (0.004 g) and toluene (10 mL) was added dropwise 3-ethoxy-2-methyl-3-oxopropane-1-diazonium (0.72 L) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained residue was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.5 mL) was added at room temperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.33 g, 63%).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([Br:21])[CH:17]=[C:18]([F:20])[CH:19]=1.[C:22](=[O:24])=[O:23]>C1COCC1>[Br:21][C:16]1[CH:15]=[C:14]([F:13])[C:19]([C:22]([OH:24])=[O:23])=[C:18]([F:20])[CH:17]=1
Reactant: O=C=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(F)cc(Br)cc1F
Temperature: -50 °C
Yield: 38 %

Procedure:
n-BuLi (220 mL, 550 mmol, 2.5 M) was added dropwise to a solution of diisopropylamine (61 g) in THF (500 mL) with stirring at −50° C. under N2. After the addition, the reaction mixture was stirred at −50° C. for 15 minutes, and then warmed to 0° C. for 1 hour. The reaction was cooled to −50° C. and then a solution of 3,5-difluorobromobenzene (96 g, 0.5 mole) in THF (500 mL) was added dropwise. After the addition, the reaction mixture was stirred at −50° C. for 2 hours and then dry ice (about 200 g) was added portion-wise. The resulting mixture was warmed gradually to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, and the resulting residue was partitioned between CH2Cl2 (1 L) and water (1 L). An aqueous NaOH solution was added to adjust the pH of the mixture to 10. The organic layer was discarded and the water phase was adjust the pH to 2 with HCl solution. The mixture was extracted with CH2Cl2 (3×400 mL), and the extracts were combined, dried over MgSO4, filtered and evaporated under vacuum to provide the title compound (45 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]=[O:24])[C:11]1=[O:25])=[O:4].[CH3:32][Mg+].[Br-]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][C@H:23]([OH:24])[CH3:32])[C:11]1=[O:25])=[O:4].[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][C@@H:23]([OH:24])[CH3:32])[C:11]1=[O:25])=[O:4]
Reactant: C[Mg+]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](CC=O)OC[C@H]1C1CCCCC1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](C[C@@H](C)O)OC[C@H]1C1CCCCC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](C[C@H](C)O)OC[C@H]1C1CCCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 29 %
Yield: 40.7 %

Procedure:
To a solution of 3-[(2R,5R)-5-cyclohexyl-3-oxo-2-(2-oxo-ethyl)-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (1.9 g, 4.26 mmol, 1.0 equiv) in THF (200 mL) at −10° C., was added MeMgBr (1.85 mL, 3.0 M solution in THF, 5.54 mmol, 1.3 equiv). The resulting solution was stirred at −10° C. for 20 minutes. The reaction was quenched by addition of 3.0 N HCl aqueous solution until pH=1. The volatile solvent was removed under vacuum and the residue was partitioned between EtOAc (100 mL) and brine (5 mL). The separated organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography [Et2O (2% EtOAc)/Heptane, 25% to 50%] to give 3-[(2R,5R)-5-Cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (0.57 g, 29.0%) and 3-[(2R,5R)-5-Cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (0.80 g, 40.7%). MS: 462.4 [M−H+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].Br[CH2:15][CH:16]([OH:21])[CH:17]([OH:20])[CH2:18]Br.[C:22](=[O:25])([O-])[O-].[K+].[K+]>CCOCC>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:15][CH:16]([OH:21])[CH:17]([OH:20])[CH2:18][O:25][C:22]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2]
Reactant: OC(CBr)C(O)CBr
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(OCC(O)C(O)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
A mixture of 19.2 gm (0.1 mol) of 2,4-dinitrophenol (96%), 12.4 gm (0.05 mol) of 1,4-dibromo-butan-2,3-diol, and 6.9 gm (0.05 mol) of potassium carbonate was refluxed for six hours in 20 ml of diethyleneglycoldimethyl ether. After cooling, the product was removed by suction, washed with water, and dried. The intermediate obtained melted at 207°-210° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1.[H][H]>C(O)C.[Pd]>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:23]=1
Reactant: CCOC(=O)/C=C/c1ccc(CN2C(=O)c3ccccc3Oc3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(CN2C(=O)c3ccccc3Oc3ccccc32)cc1
Yield: 94.5 %

Procedure:
Compound 416 (0.364 g, 0.912 mmol) was dissolved in ethanol (10.0 mL) and the palladium on charcoal (0.037 g, 10% w/w) was added. The reaction mixture was stirred over 1 atmosphere of hydrogen at room temperature for 1 hour. The catalyst was filtered and the filtrate was concentrated to afford title compound 417 (346 mg, 95%) that was used crude for next step. MS (m/z): 402.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[C:20]([CH:23]=3)[CH:21]=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:32]([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[C:20]([C:21]#[CH:32])[CH:23]=3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
152 mg (0.79 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphate in 2 mL MeOH are added to a solution of 300 mg (0.66 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (Example 3.55b) and 183 mg (1.32 mmol) K2CO3 in 9 mL MeOH. The reaction solution is stirred for for 3 h at RT and diluted with 20 mL DCM. The organic phase is extracted twice with saturated NaHCO3 solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by HPLC-MS.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Li][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:14]([C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:15][CH2:16][CH3:17].[CH2:14]([C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[NH2:1])[CH2:15][CH2:16][CH3:17]
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: [Li]CCCC
Product: CCCCc1c(N)ccc2nc[nH]c12
Product: CCCCc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitrobenzimidazole (0.41 g, 2.5 mmol) was added a solution of n-BuLi (7.5 mmol) and reaction mixture was stirred for 1 h at 0° C. The reaction mixture was quenched by adding a few drops of H2O and concentrated in vacuo yielding an oil which was subjected to silica gel column chromatography (5% MeOHI EtOAC) to provide 0.13 g of 4-n-butyl-5-nitrobenzimidazole and 0.19 g of 4-n-butyl-5-aminobenzimidazole. The nitrobenzimidazole was converted to the amine in hydrogenation (H2/Pd—C) to provide 0.28 g,(1.5 mmol, 60%) of the desired product.