Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:25]2[N:24]([CH2:28][CH2:29][OH:30])[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:22][C:21]=2[C:20]=1[C:35]#[N:36].C(N(CC)CC)C>ClCCl>[C:31]([C:23]1[N:24]([CH2:28][CH2:29][OH:30])[C:25]2[C:21]([CH:22]=1)=[C:20]([C:35]#[N:36])[C:19]([NH:18][C:14]([C:11]1([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]1)=[O:15])=[CH:27][CH:26]=2)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)c1cc2c(C#N)c(N)ccc2n1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc2c(C#N)c(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (196 mg, 0.75 mmol) was added to a solution of 5-amino-2-tert-butyl-1-(2-hydroxyethyl)-1H-indole-4-carbonitrile (150 mg, 0.58 mmol) and triethylamine (242 μL, 1.74 mmol) in dichloromethane (2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with 1N HCl solution (×2), saturated NaHCO3 solution (×2), brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield the product, N-(2-tert-butyl-4-cyano-1-(2-hydroxyethyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 481.2, found 482.5 (M+1)+. Retention time 1.99 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.28 (s, 1H), 5.05 (t, J=5.6 Hz, 1H), 4.42 (t, J=6.8 Hz, 2H), 3.70-3.65 (m, 2H), 1.51-1.48 (m, 2H), 1.44 (s, 9H), 1.19-1.16 (m, 2H).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:7][S:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C.C(OCC)(=O)C>[CH3:1][NH:2][S:17]([C:13]1[CH:12]=[C:11]([S:8]([NH:7][C:3]([CH3:6])([CH3:5])[CH3:4])(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: CN
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cccc(S(=O)(=O)NC(C)(C)C)c1
Reaction time: 2 h

Procedure:
5 ml of a 33% solution of methylamine in ethanol was added to a solution of 1.8 grams (7 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. The mixture was stirred for 2 hours. The ethyl acetate layer was separated and concentrated in vacuo. The residue was purified on silica gel eluting 5% methanol in diochloromethane to give 1.32 grams of the titled compound as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.O.[NH2:13]N.O>C(O)C>[NH2:13][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: NN
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CCO
Solvent: O
Product: NN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 42 %

Procedure:
Phthalimide powder was added to a solution of hydrazine monohydrate (28.9 mL, 462.4 mmol) in ethanol (415 mL). The resulting solution was stirred at room temperature for 2 minutes and then stirred under reflux for 8 minutes. The resulting mixture was added to icy water to precipitate solid. The resulting solid was filtered, collected, washed with a small volume of water, and then dried in vacuum. The target compound was yielded as white solid (29.5 g, 182.1 mmol, 42% yield).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:39])([CH3:40])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Product: COc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (337 mg, 1.0 mmol) and 5-Bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (example B.7) (440 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (135 mg, 23%). MS (ISP) 595.3 [(M+H)+]; mp 178-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(OP([CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([CH2:33]P(OCC)(OCC)=O)=[CH:27][C:26]=1[O:42][CH2:43][CH:44]([CH2:49][CH3:50])[CH2:45][CH2:46][CH2:47][CH3:48])(OCC)=O)C.[C:51](O[K])([CH3:54])([CH3:53])[CH3:52].S(=O)(=O)(O)O>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([CH:33]=[C:52]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:51]3[CH:54]=[CH:15][C:2]([Br:1])=[CH:3][CH:53]=3)=[CH:27][C:26]=2[O:42][CH2:43][CH:44]([CH2:49][CH3:50])[CH2:45][CH2:46][CH2:47][CH3:48])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: CCCCC(CC)COc1cc(CP(=O)(OCC)OCC)c(OC)cc1CP(=O)(OCC)OCC
Reactant: CC(C)(C)O[K]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC(CC)COc1cc(C=C(c2ccccc2)c2ccc(Br)cc2)c(OC)cc1C=C(c1ccccc1)c1ccc(Br)cc1
Reaction time: 3.5 h

Procedure:
Under an inert atmosphere, 4-bromobenzophenone (0.783 g, 3mmol), and 1,4-bis-(diethylphosphonomethyl)-2-(2-ethylhexyloxy)-5-methoxy benzene (0.660 g, 1.23 mmol) were dissolved in tetrahydrofuran (10 g). At room temperature, tetrahydrofuran (3.28 g) solution of tert-butoxy potassium (0.414 g, 3.69 mmol) was added dropwise for 5 minutes, and successively stirred for 3.5 hours. The reaction mixture was charged into water (100 ml) and neutralized with 5% sulfuric acid. After neutralization, ethyl acetate (250 ml) was added and the organic layer was partitioned. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant raw product was purified by silica gel chromatography to give the desired product. (Yield: 0.86 g, 93%)
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:7]([F:22])[CH:6]=1)#[N:4]>CCO>[NH2:4][C:3](=[N:1][OH:2])[C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[C:7]([F:22])[CH:6]=1
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1F
Reactant: NO
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.7 %

Procedure:
A 50% aqueous solution of hydroxylamine (345 mL, 5.85 mol) was added dropwise over 10 minutes into a solution of tert-butyl N-(4-cyano-2-fluorobenzyl)-N-methylglycinate (325 g, 1.17 mol) in EtOH (2.1 L). The reaction mixture was stirred at RT for 20 hours. Solvents were concentrated under vacuum and water (2 L) was added. The resulting suspension was filtered off, washed with water (1 L) and dried under vacuum to give title compound as white powder (323 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 9.74 (s, 1H), 7.51 (dd, J=8.0, 1.6 Hz, 1H), 7.45-7.36 (m, 2H), 5.87 (s, 2H), 3.70 (s, 2H), 3.17 (s, 2H), 2.26 (s, 3H), 1.42 (s, 9H). LC/MS (Method B): 312.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[N+:20]([O-])=O.Cl[CH2:24]Cl>>[F:15][C:14]1[C:9]2[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=[N:20][C:10]=2[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(F)c1F
Reactant: Nc1ccccc1
Product: Fc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Temperature: 110 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of aniline (1.12 ml, 12.3 mmol) and 2,3-difluoro-1-nitro-5-trifluoromethylbenzene (2.8 g, 12.3 mmol) was heated at 110° C. for 24 h. Dichloromethane was added and the resulting precipitate filtered off. The filtrate was concentrated under reduced pressure then redissolved in ethyl acetate. 10% Palladium on carbon (0.5 g, Degussa) was added and the resulting suspension hydrogenated at 5 bar for 1 h. The reaction mixture was filtered through celite, washed with ethyl acetate and, the filtrate concentrated under reduced pressure. Formic acid (10 mL) was added and the mixture heated at 110° C. for 24 h. Concentration under reduced pressure gave 7-fluoro-1-phenyl-5-trifluoromethylbenzimidazole as a purple solid (3.0 g, 87%) m/z, 281.0 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10](=[CH:13][N:14]([CH3:16])C)[NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K].[O-][CH2:20][CH2:21][CH2:22][CH3:23].[C:24](O)(=O)C>CN(C)C=O.O1CCCC1>[C:1]1([N:7]2[C:11](=[O:12])[C:10]3=[CH:13][NH:14][C:16]4[CH2:23][CH2:22][CH2:21][CH2:20][C:24]=4[N:9]3[C:8]2=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=C1NC(=O)N(c2ccccc2)C1=O
Reactant: CCCC[O-]
Reactant: CC(=O)O
Agent: [K]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1c2c[nH]c3c(n-2c(=O)n1-c1ccccc1)CCCC3
Reaction time: 0.5 h

Procedure:
To a solution of 3-Phenyl-5-(dimethylaminomethylene)-imidazoline-2,4-dione (1.3 g) in dimethylformamide (20 mL) at 0° C was added 1M potassium terr-butoxide (5 mL ) in tetrahydrofuran. After 5 min 2-Chlorocycloxeanone (700 mg) was added and the mixture was stirred for 30 min. Acetic acid (1 mL) was added and the solvent was removed at reduced pressure. To the resulting residue was added ammonium acetate (10 gm) and acetic acid (25 ml) and the mixture was heated to reflux for 4 h. The solvent was removed at reduced pressure and water (50 mL) was added. The resulting solid was collected, washed with methanol and dried to yield 2-Phenyl-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 21) as an off white solid. m.p. 236°-240° C.
Reaction SMILES: N1C=CC=N1.[CH3:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([CH2:14][C:15]#[N:16])=O)=[CH:10][CH:9]=1.Cl.[C:20]([NH:24][NH2:25])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([N:24]1[C:15]([NH2:16])=[CH:14][C:12]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:18][CH:17]=2)=[N:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)NN
Reactant: COc1ccc(C(=O)CC#N)cc1
Agent: Cl
Agent: c1cn[nH]c1
Product: COc1ccc(-c2cc(N)n(C(C)(C)C)n2)cc1

Procedure:
General procedure for pyrazole formation: An ethanolic solution (3 mL) of 4-methoxybenzoylacetonitrile (500 mg, 2.85 mmol), t-butylhydrazine hydrochloride (391 mg, 3.14 mmol), and catalyticp-toluenesulfonic acid was stirred under argon at 90° C. for 4 h in a sealed tube. The reaction was concentrated and the residue partitioned between EtOAc and sat. NaHCO3. The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with a gradient of 10-30% EtOAc in Hexanes which yielded 2-tert-Butyl-5-(4-methoxyphenyl)-2H-pyrazol-3-ylamine: 1H NMR (400 MHz, CDCl3) δ 1.70 (s, 9H), 3.58 (br.s, 2H), 3.84 (s, 3H), 5.85 (s, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.8 Hz, 2H); MS (ES+): m/z 246 [MH+], m/z 190 [M-tbutyl].
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1.[Si:18]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=[O:30])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(OCC)C.C(OCC)(=O)C>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[CH:29]([OH:30])[C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:25][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19])[CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2nccs2)c1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 26.4 %

Procedure:
A solution of 1.6M n-butyllithium in hexane (206 mL, 0.33 mol) was cooled to -45° C. under nitrogen. A slurry of 2-bromothiazole (50 g, 0.30 mol) in 75 mL of diethyl ether was added in portions, maintaining a temp between -35° C. and -45° C. The resulting dark brown solution was stirred an additional 15 minutes at -40° C. before adding 3-(tert-butyldimethylsilyloxy)benzaldehyde (70.9 g, 0.30 mol, Example 54, infra) dropwise via syringe at a rate to maintain temperature between -25° C. and -35° C. The resulting mixture was stirred an additional 30 minutes at -15° C., then poured into a mixture of 1 L ice/600 mL 1M HCl. The organic phase was dried over sodium sulfate, and evaporated to give a brown oil. Chromatography on silica gel with hexane:ethyl acetate (gradient from 90:10 to 80:20) gave 25.5 g (26.4%) of a-(2-thiazolyl)-3-((tert-butyldimethyl-silyl)oxy)benzyl alcohol as a viscous yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:11]1)C(=O)OC(C)(C)C.C([Cl:24])(=O)C>C(O)C>[ClH:24].[ClH:24].[CH3:1][NH:2][CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccncc2)C1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CNC1CCN(c2ccncc2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
tert-Butyl methyl(1-(pyridin-4-yl)pyrrolidin-3-yl)carbamate (3.028 mmol, 1 eq) was dissolved in ethanol (11 ml), and acetyl chloride (15.14 mmol, 5 eq) was added, while cooling with ice. After stirring for 16 h at RT, a solid precipitated. Ethanol was concentrated slightly, and the precipitate was filtered off, washed with diethyl ether and dried. Yield: 94%.
Reaction SMILES: [CH:1]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1)=[CH2:2].[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O>[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[NH2:9][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC1=CCCCC1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Pd]
Product: CCc1ccccc1
Product: Nc1ccccc1

Procedure:
It is not necessary to use pure oxygen as the source of oxygen. Air is a suitable source of oxygen and is desirable for reasons of economy. Alternatively, the oxidizing agent can be ozone (under conditions which prevent direct interaction of ozone and olefin) or a compound which can generate oxygen under reaction conditions (e.g., peroxides and hydroperoxides), or it can be a compound which contains an active-oxygen functional group (e.g., nitro derivatives). Aliphatic and aromatic nitro compounds which have a boiling point below about 250° C. are particularly useful as an oxidizing agent in place of molecular oxygen in the invention process. Thus, in another embodiment this invention provides a process for the production of ethylbenzene and aniline which comprises contacting vinylcyclohexene with a present invention palladium on non-acidic zeolite catalyst in the presence of nitrobenzene at a temperature between about 200° C. and 500° C. and a pressure between about 1 and 200 psi to yield ethylbenzene and aniline product.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@@H:10]([C:12](O)=[O:13])[NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].II>C1COCC1>[NH2:11][C@@H:10]([CH2:9][O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][OH:13]
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N[C@H](CO)COCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
A mixture of O-(phenylmethyl)-L-serine (commercial product) (139.0 g; 0.712 mol) and NaBH4 (96%; 75 g; 1.9 mol) in dry THF (700 mL, distilled on sodium/benzophenone), under N2 atmosphere, was slowly added (1.5 hours) with a solution of I2 (181.0 g; 0.713 mol) in dry THF (350 mL) at a temperature of 0 to 15° C. When the addition was completed and the dark color had disappeared, the mixture was refluxed for 18 hours, then cooled at 0° C. and the NaBH4 excess was destroyed with cold water (30 mL), followed by 15N KOH (320 mL). When bubble evolution was no longer observed, the mixture was heated, distilling most of the organic solvent (THF). The aqueous mixture was refluxed for 6 hours, then stirred at r.t. for a further 18 hours. CHCl3 (700 mL) and Et2O (300 mL) were added thereto under strong stirring; after 15 minutes the diphasic mixture was filtered through Celite® and the separated solid was repeatedly washed with CHCl3 /Et2O 3:1 (4 L). The filtered solution was concentrated, removing water by repeated azeotropical distillations with CH3CN. The crude oil (130 g) was purified twice by flash chromatography (CH2Cl2 /CH3OH/NH4OH 25% (wlw) 54:40:6 to 90:9:1), thereby obtaining the desired compound (92.63 g; 0.511 mol).
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.ClCCl>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([NH:2][CH3:1])[CH:5]=1
Reactant: CN
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CNc1cc(OC)ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
83.5 mL (167.0 mmol) of a 2 molar solution of methylamine in THF are added dropwise to 14.3 g (83.56 mmol) 3-fluoro-4-nitro-anisol and 12.71 g (92.02 mmol) potassium carbonate in 200 mL dichloromethane. The mixture is stirred overnight and then combined with water. The organic phase is washed successively with water and ammonium chloride solution, dried and evaporated down. The yellow solid remaining is stirred with hexane. Yield: 12.7 g (84%); mass spectroscopy: [M+H]+=183.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)(=O)=O.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[S:10]1[CH:11]=[CH:12][C:8]([CH2:7][CH2:6][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[CH:9]1
Reactant: CS(=O)(=O)OCCc1ccsc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1ccsc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of the above crude 2-(3-thienyl)ethyl methanesulfonate in 400 ml of N,N-dimethylformamide, 12.8 g (69.0 mmol) of potassium phthalimide was added, followed by overnight stirring at 100° C. After cooling to room temperature, the reaction mixture was added to water with vigorous stirring. The resulting precipitate was filtered, washed with water and dried to yield the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-])=O)[CH:6]=[C:5]1[C:16]1[S:17][CH:18]=[CH:19][N:20]=1.O1CCCC1.O.NN>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.CO>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:13])[CH:6]=[C:5]1[C:16]1[S:17][CH:18]=[CH:19][N:20]=1
Reactant: COCn1c(-c2nccs2)cc2cccc([N+](=O)[O-])c21
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCn1c(-c2nccs2)cc2cccc(N)c21
Yield: 97.5 %

Procedure:
A mixture of 1-(methoxymethyl)-7-nitro-2-(1,3-thiazol-2-yl)-1H-indole (2.14 g), iron(III) chloride hexahydrate (0.12 g), activated carbon (1.20 g), tetrahydrofuran (10 mL) and methanol (10 mL) was heated under reflux for 20 min. To the reaction mixture was added hydrazine monohydrate (2.20 g) over 15 min while heating under reflux. The reaction mixture was heated under reflux for 2 hr, filtrated, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (1.87 g, yield 97%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:61][O:62][CH2:63][CH2:64][NH2:65]>CN(C=O)C.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:65][CH2:64][CH2:63][O:62][CH3:61])=[O:26])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCCN
Reactant: O=C(O)[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1

Procedure:
(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexanecarboxylic acid (HCl salt)(0.05 g, 0.12 mmol), HATU (0.09 g, 0.24 mmol), diisopropylethylamine (0.06 g, 0.47 mmol) and 2-methoxyethanamine (0.04 g, 0.47 mmol) were stirred together in 1 ml each of DMF and CH3CN at room temperature overnight. All volatiles were removed with a stream of nitrogen and heat. The residue was dissolved in methanol and purification with phase preparatory HPLC with 10-90% MeOH/water (HCl modifier) gave the desired product as the HCl salt.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:18][CH:17]=1)#[N:6].[CH3:34][NH2:35]>ClCCl>[CH3:34][NH:35][C:13]([C:11]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[S:23][CH:24]=[CH:25][C:26]=3[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:20][CH:21]=2)=[C:7]([C:5]#[N:6])[CH:12]=1)=[O:15]
Reactant: CN
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)O)cc2C#N)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)c(C#N)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Add thionyl chloride (0.2 mmol) to a suspension of 2-Cyano-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid (0.1 mmol) in dichloromethane at RT. Stir mixture for 1 h at 50° C. and concentrate to dryness under reduced pressure. Add to the resultant residue 0.5 mmol MeNH2 (2M in THF). Concentrate the reaction to dryness and purify with flash chromatography (Silica gel-5%MeOH/CH2Cl2). Concentrate the desired fractions to provide the title compound. MS (ES−):438 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@@H:10]([CH:18]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@@H:10]([CH2:18][N:24]2[CH2:25][CH2:26][C:21]([OH:20])([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22][CH2:23]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(CCCc2ccccc2)CCNCC1
Reactant: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccsc1
Product: OC1(CCCc2ccccc2)CCN(C[C@H]2CN(Cc3ccccc3)C[C@@H]2c2ccsc2)CC1

Procedure:
The title compound was prepared from 1-Benzyl-3-(R)-formyl-4-(S)-(3-thienyl)pyrrolidine [which was prepared from (S)-N-(1-benzyl-4-(S)-(3-thienyl)-3-(R)-pyrrolidinylcarbonyl)-4-benzyl-2-oxazolidinone (Example 241 Step 2)] and 4-hydroxy-4-(3-phenylpropyl)piperidine (Example 122, Step 1) by procedures analogous to those described in Example 241.