Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][OH:36].N1C=CC=CC=1>CO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[N:35]/[OH:36])[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C=O)cc2n1Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(/C=N/O)cc2n1Cc1ccccc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-formyl-2-isopropyl-1H-indole-3-carboxamide (Compound 53, 12 mg, 0.027 mmol) in MeOH (6 ml) was hydroxylamine hydrochloride (6.0 mg, 0.081 mmol) and pyridine (3 mg, 0.16 mmol). The mixture was stirred at 65° C. for 12 h, and then added concentrated in vacuo. The residue was purified by chromatography on silica gel (0→40% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9](=[O:22])[NH:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCOC[C@@H]3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCOC[C@@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 3-(3-methylmorpholino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, crude) in dichloromethane (30 mL) was added pyridine (79 mg, 2.64 mmol). Then Tf2O (372 mg, 1.32 mmol) was added and stirred overnight at room temperature. The reaction was then quenched by the addition of ice-water (100 mL) and extracted with dichloromethane (3×15 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford (S)-methyl 3-(3-methylmorpholino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (250 mg, crude).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>CN(C=O)C>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:5]2[C:6]([CH:8]=[O:9])=[CH:7][N:3]=[CH:4]2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cncc2C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH 60% (37.65 g, 0.94 mol) in DMF (175 ml) was carefully added a solution of 1-H-imidazole-4-carboxaldehyde (75.36 g, 0.784 mol) in DMF (350 ml). The mixture was stirred at room temperature for 0.5 h, then a solution of 4-bromomethylbenzoic acid methyl ester (215.6 g, 0.94 mol) in DMF (475 ml) was added and the reaction was stirred overnight. The solvent was evaporated under vacuum, the residue taken in ethyl acetate and water. The organic phase was separated, washed with brine and dried over MgSO4. The crude oil was purified several times by flash chromatography on silica gel using (toluene/ethyl acetate/NH4OH: 60/40/1) as eluent to give quantitatively the desired products.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH2:13]Br)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C[O:16][P:17]([O:20][CH3:21])[O:18][CH3:19]>C1(C)C=CC=CC=1>[CH3:19][O:18][P:17]([CH2:2][C:3]1[C:12]([CH2:13][P:17](=[O:16])([O:20][CH3:21])[O:18][CH3:19])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:16])[O:20][CH3:21]
Reactant: BrCc1cc2ccccc2cc1CBr
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1cc2ccccc2cc1CP(=O)(OC)OC)OC
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A flask is charged with 2,3-bis(bromomethyl)naphthalene (Example 22(b), 2.80 g, 8.9 mmol) and toluene (50 mL). The solution is heated at reflux and 25 mL of the toluene is collected in a Dean-Stark trap. The solution is then cooled to room temperature and trimethylphosphite (4.0 mL, 0.034 mol) is added. The reaction is heated to reflux temperature for 24 hours. The excess trimethylphosphite and toluene are removed at reduced pressure, giving a white solid (3.24 g). The solid is recrystallized from ethyl acetate-hexane to give 2.55 g of white crystals, mp 119.5°-120.5° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([C:37]([OH:39])=O)[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.[NH2:41][C@H:42]([CH2:60][C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=1)[C:43]([NH:45][C@@H:46]([C:54]1[O:58][N:57]=[C:56]([CH3:59])[N:55]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44].C(N(CC)CC)C>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([C:37](=[O:39])[NH:41][C@@H:42]([C:43](=[O:44])[NH:45][C@@H:46]([C:54]2[O:58][N:57]=[C:56]([CH3:59])[N:55]=2)[CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:60][C:61]2[CH:70]=[CH:69][C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH:62]=2)[CH2:32]1)=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Yield: 87 %

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.42 g, 2.18 mmol) and 1-hydroxybenzotriazole monohydrate (0.33 g, 2.18 mmol) were added to a solution of (R)-N-tertbutoxycarbonyl-3-piperidine carboxylic acid (0.50 g, 2.18 mmol) in N,N-dimethylformamide (7 ml). After 30 min at 20° C. a mixture of (2R)-2-amino-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]-3-(2-naphthyl)propionamide hydrochloride (0.68 g, 1.56 mmol) and triethylamine (0.16 g, 1.56 mmol) in N,N-dimethylformamide (8 ml) was added. After 18 h at 20° C. the reaction mixture was poured on ice water (90 ml) and extracted several times with ethyl acetate (total 90 ml). The organic phases were collected and washed with aqueous citric acid (10%, 15 ml), a saturated solution of sodium hydrogencarbonate (3×15 ml) and water (3×15 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and purified by flash chromatography on silica gel (90 g) using ethyl acetate and heptane (3:2) as eluent to give 0.83 g of (3R)-3-{(1R)-1-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethylcarbamoyl]-2-(2-naphthyl)ethylcarbamoyl}piperidine-1-carboxylic acid tertbutyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:31][C:32]#[N:33])=[CH:25][C:24]=2[O:23]1>>[O:30]1[C:29]2[CH:28]=[CH:27][C:26](/[C:31](=[CH:18]/[C:17]3[CH:20]=[CH:21][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:15][CH:16]=3)/[C:32]#[N:33])=[CH:25][C:24]=2[O:23][CH2:22]1
Reactant: O=Cc1ccc(OCCCCCCCCCCCO)cc1
Reactant: N#CCc1ccc2c(c1)OCO2
Product: N#C/C(=C\c1ccc(OCCCCCCCCCCCO)cc1)c1ccc2c(c1)OCO2
Yield: 73 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(11-hydroxyundecyl)oxy]phenyl}prop-2-enenitrile is prepared starting from 4-[(11-hydroxyundecyl)oxy]benzaldehyde and commercial [3,4-(methylenedioxy)phenyl]acetonitrile according the same procedure following for example 1 in 73% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](Cl)=[O:6].[C:12]([NH:16][NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2[CH2:27][O:26][B:25]([OH:28])[C:24]=2[C:29]=1[F:30])=[O:19])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(OCC)C>[C:12]([N:16]([C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[CH:8]=1)[NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2[CH2:27][O:26][B:25]([OH:28])[C:24]=2[C:29]=1[F:30])=[O:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: CC(C)(C)NNC(=O)c1ccc2c(c1F)B(O)OC2
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccc3c(c2F)B(O)OC3)C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
3,5-dimethylbenzoyl chloride (0.076 g, 0.451 mmol) in a round bottom flask was dissolved in diethyl ether (2.0 ml). To this, N′-(tert-butyl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide (0.100 g, 0.376 mmol) was added following by TEA (0.105 ml, 0.752 mmol). After triethyl amine addition a precipitant came out of solution. After 90 min of stirring, another equivalent of TEA was added and reaction was allowed to stir for 60 min at room temperature. The solvent was evaporated and the residue was purified by using preparative HPLC to give Cpd. No. 58. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 6.97 (d, J=7.7 Hz, 1H), 6.89-6.83 (m, 3H), 6.72-6.64 (m, 1H), 4.76 (s, 2H), 2.04 (d, J=4.5 Hz, 6H), 1.29 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([O:21][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncccc2O)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccnc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A stirring solution of 1.4 g (0.0048 mol) of 4-(3-hydroxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in THF (24 mL) was cooled to 0° C., and 0.13 g (0.0052 mol) of NaH was added. After 30 min, 0.8 g (0.0052 mol) of ethyl bromoacetate was added, and reaction was allowed to warm to room temperature and stirred overnight. Saturated NaHCO3 (20 mL) was added and the reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 (75 mL). The organic layer was washed with water (50 mL) and NaCl (50 mL), dried over Na2SO4, and concentrated to afford 0.9 g (49%) of a white powder. MS (electrospray): exact mass calculated for C19H29N3O5, 379.21. m/z found, 380.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.74 (d, J=5.3 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.46 (dd, J=7.8 Hz, 5.3 Hz, 1H), 5.05 (d, J=7.33 Hz, 1H), 4.59 (s, 2H), 4.26 (q, J=7.3 Hz, 2H), 4.18-3.92 (m, 3H), 2.97 (t, J=11.6 Hz, 2H), 2.06 (d, J=12.1 Hz, 2H), 1.46 (s, 9H), 1.46-1.34 (m, 2H) 1.29 (t, J=7.3 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[N:16]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:15]2=[O:29])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:23][C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15](=[O:29])[N:16]([CH2:24][C:25]([F:27])([F:28])[F:26])[C:17]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CC(F)(F)F)c3cc(F)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=c1n(CC(F)(F)F)c2cc(F)ccc2n1C1CCNCC1
Reaction time: 9 h

Procedure:
A solution of 1-tert-butoxycarbonyl-4-(5-fluoro-3-(2,2,2-tri-fluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine (4.17 g, 10 mmol.) in chloroform (50 mL) containing trifluoroacetic acid (5.5 mL) was stirred at room temp. under an inert atmosphere for 6-12 hours until reaction was complete. The solvent and excess TFA were removed and the residue redissolved in chloroform. This solution was washed with Na2CO3 /NaOH solution. The organic layer was dried (Na2SO4), filtered through a pad of charcoal, and the solvent evaporated to give 4-(5-fluoro-3-(2,2,2-trifluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine as a viscous oil which was used as is. A sample of this material was converted to the HCl salt and after crystallization from methanol gave a white solid, mp: >280° C.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18](Br)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[CH2:18]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=1)[NH2:9])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(NN)cc1
Reactant: BrCCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(N(N)CCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
p-Tolylhydrazine hydrochloride (10.0 g, 63 mmol) was suspended in EtOH (45 mL). To this suspension was added triethylamine (9.0 mL, 63 mmol) drop-wise over a period of 5-10 minutes. The reaction mixture was stirred for additional 10 minutes. Phenethyl bromide (9 mL, 63 mmol) was added drop-wise at 25° C. over a period of 10 to 15 minutes. The reaction mixture was heated at 80° C. for 2 h at which point the reaction was found complete by TLC and LC-MS. The reaction mixture was concentrated under reduced pressure, the residue was suspended in saturated aqueous NaHCO3 (pH 9) and extracted with ethyl acetate (100 mL×2). The organic layer was separated, dried (Na2SO4) and concentrated to obtain crude product as a dark brown oil (14 g). Purification of crude product by flash column chromatography (silica gel, 230-400 mesh, eluent: 8-10% ethyl acetate-hexanes) furnished 3.7 g of pure product as yellow oil. Yield: 26% (unoptimized).
Reaction SMILES: [CH:1]1([CH:7]([C:11](=[S:21](=[O:23])=[O:22])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[C:15]1([N:14]2[C:12](=[O:13])[C:11](=[S:21](=[O:23])=[O:22])[CH:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]2=[O:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Nc1ccccc1)C(C(C(=O)O)C1CCCCC1)=S(=O)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1C(=S(=O)=O)C(C2CCCCC2)C(=O)N1c1ccccc1
Yield: 86 %

Procedure:
3.39 g. (0.01 mole) of 2-cyclohexyl-sulfonyl-4-phenylamino-4-oxo-butanoic acid are dissolved in 20 ml. of acetic acid anhydride and 0.82 g. (0.01 mole) anhydrous sodium acetate and the solution is heated for 1 hour at 100° C. The reaction mixture is then poured on crushed ice and the precipitated compound named filtered off and washed with water in order to remove acid. 2.76 g. (86%) of the named compound are obtained. M.p.: 149°-151° C. After recrystallization from methanol m.p.: 150°-152° C. Minimal inhibitory concentration inhibiting the growth of Trychophyton mentagrophytes: 2.5 μg/ml. and of Epidermophyton floccosum: 1.0 μg./ml.
Reaction SMILES: Br[C:2]1[S:34][C:5]2[N:6]=[C:7]([CH2:30][CH2:31][CH2:32][CH3:33])[N:8]=[C:9]([NH:10][C@H:11]([C:13]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17](=[O:25])[C:16]4=[C:26]([CH3:29])[CH:27]=[CH:28][N:15]4[N:14]=3)[CH3:12])[C:4]=2[CH:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>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>[CH2:30]([C:7]1[N:8]=[C:9]([NH:10][C@H:11]([C:13]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17](=[O:25])[C:16]3=[C:26]([CH3:29])[CH:27]=[CH:28][N:15]3[N:14]=2)[CH3:12])[C:4]2[CH:3]=[C:2]([CH3:35])[S:34][C:5]=2[N:6]=1)[CH2:31][CH2:32][CH3:33]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1nc(N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c2cc(Br)sc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Product: CCCCc1nc(N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c2cc(C)sc2n1
Yield: 36 %

Procedure:
(S)-2-(1-((6-Bromo-2-butylthieno[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (obtained as by-product in Preparation 82, 53 mg, 0.10 mmol) was treated with potassium carbonate (273 mg, 1.97 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) and trimethylboroxine (124 μl, 0.89 mmol) according to the method described in Example 56. The residue was purified using SP1® Purification System (0% to 35%, hexane-ethyl acetate) to obtain 17 mg (37% yield) of the title compound as a white solid. Purity 86%.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][C@@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[C:10]1([CH3:25])[CH3:24])=O)(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][C@@H:16]([CH:21]([CH3:22])[CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[C:10]1([CH3:24])[CH3:25]
Reactant: COC(=O)[C@@H](NC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](NC(=O)[C@H]1C[C@@H](N)C1(C)C)C(C)C
Yield: 100 %

Procedure:
A stirred solution of (S)-methyl 2-((1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxamido)-3-methylbutanoate (step 1, 0.430 g, 1.21 mmol) in TFA:DCM (1:4) (4 ml) at 0° C.-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (1.0 ml, 7.25 mmol) then the resulting solution as such used for next reaction immediately. Wt: 0.309 g (Based on 100% yield calculated and proceeded for next reaction).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.[NH2:11][NH2:12]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:11][NH2:12])=[O:9])[CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)C1CCOCC1
Solvent: CO
Product: NNC(=O)C1CCOCC1
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A solution of methyl tetrahydro-2H-pyran-4-carboxylate (1.44 g, 10.0 mmol) in methanol (50 mL) was stirred at 50° C. To the reaction mixture, hydrazine.monohydrate (0.675 g) was added, followed by stirring at the same temperature for 2 hours, after completion of the reaction, the reaction mixture was concentrated and diluted with methylene chloride, the solution was then washed with saturated sodium bicarbonate aqueous solution and saturated brine, and the organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to afford 952 mg of the title compound (yield 66.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19][OH:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH:19]=[O:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(OCc2ccccc2)c2ccccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1cc(OCc2ccccc2)c2ccccc2c1
Yield: 80.8 %

Procedure:
4.00 g (15.1 mmol) of (4-benzyloxy-naphthalen-2-yl)-methanol [PCT Int. Appl. (1997), WO 97/09311A1] was dissolved in 160 ml of EtOAc; then, 54.1 g of manganese dioxide was added in small portions and the reaction mixture was stirred for 30 Min. at ambient temperature. The dark suspension was filtered with the aid of dicalite; then, the solvent was evaporated. Flash chromatography (SiO2, hexane/EtOAc=4:1) gave 3.20 g of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][C:5]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:6]#[N:7])[C:8]#[N:9]
Reactant: N#CC(C#N)Cc1ccc(F)cc1Cl
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)cc1Cl
Yield: 35.9 %

Procedure:
Using 0.51 g of (2-chloro-4-fluorobenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.34 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.21 g of 2-(2-chloro-4-fluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (44)).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.C(C1C=CC=CC=1C(O)=O)#[N:14].C[Li]>O1CCCC1>[NH2:14][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:12])([CH3:1])[NH:3][C:4]2=[O:11])=[CH:9][CH:8]=1
Reactant: N#Cc1ccccc1C(=O)O
Reactant: CC1(C)NC(=O)c2ccccc21
Agent: [Li]C
Solvent: C1CCOC1
Product: CC1(C)NC(=O)c2cc(N)ccc21
Temperature: -78 °C

Procedure:
3,3-Dimethylisoindolin-1-one. 2-Cyanobenzoic acid (3 g, 20.39 mmol) was dissolved in tetrahydrofuran (300 mL) and then cooled to −78° C. Methyllithium (127 mL, 204 mmol) was added dropwise and the reaction was slowly warmed to room temperature over 2 hours. The reaction was quenched with brine then extracted twice with ethyl acetate. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography to give the desired product. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.58-8.69 (m, 1H), 7.53-7.66 (m, 3H), 7.45 (dd, J=1.56, 7.42 Hz, 1H), 1.44 (s, 6H). MS (ESI) m/z 162.2 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [3-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-methanol (281.0 g, 1.044 moles) in dichloromethane (2.0 L) at −5° C. was added dropwise over a 25 min period thionyl chloride (136.6 g, 1.148 mol). A few minutes into the addition, a white substance separated but this went into solution several minutes later. The reaction was stirred at ambient temperature for 1 h and then was concentrated in vacuo to near dryness (357 g). 200 mL of toluene was added to the residue and the solution was again concentrated in vacuo to near dryness. 200 mL of toluene was added and some solid (˜8 g) was filtered off. The filtrate was concentrated in vacuo to ˜390 g of dark yellow liquid.
Reaction SMILES: [C:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:4]([CH2:5][CH3:6])[CH2:3][CH:2]=[CH:1][C:7]#[N:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC1=CCCCC1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(CC=CC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cyclohexenecarbonitrile (9 mL, 80.6 mmol) and benzene (75 mL) was treated portionwise with AlCl3 (13 g, 97 mmol) then stirred at room temperature for 2 hours. The mixture was poured onto ice and extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried (MgSO4), and concentrated. The residue was distilled at 125° C. (0.6 mm Hg) to provide the title compound.