Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1.[Cl:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:20]([O:22][CH3:23])=[O:21])=[C:10]([CH3:19])[NH:11][C:12]([CH3:18])=[C:13]2[C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][CH:7]=1)=[O:28]
Reactant: O=C(Cl)CCCl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(N)c1
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(NC(=O)CCCl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester (0.8 g, 2.53 mmol) was dissolved in THF (50 mL) and cooled to 0° C. 3-Chloropropionyl chloride (0.32 g, 2.53 mmol) was dissolved in THF (15 mL) and added dropwise to the mixture over 10 min. The mixture was stirred at 0° C. for 1 h., concentrated in vacuo, and the residue extracted with CH2Cl2 /brine. The CH2Cl2 layer was dried over Na2SO4 ; filtered, and concentrated in vacuo. Silica gel chromatography (1:1 to 1:0 EtOAc:hexane gradient) gave the title compound (1.05 g, 100%) as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:56][N:57]1[CH2:61][CH2:60][CH2:59][C@H:58]1[CH:62]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:62]/[C@@H:58]4[CH2:59][CH2:60][CH2:61][N:57]4[CH3:56])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOP(=O)(CC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1)OCC
Reactant: CN1CCC[C@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1CCC[C@H]1/C=C/C(=O)Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 4f (277 mg, 0.50 mmol) was dissolved in 2.5 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (750 μL, 0.75 mmol). After stirring for 45 minutes, the reaction mixture was added with (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (113 mg, 2 mmol), and stirred for 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]quinazolin-6-yl]-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamide 4 (85 mg, yield 33.0%) as a yellow solid.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=3)[CH2:5]2)[CH2:3][O:2]1.CC1C=CC(S(O[CH:28]2[CH2:31][N:30]([C:32]([C:34]3[O:35][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[N:37][N:38]=3)=[O:33])[CH2:29]2)(=O)=O)=CC=1>>[CH2:3]1[C:4]2([CH2:5][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:28]4[CH2:29][N:30]([C:32]([C:34]5[O:35][C:36]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)=[N:37][N:38]=5)=[O:33])[CH2:31]4)=[C:11]([Cl:16])[CH:10]=3)[CH2:7]2)[CH2:1][O:2]1
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Reactant: Oc1ccc(CN2CC3(COC3)C2)cc1Cl
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2Cl)C1
Yield: 51.6 %

Procedure:
Using a similar protocol as described in Example 2 but employing 8A (130 mg, 0.54 mmol) and 8B (220 mg, 0.55 mmol) as starting materials afforded 130 mg (51%) of 8 as a gum. 1H NMR (500 MHz, CD3OD): δ 3.38 (s, 4H), 3.48 (s, 2H), 4.25 (dd, 1H), 4.6-4.8 (m, 6H), 5.15 (m, 2H), 6.78 (d, 1H), 7.15 (d, 1H), 7.32 (s, 1H), 7.56 (t, 2H), 7.61 (t, 1H), 8.09 (d, 2H), MS (APCI+) m/z 467 [M+H]+, LC purity: 91%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1>[CH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Yield: 70.3 %

Procedure:
In the same manner as that described in Example 2(1), a reaction was carried out using commercially available 4-(trifluoromethyl)aniline (446 mg, 2.8 mmol), triethylamine (0.6 ml, 4.4 mmol), 4-formylbenzoyl chloride (700 mg, 4.2 mmol) and 4-(dimethylamino)pyridine (a catalytic amount) and the reaction mixture was treated according to a similar procedure to that described in Example 2(1) to afford 4-formyl-4′-(trifluoromethyl)benzanilide (577 mg, yield 71%) as a white solid which was recrystallized from ethyl acetate-hexane to give white fluffy crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.Cl.[C:15]1([CH:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:29]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[CH:6]3)[CH2:25][CH2:24]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: ClCCCn1cnc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: c1ccc(C(OC2CCN(CCCn3cnc4ccccc43)CC2)c2ccccc2)cc1

Procedure:
A mixture of 6 parts of 1-(3-chloropropyl)-1H-benzimidazole, 7.6 parts of 4-(diphenylmethoxy)piperidine hydrochloride, 10.6 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethoxy)-1-piperidinyl]propyl}-1H-benzimidazole; mp. 110.2° C.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]#[N:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[Cl-].[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]#[N:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(O)(c1ccc2cc(C#N)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)C(O)(c1ccc2cc(C#N)ccc2c1)c1c[nH]cn1
Yield: 96.4 %

Procedure:
A solution of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthonitrile (1.40 g) and pyridinium chloride (606 mg) in methanol-CHCl3 (1:1, 8 mL) was heated at 60° C. for 2 h. The reaction mixture was neutralized with aq. NaHCO3 solution and concentrated. The residue was extracted with ethanol, and the extract was purified by silica gel chromatography (eluent; dichloromethane:MeOH=30:1→10:1). Crystallization from ethyl acetate gave the titled compound (737 mg) as a colorless powder.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+].[NH:49]1[CH2:54][CH2:53][CH:52]([O:55][N:56]=[C:57]2[CH2:62][CH2:61][N:60]([C:63]3[CH:68]=[CH:67][C:66]([S:69]([CH3:72])(=[O:71])=[O:70])=[CH:65][C:64]=3[F:73])[CH2:59][CH2:58]2)[CH2:51][CH2:50]1.Br[C:75]1[CH:80]=[CH:79][C:78]([CH3:81])=[CH:77][N:76]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:81][C:78]1[CH:79]=[CH:80][C:75]([N:49]2[CH2:54][CH2:53][CH:52]([O:55][N:56]=[C:57]3[CH2:62][CH2:61][N:60]([C:63]4[CH:68]=[CH:67][C:66]([S:69]([CH3:72])(=[O:70])=[O:71])=[CH:65][C:64]=4[F:73])[CH2:59][CH2:58]3)[CH2:51][CH2:50]2)=[N:76][CH:77]=1
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Reactant: Cc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCC(ON=C3CCN(c4ccc(S(C)(=O)=O)cc4F)CC3)CC2)nc1
Temperature: 100 °C

Procedure:
Pd2 dba3 (1.5 mg, 0.0016 mmol), Xantphos (2.8 mg, 0.0048 mmol), NaOtBu (11.5 mg, 0.12 mmol), 63a (29.5 mg, 0.08 mmol) and 2-bromo-5-methyl-pyridine (27.5 mg, 0.16 mmol) were combined. Toluene (0.3 mL) was added and the mixture was flushed with nitrogen, sealed and heated at 100° C. overnight. The solvent was removed and the crude mixture was purified on preparative HPLC to give 67-1: LC-MS 461.2 (MH+).
Reaction SMILES: [CH3:1][C:2](=[O:8])/[CH:3]=[CH:4]\[C:5](=[O:7])[CH3:6].[CH2:9]([SH:12])[CH2:10][CH3:11].N1CCCCC1>N1CCCCC1.CCOCC>[CH2:9]([S:12][CH:4]([CH2:3][C:2](=[O:8])[CH3:1])[C:5](=[O:7])[CH3:6])[CH2:10][CH3:11]
Reactant: CC(=O)/C=C\C(C)=O
Reactant: CCCS
Solvent: C1CCNCC1
Solvent: CCOCC
Product: CCCSC(CC(C)=O)C(C)=O
Reaction time: 18 h
Yield: 86.6 %

Procedure:
In a 500 ml flask fitted with thermometer, addition funnel, reflux condenser and magnetic stirrer are placed 95 ml of ether, 35.4 g of cis-3-hexene-2,5-dione and one drop of piperidine. Addition of 24 g of n-propanethiol is started and as the addition progresses more piperidine is added (33 drops total) periodically. After standing 18 hours, the solution is washed successively with two 7.5 ml portions of 10% hydrochloric acid, saturated sodium chloride solution (10 ml), 5% sodium bicarbonate solution and two 10 ml portions of saturated sodium chloride solution. The ether solution is dried over sodium sulfate and concentrated to give 51.4 g of a dark yellow oil. Analysis by GLC shows the material to be essentially pure 3-thiopropyl-2,5-hexanedione. Mass spectral analysis shows molecular ion 188 then descending order 43, 103, 41, 145, 71, 114 and 61 m/e units.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:24])[C:9](=O)[CH:10]([CH3:22])[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:12][CH3:13]>CCOCC>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:11]([CH2:12][CH3:13])[CH:10]([CH3:22])[CH2:9][N:8]([CH3:24])[CH3:7])[CH:19]=[CH:18][CH:17]=1
Reactant: CCC(c1cccc(OC)c1)C(C)C(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC(c1cccc(OC)c1)C(C)CN(C)C
Temperature: 0 °C
Yield: 85 %

Procedure:
The steps are: add anhydrous ether into a reaction flask, and add lithium aluminum hydride under the condition of ice bath; dip compound 7, control the temperature within 10, after the dipping detect the reaction process by TLC; after the reaction is ended, pour the reaction liquid in the ice water slowly, separate the ether layer out, rinse by water, perform drying, and recycle the solvent by decompression to obtain a light yellow liquid, 3-(3-methoxy-phenyl)-N,N,2-trimethyl pentylamine. Yield: 85%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:20]([Br:21])=[CH:19][C:12]([C:13](N(OC)C)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.O1CCC[CH2:30]1>>[CH2:1]([O:8][C:9]1[C:20]([Br:21])=[CH:19][C:12]([CH:13]=[O:14])=[C:11]([CH3:30])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccccc2)c(Br)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: Cc1cc(OCc2ccccc2)c(Br)cc1C=O

Procedure:
To a suspension of 4-(benzyloxy)-5-bromo-2-methylbenzoic acid (16.6 g, 51.7 mmol) in chloroform (80 mL) were added oxalyl chloride (5 mL, 56.9 mmol) and N,N-dimethylformamide (6 drops), and the mixture was stirred for an hour at room temperature. And then the reaction solution was concentrated to obtain 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride. Then to a chloroform suspension (60 mL) of N,O-dimethylhydroxylamine hydrochloride (5.55 g, 56.9 mmol) and triethylamine (15 mL, 103 mmol) cooled in ice was added dropwise a chloroform solution (60 mL) of 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride, and the mixture was stirred for an hour at room temperature. To the reaction solution cooled in ice were added water and chloroform to separate an organic layer. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide. To a tetrahydrofuran solution (150 mL) of the 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide was added at −10° C. lithium aluminum hydride (1.96 g, 51.7 mmol), and the mixture was stirred for an hour at the same temperature. To the reaction solution were added 1 M hydrochloric acid, and then ethyl acetate to separate an organic layer. The organic layer was washed with 1 M hydrochloric acid, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde. To a toluene solution (120 mL) of the 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde were added ethylene glycol (30 mL, 517 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.58 mmol), and heated to reflux for 1.5 hours with a Dean-Stark apparatus. To the reaction solution was added ethyl acetate to separate an organic layer. The organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1). In addition, the residue was further purified with NH type silica gel column chromatography (chloroform) to obtain the title compound (12.8 g, 71%, 3 steps) as a colorless powder.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[NH:49]1[CH2:54][CH2:53][CH:52]([NH:55][C:56]2[CH:63]=[CH:62][C:59]([C:60]#[N:61])=[C:58]([C:64]([F:67])([F:66])[F:65])[CH:57]=2)[CH2:51][CH2:50]1.C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[F:67][C:64]([F:65])([F:66])[C:58]1[CH:57]=[C:56]([NH:55][CH:52]2[CH2:53][CH2:54][N:49]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:23])([F:2])[F:22])=[CH:9][CH:8]=4)[CH2:15][CH2:14]3)[CH2:50][CH2:51]2)[CH:63]=[CH:62][C:59]=1[C:60]#[N:61]
Reactant: N#Cc1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: O=C([O-])CCCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCN(C(=O)CCCC3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F
Reaction time: 2 h
Yield: 70 %

Procedure:
To a stirred suspension of 4-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 133) in tetrahydrofuran (1.0 mL) is added a solution of tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.5 mL). 15 minutes later, a solution of 4-(piperidin-4-ylamino)-2-trifluoromethyl-benzonitrile hydrochloride (15 mg; 0.05 mmol, prepared in accordance with Example 155) in dimethylformamide (10.5 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) is added. After 2 hours at room temperature, aluminium oxide (90 active basic) is added and stirring is continued. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (20 mg; 0.035 mmol). The structure was confirmed using Protocol I-D. Calculated mass=567; observed mass=567; HPLC retention time=2.17 min.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]([C@@H:27]([OH:29])[CH3:28])[C:15]([NH:17][NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[OH:29][C@@H:27]([CH3:28])[C@@H:14]([NH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:15]1[O:16][C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:18][N:17]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
The crude material of N′-((2R,3S)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 13b) (602 mg, 1.5501 mmol) was added to THF (100 mL) stirred at room temperature. PS-BEMP (2.11 g, 4.65 mol base) was added to the solution followed by slow addition of p-TSCl (355 mg, 1.8601 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to give the product (160 mg, 28%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.11 (d, J=9 Hz, 1H), 8.01 (d, J=9 Hz, 1H), 7.83 (d, J=9 Hz, 2H), 7.69 (d, J=9 Hz, 1H), 7.62 (t, J=9 Hz, 1H), 7.52 (t, J=9 Hz, 1H), 7.45 (t, J=9 Hz, 1H), 7.36 (t, J=9 Hz, 2H), 6.64 (d, J=9 Hz, 1H), 6.20 (d, J=9 Hz, 1H), 4.93 (dd, J=5.0, 9.0 Hz, 1H), 4.70 (m, 1H), 4.06 (d, J=5 Hz, 1H), 1.47 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([C:20](=[NH:24])OCC)[CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:26]([NH:28][NH2:29])=O>CO>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:13])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][CH:26]=[N:28][N:29]=3)[CH:15]=2)[C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C(=N)OCC)c1
Reactant: NNC=O
Solvent: CO
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2nnc[nH]2)c1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
To a solution of crude ethyl 3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzenecarboximidoate (Preparation 42, 700 mg, 1.86 mmol) in methanol (5 ml) was added formic acid hydrazide (123 mg, 2.05 mmol) and the mixture was heated under reflux for 90 min. After cooling to room temperature, the solvent was removed in vacuo and the residue was heated to 150° C. for 12 h. The mixture was cooled and purified directly by silica column chromatography eluting with ethyl acetate:methanol (95:5) to afford the title compound (400 mg, 64%) as a colourless gum.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[N:23]=[CH:22][C:21]([N:24]4[CH2:28][CH2:27][NH:26][C:25]4=[O:29])=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[CH3:30]I>>[CH3:30][N:26]1[CH2:27][CH2:28][N:24]([C:21]2[CH:22]=[N:23][C:18]([C:16]([N:13]3[CH2:12][CH2:11][N:10]([C:3]4[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=4)[CH2:15][CH2:14]3)=[O:17])=[CH:19][CH:20]=2)[C:25]1=[O:29]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCNC4=O)cn3)CC2)nc1C
Reactant: CI
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cn3)CC2)nc1C

Procedure:
Using 1-{6-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-3-yl}imidazolidin-2-one (136 mg) described in Example 397 and methyl iodide (26 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (109 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]C(O)=O)=[CH:5][C:4]=1[CH3:14])#[N:2].C([N:17](CC)CC)C>C(O)(C)(C)C>[NH2:17][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([CH3:14])[CH:5]=1
Reactant: Cc1cc(CCC(=O)O)ccc1C#N
Reactant: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Cc1cc(CCN)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.20 g 3-(4-Cyano-3-methyl-phenyl)-propionic acid and 4.57 ml triethylamine in 100 ml tert-butanol 9.10 g diphenylphosphorylazide were given and the mixture heated under reflux overnight. The cooled reaction mixture was evaporated in vacuo. The resulting residue was dissolved in 150 ml ethyl acetate, washed with 50 ml citric acid/brine=1:1 and 50 ml saturated NaHCO3 solution and then dried over MgSO4. The residue was dissolved in 50 ml dichloromethane and 20 ml trifluoroacetic acid were added. The reaction mixture was stirred at room temperature for two hours. The solvent was removed in vacuo. The residue was coevaporated four times with portions of 100 ml toluene. The resulting brown residue was taken up in 50 ml acetonitrile and stirred at room temperature. The solid material was filtered off and dried in vacuo to obtain 2.45 g 4-(2-Amino-ethyl)-2-methyl-benzonitrile as its trifluoroacetate salt. The filtrate was evaporated in vacuo, the resulting residue was taken up in 100 ml diethyl ether and stirred at room temperature. The solid material was filtered off and dried in vacuo to obtain 1.17 g 4-(2-Amino-ethyl)-2-methyl-benzonitrile as its trifluoroacetate salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.Cl[CH:17](Cl)[CH3:18]>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH2:8][C:9](=[O:11])[CH2:18][CH2:17]2
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2cc(F)ccc2C1
Temperature: 0 °C

Procedure:
4-fluorophenylacetic acid (1 equivalent) was dissolved in dichloroethane (1.3 M) containing SOCl2 (3 equivalents), the mixture was refluxed for 90 minutes and the solvent was removed. Solution of this crude product in CH2Cl2 was added dropwise within 60 minutes to AICl3 (2 eq) in CH2Cl2 (0.4 M) while stirring at 0° C. Thereafter, ethylene was introduced at 0° C. over 45 minutes, whereupon the mixture was stirred further at room temperature for 1 hour, and thereafter was treated at 0° C. with ice-water. The organic phase was washed with 1N HCl (2×), NaHCO3 (sat. sol.), dried and evaporated. The residue was triturated with hexane, yielding the product as a bright yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](/[C:5](=[CH:10]/[C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1)/[CH2:6][C:7]([OH:9])=O)=[O:4].[C:17]([O-])(=[O:19])[CH3:18].[K+].O.C(OCC)(=O)C>C(OC(=O)C)(=O)C>[CH3:16][C:13]1[O:12][C:11]2[CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[C:7]([O:9][C:17](=[O:19])[CH3:18])[C:15]=2[CH:14]=1
Reactant: COC(=O)/C(=C/c1ccc(C)o1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC(C)=O)c2cc(C)oc2c1
Temperature: 140 °C

Procedure:
A mixture of E-3-methoxycarbonyl-4-(5-methylfur-2-yl)-but-3-enoic acid (Method 15; 1.39 g, 6.2 mmol) and potassium acetate (620 mg, 6.3 mmol) in acetic anhydride (12.5 ml) was heated at 140° C. for 15 mins. The reaction mixture was cooled and poured on to a water/ethyl acetate mixture; the aqueous layer was separated and the organic layer washed sequentially with saturated sodium bicarbonate solution and brine, dried (MgSO4) and evaporated in vacuo to yield the crude product as a dark crystalline mass. This was chromatographed (50 g Bondelut, eluting with hexane containing ethyl acetate, 0-100%) to give the title compound as a pale yellow solid, 1.42 g (92%). NMR: 2.36 (s, 3H), 3.34 (s, 3H), 3.87 (s, 3H), 6.68 (s, 1H), 7.56 (s, 1H), 7.96 (s, 1H); m/z 247 (M−H)−, 97.1% by LC-MS.