Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:17]([C:19]1[N:20]=[C:21]([CH3:31])[S:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:18].[Br:32]Br>C(OCC)C.ClCCl>[Br:32][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:17]([C:19]1[N:20]=[C:21]([CH3:31])[S:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:18]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3o2)c(-c2ccc(F)cc2)s1
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nc(C(=O)N2CCCCC2Cc2oc3ccccc3c2Br)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To (RS)-2-(2-benzofuranylmethyl)-1-((5-(4-fluorophenyl)-2-methyl-thiazol-4-yl)-carbonyl)-piperidine, E1 (0.90 g, 2 mmol) in dry diethyl ether (10 ml) and dichloromethane (20 ml) cooled to −12° C. under argon, was added drop-wise a solution of bromine (0.36 g, 2 mmol) in dichloromethane (10 ml) over 0.5 h. The resulting solution was warmed to ambient temperature over 1.5 h, then stirred for a further 18 h. The reaction mixture was evaporated then re-evaporated from dichloromethane (3×). The resulting amorphous solid was chromatographed (silica gel with ethyl acetate-hexane mixtures) to afford the title compound as an amorphous solid (0.27 g, 25%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:13][CH:14]=[CH:15][CH2:16]Cl.O.CCOCC>C(O)C>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16][CH:15]1[CH:14]=[CH2:13])=[O:8])[CH3:11]
Reactant: ClCC=CCCl
Reactant: CCOC(=O)CC(=O)OCC
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC

Procedure:
To a solution of 18.4 g (2 equivalents) in 300 ml of anhydrous ethanol is added rapidly 164 g (1 equivalent) of diethyl malonate. 1,4-Dichloro-2-butene (98% mixture of cis and trans, Aldrich) (50 g, 1 equivalent) is slowly added to the warm, stirred suspension of the diethyl sodio malonate during 15 minutes after which the mixture is refluxed for 3 hours. Upon cooling, the mixture is poured into 1.2 liters of water and an oil isolated by ether extraction. The ether extract is dried over magnesium sulfate and distilled to give 1,1-bis-ethoxycarbonyl-2-vinylcyclopropane, B.P. 108°-116° C./14 mm.
Reaction SMILES: Cl.C1(S(Cl)(=O)=O)C2C(=CC=CC=2)C=CN=1.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26]([N:29]3[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]3)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O>ClCCl>[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26]([N:29]3[CH2:33][CH2:32][C:31](=[O:34])[CH2:30]3)(=[O:27])=[O:28])[C:20]=2[CH:19]=[CH:18][N:17]=1
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCC(O)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(Cl)c1nccc2ccccc12
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CCN(S(=O)(=O)c2cccc3cnccc23)C1

Procedure:
Substantially the same procedures as in Example 1 were repeated except that 2.64 g of 1-isoquinolinesulfonyl chloride hydrochloride was used in place of 6.0 g of 1-chloro-5-isoquinolinesulfonyl chloride hydrochloride and that 2.22 g of the thus obtained 1-(5-isoquinolinesulfonyl)-3-hydroxypyrrolidine was reacted in dichloromethane with 1.08 g of oxalyl chloride and 0.67 g of dimethylsulfoxide. There was obtained 1-(5-isoquinolinesulfonyl)-3-pyrrolidone.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:14]2[S:15][C:16]([CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])=[C:17]([OH:19])[N:18]=2)[CH2:12][CH3:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Li+].[BH4-]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:14]2[S:15][C:16]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[C:17]([OH:19])[N:18]=2)[CH2:12][CH3:13])=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCCc1sc(C(CC)c2ccc(CC(C)C)cc2)nc1O
Agent: [BH4-]
Agent: [Li+]
Product: CCC(c1ccc(CC(C)C)cc1)c1nc(O)c(CCCCO)s1

Procedure:
The desired compound is prepared from the product of Example 19 by reduction with LiBH4.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH2:26]Cl)[CH:25]=1)[CH2:13][CH2:12]2.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH2:26][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:25]=1)[CH2:13][CH2:12]2
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(CCl)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(Cn2ccnc2)c1
Temperature: 3.5 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a solution of 1H-imidazole (50 mg, 0.73 mmol) dissolved in DMF (5.0 mL) was added NaH (60% dispersion in mineral oil, 25 mg, 0.63 mmol) at 0° C. The reaction mixture was stirred at 2-5° C. for 0.5 h before 6-chloro-2-(5-chloromethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (example 140 [A]) (85 mg, 0.28 mmol) was added. The mixture was then stirred at 2-5° C. for additional 2 hours before it was warmed up to room temperature and poured into water (5.0 mL). After extraction with EtOAc (2×50 mL), the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give the title compound (30 mg, 31%) as a white foam. MS: 339.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=2[CH:25]=O)[C:17]([O:19][CH2:20]C)=[O:18])=O)=[CH:5][CH:4]=1)#[N:2].[NH3:27]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:27]=[CH:25][C:24]3[C:14](=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:22][CH:23]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N
Reactant: CCOC(=O)c1ccc(C=O)c(NC(=O)CCc2ccc(C#N)cc2)c1
Product: COC(=O)c1ccc2cnc(CCc3ccc(C#N)cc3)nc2c1

Procedure:
0.6 g (1.8 mmol) of ethyl 3-[3-(4-cyanophenyl)-propionylamino]-4-formyl-benzoate and 10 ml of methanolic ammonia solution were agitated in a pressure vessel for 36 hours. Then the solvent was distilled off, the residue was chromatographed on silica gel and eluted with methylene chloride containing 0 to 1% methanol. Yield: 0.35 g (62% of theory), Rf value: 0.38 (silica gel, ethyl acetate/cyclohexane=1:1)
Reaction SMILES: [C:1]1([CH:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[C:1]1([CH:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH:24][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:17][CH2:16]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(NC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(NC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 51.3 %

Procedure:
3.12 g of 4-(diphenylmethylamino)-1-piperidinepropanamine and 1.72 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 180° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized by the addition of ethyl ether-hexane (1:3), collected by filtration, washed with hexane and dried to yield 1.83 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[NH:4][N:3]=1.[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1>[NH2:9][C:5]1[N:4]([C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=[C:2]([NH:1][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[C:7]#[N:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1c(N)n[nH]c1N
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1nn(C(=O)C(C)(C)C)c(N)c1C#N

Procedure:
The above compound was prepared from 3,5-diamino-4-cyanopyrazole, prepared as in Example 13, by reaction thereof with two moles of pivaloyl chloride in pyridine in an analogous manner to that described in Example 1(b). Melting point 181°-184° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2([Cl:16])[CH2:15][CH2:14]2)=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:3]([C:13]2([Cl:16])[CH2:14][CH2:15]2)=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(Cl)c(C2(Cl)CC2)nn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C2(Cl)CC2)c(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
517 mg (1.76 mmol) of ethyl 4-chloro-3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate (purity 89%) are dissolved in 10 ml of ethanol p.a. 3.5 ml (3.5 mmol) of 1 N aqueous sodium hydroxide solution are then added to the solution, and the mixture is stirred at room temperature for 16 h. The reaction mixture is acidified by addition of 1 N hydrochloric acid. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. This gives 422 mg (99%) of 4-chloro-3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylic acid.
Reaction SMILES: CC(N(C)C)=O.[Li+].[Cl-].[Cl:9][C:10]1[CH:11]=[C:12]([N:17]=C=O)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[NH2:17]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: Nc1cc(Cl)cc(Cl)c1

Procedure:
The saccharide-bonded silica gel was dispersed into a mixture of 8 ml of anhydrous DMA-LiCl and 3 ml of pyridine, and 5 g of 3,5-dichlorophenyl isocyanate (this was formed from 3,5-dichloroaniline by an ordinary method) dissolved in 5 ml of DMA were added thereto and reacted at 80° C. in nitrogen for 12 hours. The presence of excess isocyanate groups in the reaction mixture was confirmed by the peak of C=N stretching vibration at 2,270 cm-1 in its IR spectrum. The saccharide-bonded, surface-treated silica gel was washed with tetrahydrofuran, methanol, acetone and hexane and dried in vacuum at 60° C. for 2 hours. The resultant compound was then subjected to IR spectrometry and elementary analysis. Results of elementary analysis are shown in Table 1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=3[CH:17]=2)=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Cl-].[CH3:32][NH3+:33]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:33]([CH3:32])[C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=4[CH:17]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: C[NH3+]
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Cl-]
Product: COC(=O)c1ccc(-c2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2C)cc1
Yield: 68.5 %

Procedure:
8.0 g (20 millimoles) of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione (for preparation see Example 9) and 6.7 g (0.1 mole) of methylammonium chloride were converted similarly to Example 10 and the product was recrystallized from methanol to give 5.5 g of the title compound of melting point 104°-105° C.
Reaction SMILES: B(F)(F)F.CCOCC.C([NH2:13])(=O)C.[C:14]([C:18]1[CH:58]=[CH:57][C:21]([C:22]([NH:24][C@H:25]([C:53]([O:55][CH3:56])=[O:54])[CH2:26][C:27]2[CH:52]=[CH:51][C:30]([C:31]([O:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=3)=O)=O)=[CH:29][CH:28]=2)=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CC(=O)OCC>[C:14]([C:18]1[CH:58]=[CH:57][C:21]([C:22]([NH:24][C@@H:25]([CH2:26][C:27]2[CH:52]=[CH:51][C:30]([C:31]3[O:33][CH:34]=[C:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=4)[N:13]=3)=[CH:29][CH:28]=2)[C:53]([O:55][CH3:56])=[O:54])=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reactant: CC(N)=O
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCOc1ccc(-c2coc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To boron trifluoride diethyl etherate (33.3 μl, 0.27 mmol) was added a mixture of acetamide (763 mg, 12.9 mmol) and (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (159 mg, 0.26 mmol). The reaction mixture was stirred at 140° C. for 1 h. The reaction mixture was allowed to cool to room temperature, diluted with EA (15 mL) and extracted with NaHCO3 (3×15 mL) and brine (15 mL). The combined organics were dried over MgSO4, filtered and concentrated. The residue was recrystallized from Et2O (5 mL), filtered and rinsed with Et2O. The filtrate was concentrated to afford 55 mg (16%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoate as an orange oil. LCMS-ESI (m/z) calculated for C37H44N2O5: 596.8. found 597.0 [M+H]+, tR=3.11 min. (Method 4).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C-:13]#[N:14].[K+]>CN(C=O)C>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][C:13]#[N:14]
Reactant: [C-]#N
Reactant: BrCc1ccc2ccccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
2-Bromomethylnaphthalene (5.00 g, 23 mmol) was dissolved in N,N'-dimethylformamide (50 ml) and potassium cyanide (2.95 g, 45 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The supernatant was decanted and partitioned between water (100 ml) and diethyl ether (2×75 ml). The combined organic phases were washed with water (100 ml), dried (MgSO4), filtered and evaporated in vacuo affording 2.53 g (67%) of 2-naphtylacetonitrile as a solid.
Reaction SMILES: [N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:2].[CH3:9][N:10]([NH2:12])[CH3:11]>C(O)C>[CH3:9][N:10]([CH3:11])[N:12]=[N+:1]([O-:2])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Nc1ccccc1
Reactant: CN(C)N
Solvent: CCO
Product: CN(C)N=[N+]([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7.5 g. of nitrosobenzene in 80 ml. of ethanol at 0° was added in a dropwise manner 4.2 g. of unsymmetrical-dimethylhydrazine as a saturated solution in ethanol. After stirring at 0° for 2 hours, the reaction mixture was allowed to warm to 25° C. and stirred for 16 hours longer. The solution was concentrated in vacuo, and the red-brown oil was chromatographed on silica gel in benzene. The product was eluted with 5-10 percent ethyl acetate in benzene. Three grams of 3,3-dimethyl-1-phenyltriazene-1-oxide was obtained as a light brown oil which gave a suitable n.m.r. spectrum.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[N:8][CH:9]=1.Cl([O-])(=O)(=O)=O.[Li+].[N-:20]=[N+:21]=[N-:22].[Na+]>C(#N)C>[N:20]([C@@H:2]([C:4]1[CH:9]=[N:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)[CH2:3][OH:1])=[N+:21]=[N-:22]
Reactant: FC(F)(F)c1ccc([C@@H]2CO2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: [N-]=[N+]=N[C@H](CO)c1ccc(C(F)(F)F)nc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-5-(oxiran-2-yl)-2-(trifluoromethyl)pyridine (2.72 g, 14.4 mmol) in acetonitrile (200 mL) were added lithium perchlorate (20 g, 0.19 mol) and sodium azide (3.7 g, 57 mmol). The mixture was stirred at 60° C. overnight and TLC indicated completion of the reaction. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was treated with water and extracted with EtOAc. The combined organic layers were dried, and concentrated. The residue was purified by silica gel column to afford the title compound.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([C:46]([F:49])([F:48])[F:47])[CH2:13][C:14]([NH:16][C@@:17]([C:32]1[CH:37]=[C:36]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=1)([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15].NN>CO>[NH2:3][CH:12]([C:46]([F:49])([F:48])[F:47])[CH2:13][C:14]([NH:16][C@@:17]([C:32]1[CH:37]=[C:36]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=1)([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15]
Reactant: O=C(CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: NN
Solvent: CO
Product: NC(CC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)C(F)(F)F
Temperature: 50 °C
Yield: 31 %

Procedure:
To a solution of 3-(1,3-dioxoisoindolin-2-yl)-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 325, 30 mg, 0.04 mmol) in MeOH (1 mL) was added hydrazine (0.03 mL, 1 mmol) and the reaction mixture was heated at 50° C. for 4 h. The reaction mixture was purified by preparative HPLC (Axia luna column, 30×75 mm, 10-100% ACN/H2O with 0.1% TFA over 10 min, flow rate 40 mL/min, monitoring at 220 nm) to yield 3-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 326) as white solid (7 mg, 24% yield). LCMS: RT=3.62 min [M+H] 565.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.34 (1H, d, J=17.94 Hz), 7.13-7.24 (3H, m), 6.96-7.11 (4 H, m), 6.82-6.92 (3H, m), 6.62 (2H, d, J=7.83 Hz), 5.86 (1H, t, J=1.77 Hz), 3.88 (1H, t, J=12.63 Hz), 3.75-3.84 (1H, m), 3.70 (1H, d, J=13.14 Hz), 2.82-2.93 (1H, m), 2.77 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([O-:11])=[O:10].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:8])[CH:3]=1
Reactant: Cc1cccc(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
3-Fluorotoluene (1 mole) in concentrated sulfuric acid (200 ml.) is stirred at 0° C. while a cold solution of potassium nitrate (1.5 mole) in concentrated sulfuric acid (750 ml.) is added slowly during 3 hours, the temperature being kept below 5° C. with an ice-ethanol bath After the addition is complete, the ice-bath is removed and stirring is continued for 3 hours at room temperature. Water (400 ml.) is added, and the organic layer is separated, dried (MgSO4) and filtered. The oil is separated by vapor-phase chromatograph on a 200×1 cm. silicone oil column (DC 200 20%) on Chromosorb R (60/80) at 191° C. and a helium flow rate of 86 ml./min. The desired pure nitro-isomer is collected.
Reaction SMILES: [CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[CH:24]=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:29][C:30]([Cl:35])([Cl:34])[C:31](Cl)=[O:32]>ClCCl>[Cl:29][C:30]([Cl:35])([Cl:34])[C:31]([C:24]1[N:16]2[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:27]=[CH:28][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17]2)=[CH:26][CH:25]=1)=[O:32]
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of 10-(4-cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Example 4 (1.85 g) in dichloromethane (50 mL) was added trichloroacetyl chloride (1 g). After stirring overnight at room temperature, the mixture was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and filtered through a short column of Magnesol®. After eluting with several additional volumes of dichloromethane, the eluate was combined and refluxed with gradual addition of hexane until crystallization was observed. The title compound (1.5 g) was obtained upon cooling, as colorless crystals, m.p. 172–174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
1,1-Dimethylethyl {4-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]piperidin-1-yl}acetate was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and tert-butyl bromoacetate using the same methods as described by Procedure I.
Reaction SMILES: C(O[Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.[CH:14]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>COC(C)(C)C>[CH:14]1([Si:4]([O:5][CH2:6][CH3:7])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Br[Mg]C1CCCC1
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: CCO[Si](OCC)(OCC)C1CCCC1
Reaction time: 6 h

Procedure:
60 ml of dry t-butyl methyl ether and 14.0 gram (0.067 mole) of tetraethoxysilane were charged in a 250 ml flask equipped with a reflux condenser and a stirring apparatus in an atmosphere of nitrogen and the solution of cyclopentyl magnesium bromide prepared above under (a) was slowly added while keeping the internal temperature below 10° C. After completion of addition stirring was carried out at room temperature for 6 hours and at reflux temperature for 2 hours. To the resulting reaction mass 10-20 ml of saturated aqueous ammonium chloride solution was added drop wise to dissolve magnesium salt. The organic layer was separated from the aqueous layer, dried and evaporated to give crude cyclopentyltriethoxysilane. The crude was purified by fractional distillation under reduced pressure, yielding 12 gram of pure cyclopentyltriethoxysilane (76% of the theoretical maximum yield based on the amount of tetraethoxysilane).