Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:13]2=[O:30])=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[C:31]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3([C:3]4=[CH:4][C:5]5[O:9][N:8]=[C:7]([CH3:10])[C:6]=5[CH:11]=[C:2]4[O:1][CH2:31]3)[C:13]2=[O:30])=[CH:27][CH:26]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COc1ccc(CN2C(=O)C(c3cc4onc(C)c4cc3O)c3ccccc32)cc1
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(C)noc5cc43)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(4-methoxybenzyl)-3-methylspiro[furo[2,3-f][1,2]benzisoxazole-7,3′-indol]-2′(1′H)-one was obtained (17%): mp 183-184° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.29-7.21 (m, 3H), 7.13-7.10 (m, 1H), 7.05 (s, 1H), 7.03-6.98 (m, 1H), 6.89-6.86 (m, 3H), 6.82 (s, 1H), 5.07-5.00 (m, 2H), 4.79-4.74 (m, 2H), 3.78 (s, 3H), 2.51 (s, 3H); MS (ES+) m/z 412.8 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1CN(C(=O)OC(C)(C)C)Cc2scc(-c3ccccc3F)c2O1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (174 mg) obtained in Example 6, steps 1-6, (2-fluorophenyl)boronic acid (84 mg), dichlorobis(triphenylphosphine)palladium (18 mg) and potassium carbonate (207 mg) in DME-water (1:1, 5 ml,) was stirred at 85° C. for 2 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (174 mg, 96%) as a colorless oil.
Reaction SMILES: COC(=O)[CH:4]([C:13]#[N:14])[C:5]1[CH:10]=[C:9]([S:11][CH3:12])[N:8]=[CH:7][N:6]=1.[Na+].[Cl-].O>CS(C)=O>[CH3:12][S:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]([CH2:4][C:13]#[N:14])[CH:10]=1
Reactant: COC(=O)C(C#N)c1cc(SC)ncn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc(CC#N)ncn1

Procedure:
A Smith vial (10-20 mL) is charged with cyano-(6-methylsulfanyl-pyrimidin-4-yl)-acetic acid methyl ester (0.83 g, 3.72 mmol), NaCl (1.0 g), water (1 mL) and DMSO. The vial is sealed and irradiated at 160° C. for 50 minutes in Smith Synthesizer. The reaction mixture is partitioned between ethyl acetate and brine, and then filtered through a pad of celite and washed with ethyl acetate. The organic layer is separated and washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 10% to 100% to afford (6-methylsulfanyl-pyrimidin-4-yl)-acetonitrile: 1H NMR 400 MHz (CDCl3) δ 8.93 (s, 1H), 7.47 (s, 1H), 4.20 (s, 2H), 2.56 (s, 3H); MS m/z 166.00 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:12][C:11]4[N:17]=[CH:18][N:19]([C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[C:22]#[N:23])[C:10]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.N.CO.C(O)C.[Ni]>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:12][C:11]4[N:17]=[CH:18][N:19]([C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][NH2:23])[C:10]=4[C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: NCc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Reaction time: 6 h

Procedure:
To 100 mg of (0.288 mmol) 2-(8-phenyl-imidazo[4,5-c]quinolin-1-yl)-benzonitrile (Example 63) in 2 ml THF and 6 ml 10% ammonia in methanol are added ca. 50 mg Raney-Ni in ethanol. The solution is hydrogenated at rt for 6 h. The catalyst is filtered off and the raw material is purified by chromatography on silica gel (CH2Cl2-methanol 9:1) and crystallization (ethyl-acetate-hexane). mp: 163-1650° C.; MS: 351 (M++1); HPLC: tret=6.42 min (Grad 1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:17])[CH:13]2[O:14][CH:12]2[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1.[NH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=[O:24].N1C=CC=CC=1>C(O)C>[CH3:1][O:2][CH2:3][C:4]1([CH3:17])[CH:13]([OH:14])[CH:12]([N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=[O:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1
Reactant: O=c1cccc[nH]1
Reactant: COCC1(C)Oc2ccc(C#N)cc2C2OC21
Solvent: CCO
Solvent: c1ccncc1
Product: COCC1(C)Oc2ccc(C#N)cc2C(n2ccccc2=O)C1O
Reaction time: 72 h

Procedure:
A mixture of 23.1 g of 2-methoxymethyl-2-methyl3,4-epoxy-6-cyanochroman, 9.5 g of 1H-2-pyridone, 12 ml of pyridine and 600 ml of ethanol is boiled for 72 hours. About 300 ml are removed by distillation, the mixture is cooled and filtered, the solution is evaporated and the residue is worked up in the customary manner. 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano3-chromanol, stereoisomer mixture ("A") is obtained, which can be separated into isomer "Al" (CH3 and OH in the cis-position; m.p. 216°-218° C.) and isomer "A2" (CH3 and OH in the trans-position; m.p. 210°-212° C.) by chromatography (silica gel; ethyl acetate/methanol).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1>ClCCl.C(O)C.[Pd]>[OH:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(C)cn12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reaction time: 8 h

Procedure:
74 g (228 mmol) of ethyl 8-(benzyloxy)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 238A were initially charged in 1254 ml of dichloromethane and 251 ml of ethanol, and 20.1 g 10% palladium on activated carbon (moistened with water 50%) were added under argon. The reaction mixture was hydrogenated overnight at RT and atmospheric pressure. The reaction mixture was filtered off through silica gel and concentrated. The crude product was purified by silica gel chromatography (dichloromethane:methanol=95:5). This gave 50.4 g (94% of theory) of the target compound.
Reaction SMILES: C([SiH](CC)CC)C.O[CH:9]([C:21]1[CH:30]=[CH:29][C:28]2[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=2[CH:22]=1)[C:10]#[C:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.O>ClCCl>[CH3:31][C:27]1([CH3:32])[CH2:26][CH2:25][C:24]([CH3:33])([CH3:34])[C:23]2[CH:22]=[C:21]([CH2:9][C:10]#[C:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[CH:30]=[CH:29][C:28]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.1 ml (8.1 mmol) of BF3 ·Et2O (48%) and 50 ml of dichloromethane are introduced into a three-necked flask under a stream of nitrogen. 2.6 ml (16.2 mmol) of triethylsilane are added at -20° C., followed by a solution of 1 g (2.7 mmol) of 4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid in 30 ml of dichloromethane and the mixture is stirred at room temperature for 30 minutes. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified on a column of silica eluted with dichloromethane. After evaporation of the solvents, 780 mg (82%) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid are collected, with a melting point of 167-8° C.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.Cl[CH2:13][CH2:14][OH:15]>[OH-].[Na+]>[OH:15][CH2:14][CH2:13][S:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: OCCCl
Reactant: O=C(O)c1cc(S)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(SCCO)ccc1O
Yield: 84 %

Procedure:
85 g (0.5 mole) of 5-mercaptosalicylic acid were reacted at room temperature with 41.5 g (0.5 mole) β-chloroethanol in 500 ml sodium hydroxide solution of 20% strength, whereby 90 g 5-(β-hydroxyethyl-mercapto)-salicylic acid melting at 136° C. were obtained (yield 71% of theory). 120 g (0.55 mole) of the aryl-alkyl sulfide obtained were oxidized in 200 ml glacial acetic acid at 65° C. with 215 ml 30% hydrogen peroxide whereby 103 g 5-(β-hydroxyethyl-sulfonyl)-salicyclic acid (yield 77% of theory) melting at 175° C. were obtained. 71.5 g (0.29 mole) of the 5-(β-hydroxyethylsulfonyl)-salicylic acid were then reacted for 5 hours at 70° C. with a mixture of 20 ml (0.29 mole) chlorosulfonic acid and 150 ml anhydrous dioxane, in which reaction hydrogen chloride was split off. The dissolved 5-(β-hydroxysulfonyl-oxy-ethylsulfonyl)-salicylic acid was reacted with a suspension of 91 g (0.5 mole) barium carbonate in 250 ml water (generation of CO2). After filtration, the limpid solution was concentrated by evaporation at 40° C. 120 g of the barium salt of 5-(-hydroxysulfonyloxyethyl-sulfonyl)-salicylic acid (R'--SO2 --CH2CH2 --OSO3Ba/2, R' = barium salicylate) melting at 266° C. remained behind (yield 90% of theory).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]#[N:18])[CH:8]=2)[N:3]=1.[CH3:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25](B1OC(C)(C)C(C)(C)O1)=[CH:24][CH:23]=2.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20]([CH3:19])=[CH:28]3)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]#[N:18])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: CC(C)N(C)c1nc2cc(C#N)ccc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2cc(-c3nc4ccc(C#N)cc4nc3N(C)C(C)C)ccc2[nH]1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile (250 mg, 0.96 mmol) in DME (8 ml) was added 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (494 mg, 1.92 mmol), potassium carbonate (265 mg, 1.92 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol) and water (2 ml). The resulting solution was stirred for 1 h at 90° C. under an inert atmosphere of nitrogen. Then the mixture was quenched with water (100 ml) and extracted with ethyl acetate (3×50 ml), and the organic layers combined and dried over anhydrous magnesium sulfate. The filtrate was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (10%-20% ethyl acetate in petroleum ether) to afford 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carbonitrile as a yellow solid (200 mg, 58%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[NH:11][C:12](=[O:14])[CH3:13]>C1C=CC=CC=1>[C:12]([NH:11][C:10]1[CH:9]=[C:8]([CH:17]=[CH:16][CH:15]=1)[NH:7][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])(=[O:14])[CH3:13]
Reactant: C=C1CC(=O)O1
Reactant: CC(=O)Nc1cccc(N)c1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(NC(C)=O)c1
Yield: 91.6 %

Procedure:
20.1 g of diketene were added to a solution of 35 g of m-aminoacetanilide in 150 ml of benzene and after stirring for an hour, the mixture was evaporated to dryness under reduced pressure. The residue was added to acetone and the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was added to ether. The mixture was vacuum filtered and the precipitate was washed and dried to obtain 50 g of m-acetamido-acetylacetanilide melting at 107° C. which was used as is for the next step.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:29]1([N:35]=[C:36]=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:36]([NH:35][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:37])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: O=C=NC1CCCCC1
Reactant: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccc(F)cc2)c2ccccc2C(F)(F)F)C1
Yield: 78.3 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]azetidine hydrochloride (162) (200 mg, 0.55 mmol) in anhydrous DCM (5 mL) was added MP-carbonate (3.01 mmol/g; 550 mg, 1.65 mmol) and cyclohexyl isocyanate (72 μL, 0.55 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (16 mL), then evaporated to afford the desired product as a colourless glass (194 mg, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:13]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C#N)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of 4-hydroxy-3-propylbenzonitrile (0.97 g, 6 mmol) (Example 29) in DMF (20 mL) were added 10 drops of water, benzyl bromide (2.05 g, 12 mmol), and Cs2CO3 (2.93 g, 9 mmol), and the mixture was stirred for 12 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in EtOAc and filtered. The precipitate was washed with more EtOAc. The combined filtrates were concentrated and purified by silica gel chromatography (EtOAc/hexanes (v/v)=1:19) to give 1.23 g (82%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.48-7.32 (m, 7H), 6.92 (d, 1H), 5.13 (s, 2H), 2.67 (t, 2H), 1.72-1.60 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:7][N:6]1[C:2]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:25])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (3.22 g, 19.98 mmol) in DCM (15 mL) was added ethyl magnesium bromide (6.66 mL, 19.98 mmol, 3.0 M in diethyl ether) dropwise over a 10 minute period. The resulting orange-red solution was stirred at room temperature for 15 minutes, cooled in an ice bath to 0° C. and N-methoxy-N-methyl-4-nitrobenzamide (3.5 g, 16.65 mmol, Intermediate 7: step a) dissolved in DCM (10 mL) was added dropwise. The ice bath was removed and the solid suspension stirred at room temperature for 48 hours. Water was added followed by 6 M aqueous HCl to a neutral pH (pH=6-7). The aqueous mixture was extracted with DCM, dried over Na2SO4, filtered and concentrated. Et2O was added and the mixture sonicated. The precipitate was collected by filtration and dried to provide the title compound as a tan solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([C:28]#[N:29])[CH2:9]1)=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[OH:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][NH:30][C:23]2[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]3[C:28]#[N:29])[CH:26]=[CH:25][N:24]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C#N)C1
Reactant: NCCc1ccc(O)cc1
Product: N#CC1CNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 139 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+—CN of 388. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.32 (d, 1H) 8.27 (s, 1H) 8.23 (d, 1H) 7.75 (d, 1H) 7.62 (t, 1H) 7.55 (d, 1H) 7.14 (d, 2H) 6.71 (d, 2H) 4.38 (s, 2H) 3.92 (dd, 1H) 3.80 (d, 2H) 3.40 (t, 2H) 3.24 (t, 2H) 2.95 (t, 2H) 2.84 (t, 2H).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][C:8]=1[NH2:9])([CH3:6])([CH3:5])[CH3:4].C(Cl)(Cl)Cl.[OH-].[Na+]>CO>[Br:1][C:12]1[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][C:8]([NH2:9])=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:13]=1
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c(N)c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(Br)c(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Bromine (271 μL, 5.29 mmol) was added dropwise via syringe to a solution of 2,5-di-tert-butylaniline (1.09 g, 5.29 mmol) in methanol (80 mL). The solution was stirred at room temperature for 10 min. Chloroform and 0.1 N NaOH were added and the organic layer was dried (Na2SO4), filtered and concentrated to a pale yellow solid (1.46 g, 97%): mp 89-90° C.; 1H NMR δ1.38 (s, 9H), 1.45 (s, 9H), 3.77 (brs, 2H), 6.68 (s, 1H), 7.35 (s, 1H); 13C NMR δ29.4, 29.7, 33.7, 35.8, 111.0, 117.4, 133.1, 133.8, 143.3, 145.9; FAB-MS obsd 283.0936; calcd 283.0937; Anal calcd for C14H22BrN: C, 59.16; H, 7.80; Br, 28.11; Found, C, 59.33; H, 7.78; Br, 27.86.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[S:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:33][CH2:32][CH:31]2[C:34]([O-])=[O:35])[CH2:26][CH2:25]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:34]([CH:31]2[CH2:32][CH2:33][N:30]2[CH:27]2[CH2:26][CH2:25][S:24][CH2:29][CH2:28]2)=[O:35])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C([O-])C1CCN1C1CCSCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: [Li+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCN2C2CCSCC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(tetrahydro-2H-thiopyran-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(tetrahydro-2H-thiopyran-4-yl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as a light brown solid (quant.). MS ISP (m/e): 537.3 (100) [(M+H)]]+.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.C(O[C@@H:26]1[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]1[O:28][C:29](=[O:31])[CH3:30])(=O)C>ClCCl.C1(C)C=CC=CC=1>[C:29]([O:28][C@@H:27]1[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:43][C@H:26]1[O:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)/C=C/c1ccc(Cc2ccccc2O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a suspension of ethyl (E)-3-[4-(2-hydroxybenzyl)-phenyl]acrylate (0.34 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (1.4 g) in dichloromethane (3 mL) and toluene (9 mL) was added boron trifluoride diethyl ether complex (0.45 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give (E)-2-[4-(2-ethoxycarbonylvinyl)benzyl]phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.47 g). To the solution of the obtained (E)-2-[4-(2-ethoxycarbonylvinyl)-benzyl]phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.46 g) in methanol (5 mL) was added sodium methoxide (0.010 g), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give (E)-2-[4-(2-ethoxycarbonylvinyl)benzyl]phenyl β-D-glucopyranoside (0.31 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].CN(C)C=O.[CH2:30](I)[CH3:31]>O>[CH2:30]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[CH3:31]
Reactant: CCI
Reactant: Cc1nnc2ccc(-c3cccc(NC(=O)C4CC4)c3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)C1CC1)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 8 h

Procedure:
A mixture 1.57 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]cyclopropanecarboxamide, 0.36 g of sodium hydride (50% in oil) and 200 ml of dry dimethylformamide under argon was stirred at room temperature for 1 hour and then 0.60 ml of ethyl iodide was added. After stirring overnight, the mixture was poured into 200 ml of water and extracted with dichloromethane. The combined extracts were dried, the solvent removed and the residue chromatographed on a silica gel column with dichloromethane-methanol (97:3) as solvent. The fractions containing product were combined, the solvent removed and the solid recrystallized from dichloromethane-hexane to give 0.80 g of pale yellow crystals, mp 149°-151° C.