Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([NH:10][N:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:22])(=O)=O)=CC=1>[OH-].[Na+].ClCCl>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12](=[N+:11]=[N-:10])[C:13](=[O:22])[NH:14]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)NN=C2C(=O)Nc3cc(Cl)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: [N-]=[N+]=C1C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
33.8 g of 6-chloroisatin-3-p-toluenesulfonylhydrazone is suspended in a mixture of 970 ml of 0.2 N sodium hydroxide solution and 1.5 liters of dichloromethane. The suspension is heated at 41° for 3 hours with vigorous stirring under nitrogen, cooled to room temperature, filtered and recrystallized from methanol. Yield 13 g (68%), m.p. 197°-199° (d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([C:10]2[CH:11]=[C:12]([C:18]#[N:19])[S:13][C:14]=2[N+:15]([O-])=O)=O)[CH:5]=[CH:6][CH:7]=1.CCO>[Fe].C(O)(=O)C>[NH2:15][C:14]1[S:13][C:12]([C:18]#[N:19])=[CH:11][C:10]=1[S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1cc(S(=O)c2cccc(Br)c2)c([N+](=O)[O-])s1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1cc(Sc2cccc(Br)c2)c(N)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
4-(3-Bromo-benzenesulfinyl)-5-nitro-thiophene-2-carbonitrile (Example 25: step e; 5.20 g, 15.33 mmol) was dissolved into EtOH (45 mL) and acetic acid (5 mL). The reaction was heated to 50° C. and then iron (4.28 g, 76.69 mmol) was added and the reaction was allowed to heat with stirring overnight. The reaction mixture was filtered through celite which was washed with MeOH and EtOAc to ensure that the product does not remain on the celite. The filtrate was concentrated and then dissolved into EtOAC and washed with brine. The organic layer was dried (MgSO4) and concentrated. The crude reaction mixture was purified by flash column (20% EtOAc in Hexanes) resulting in the desired product as a brown oil (1.5 g, 32%). 1H-NMR (CDCl3): δ 7.38 (1H, s), 7.31-7.29 (1H, m), 7.18 (1H, t, J=1.8, Hz), 7.14 (1H, t, J=7.9 Hz), 6.99-6.96 (1H, m), 5.06 (2H, br s).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.C(OCC)(=[O:28])C.O>>[OH:28][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cn(-c2ccc3c(N)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Product: Cc1cn(-c2ccc3c(O)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Yield: 60 %

Procedure:
1-(4-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.2 g 0.62 mmol) is microwaved at 80 degrees Celsius for 300 seconds in the presence of excess 36% HCl. The crude product is taken up in ethyl acetate/water. The organic phase is dried over magnesium sulfate, filtered, concentrated and chromatographed to afford 1-(4-hydroxyquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one as a solid (0.12 g, 60%). LC/MS m/z=322 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)[C:2]#[CH:3].Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: C#CCN1CCc2ccc(N)cc2CC1
Product: C#CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2CC1

Procedure:
N-{(1R,2R)-2-[5-Chloro-2-(3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide was prepared from 3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 322. Product isolated as a pale yellow solid (90 mg, 36%). m.p.=193-196° C.; LCMS (m/e) 503 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.35-7.25 (m, 1H), 7.08 (d, 1H, J=7.8 Hz), 6.82 (s, 1H), 5.40 (d, 1H, J=7.5 Hz), 5.38-5.32 (m, 1H), 3.94-3.83 (m, 1H), 3.45 (d, 2H, J=2.0 Hz), 3.31-3.20 (m, 1H), 3.00-2.90 (m, 4H), 2.80 (s, 3H,), 2.83-2.71 (m, 4H), 2.28-2.18 (m, 3H), 1.89-1.79 (m, 2H), 1.45-1.33 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I-].C[O:9][CH:10]1[O:14][C:13](=[O:15])[CH2:12][CH:11]1[C:16]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:18])[CH3:17]>O.CO>[CH:10]([C:11](=[C:16]([CH3:18])[CH3:17])[CH2:12][C:13]([OH:15])=[O:14])=[O:9]
Reactant: COC1OC(=O)CC1C(C)(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)=C(C=O)CC(=O)O
Temperature: 20 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of 0.700 g of sodium carbonate in 8 ml of water was added to a solution of 0.700 g of the product of Step A in 1 ml of methanol and the mixture was stirred for 2 hours at 20° C. and was filtered. The filtrate was adjusted to a pH of 2 and was saturated with sodium chloride. The mixture was extracted with chloroform and the organic phase was evaporated to dryness. The residue was crystallized from isopropyl ether to obtain 0.095 g of 3-formyl-4-methyl-pent-3-ene-1-oic acid melting at 102° C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[N:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[N:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccn(C[C@H](O)CO)n1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccn(C[C@H](O)CO)n1
Yield: 88.2 %

Procedure:
In a Parr shaker bottle was placed (S)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (2.28 g, 12.19 mmol), 10% palladium on activated carbon (200 mg) and ethanol (30 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 5 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentrated in vacuo to afford (S)-3-(3-amino-pyrazol-1-yl)-propane-1,2-diol (1.69 g, 88%) as a yellow oil: LR-ES-MS m/z calculated for C6H11N3O2 [M]+ 157, observed [M+H]+ 158.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:13][CH2:14][CH2:15][CH:16]=[O:17])[CH3:12]>C1C=CC=CC=1>[CH2:11]([N:13]([CH2:14][CH2:15][CH:16]=[O:17])[C:9]([NH:8][C:6]1[S:7][C:3]([O:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH3:12]
Reactant: CCNCCC=O
Reactant: COc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CCN(CCC=O)C(=O)Nc1nnc(OC)s1

Procedure:
A mixture of 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-ethylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-ethyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[N:3][N:4]=1
Reactant: Nc1nccs1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Nc3nccs3)c2c1
Yield: 40.7 %

Procedure:
At 100° C. a solution of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.5 g, 1.41 mmoles), prepared as described in example 45, 2-aminothiazole (0.424 g, 4.23 mmoles), triethylamine (0.59 ml, 4.23 mmoles), palladium acetate (16 mg, 0.07 mmoles) and triphenylphosphine (56 mg, 0.21 mmoles) was stirred under N2. After 20 hours the mixture was poured into water/ice and extracted more times with CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: hexane/ethyl acetate 7:3) yielding 0.24 g of the title compound (yield: 50%). m.p.: 218-220° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@H:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[OH-].[Na+].Cl>CO>[N:11]1([C:9]([NH:8][C@H:7]([C:6]([NH:5][C@@H:4]([C:3]([OH:33])=[O:2])[CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)N1CCCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
The compound obtained in (3) (1.29 g) was dissolved in methanol (5.0 ml) and 1N NaOH (3.1 ml) was added at 0°-5° C. Then the reaction mixture was stirred at room temperature for 2 h. 1N HCl (3.1 ml) was added to the mixture and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with 1N HCl and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from methanol (5 ml)/ethyl acetate (30 ml)/hexane (60 ml) to give the product (0.97 g) as colorless crystals.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].Cl[CH2:12]CCl>C(Cl)Cl>[CH3:12][O:1][CH2:2][C@H:3]1[O:4][CH:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: ClCCCl
Solvent: ClCCl
Product: COC[C@H]1OC(O)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
Vorbr□ggen coupling To the appropriate silylated base (12.9 mmol) was added the appropriate ribose (10.3 mmol) in 15 ml dry 1,2-dichloroethane. The residue was co-evaporated twice with dry 1,2-dichloroethane and subsequently dissolved in 75 ml dry 1,2-dichloroethane. The solution was gently refluxed and after 5 minutes trimethylsilyl-trifluoromethane sulfonate (TMS triflate) (997 □l, 5.16 mmol) was added. The mixture was refluxed for 2 hr, cooled to room temperature and diluted with CH2Cl2. It was extracted with 5% NaHCO3 and water. The organic layer was dried (MgSO4), concentrated and purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6]O)=[C:4]([F:14])[CH:3]=1.P(Br)(Br)[Br:16]>C(OCC)C>[Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6][Br:16])=[C:4]([F:14])[CH:3]=1
Reactant: CC(C)Oc1cc(CO)c(F)cc1Cl
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(C)Oc1cc(CBr)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 254 %

Procedure:
124 g (0.56 mol) of 4-chloro-2-fluoro-5-isopropoxybenzyl alcohol was dissolved in 900 ml of diethyl ether, and 55 g (0.20 mol) of phosphorus tribromide was dropwise added thereto under cooling with ice. After stirring at room temperature for 3 hours, the reaction solution was poured into ice water and extracted with diethyl ether. The extract was washed with water and an aqueous sodium hydrogencarbonate solution, and then, the organic layer was dried over anhydrous magnesium sulfate. Diethyl ether was distilled off under reduced pressure to obtain 143 g (yield: 89%) of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C)C=O>[CH2:13]([O:12][C:10]([C:2]1[N:1]([CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[CH3:14]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CC(=O)OCc1ccccc1

Procedure:
Ethyl indole-2-carboxylate (22 g) was dissolved in dimethylformamide (150 ml), and sodium hydride (including 60% oil, 5.12 g) was gradually added with stirring. Then, benzyl bromoacetate (19.2 ml) was added, and the mixture was stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure. The residue thus obtained as a solid was subjected to silica gel column chromatography and eluted with a mixed solvent of ethyl acetate and hexane to give benzyl 2-ethoxycarbonyl-indole-1-acetate (28.9 g) as an oil. This compound (32.5 g) was dissolved in ethanol (350 ml), and hydrogenated in the presence of palladium/carbon (10%) catalyst at 1 atm. The catalyst was filtered off, and the solvent was concentrated under reduced pressure. The obtained residue was crystallized from isopropyl ether to give 10.22 g of 2-ethoxycarbonyl-indole-1-acetic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[Cl:33]>C(OCCO)C>[Cl:33][C:27]1[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(O)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(O)cc3Cl)c2cc1OC
Yield: 84.1 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 270.1 mg (1.5 mmol) of 4-amino-3-chlorophenol to give 299.2 mg (84.3%) of the product as a light brown solid, m.p.>250° C., mass (electrospray, m/e): M+H 355.8, 357.8.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[CH2:8]Br.[CH2:19]([N:26]1[C@@H:31]2[C@H:32]([C:34]#[N:35])[CH2:33][C@@:27]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:28]([OH:36])[CH2:29][CH2:30]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([N:26]1[C@@H:31]2[C@H:32]([C:34]#[N:35])[CH2:33][C@@:27]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:28]([O:36][CH2:8][C:7]1[CH:6]=[C:5]([C:4]([F:18])([F:17])[F:3])[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)[CH2:29][CH2:30]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
Sodium hydride (0.3 g, 7.5 mmol, 60% in oil) was added portionwise to a solution of 3,5-bis(trifluoromethyl)benzyl bromide (2.5 g, 8.3 mmol) and (1R*,2R*,5S*,6R*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 31; 1.4 g, 4.4 mmol) in THF (20 ml). The mixture was stirred at 50° C. for 18 hours then cooled with an ice-bath and quenched by dropwise addition of water. The mixture was partitioned between brine and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. Chromatography on silica gel eluting with 2.5, 5, 10 and 20% ethyl acetate/iso-hexanes afforded the title compound (2.12 g, 88%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N+:8]([O-:10])=[O:9])=[CH:20][CH:19]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-bromophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (100 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-bromophenoxy-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(N(C(C)C)CC)(C)C.[CH2:17](Br)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>O1CCCC1>[C:1]([CH:3]([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: O=C(CBr)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.6 %

Procedure:
To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide in the same manner as in Reference Example 95 and Reference Example 97 in acetonitrile (200 mL) was added 2,6-dichloro-N-fluoropyridinium triflate (6.26 g) over 10 min under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hr and at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a pale-yellow solid (yield 815 mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 mL) was added dropwise a solution of phenacyl bromide (75 g) in tetrahydrofuran (370 mL). The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77.4 g, 95%). To a solution (125 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/L hydrogen chloride-ethyl acetate solution (25 mL). The mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate as colorless crystals (yield 10.0 g, 37%). The title compound was synthesized from the thus-obtained methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[C:9]#[N:10]>CCOCC>[CH3:11][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:7])[CH2:9][NH2:10]
Reactant: CC(C)(C#N)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(CN)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled suspension of LAH (1.43 g, 35.7 mmol, 1.5 eq.) in dry Et2O (70.0 mL) under N2, a solution of 2-methyl-2-phenyl-propionitrile (3.46 g, 23.8 mmol, 1.0 eq.) in dry Et2O (3.0 mL) was added dropwise over 30 min. After 30 min the cooling bath was removed and the mixture was stirred at r.t. for 3 hours. The mixture was again cooled to 0° C. and carefully quenched by the dropwise addition of iPrOH (35 mL) and then 2M aq. NaOH (20 mL). The resulting suspension was filtered through celite and the filter cake was rinsed with THF. The fitrate was concentrated in vacuo. The residue was partitioned between DCM (125 mL) and 1M aq. NaOH (125 mL). The layers were separated and the aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×25 mL), dried over MgSO4, and concentrated in vacuo. The resulting 2-methyl-2-phenyl-propylamine was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])=[CH:9][CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@H:20]2[C@@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17][C@@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:44])=[O:5])=[CH:12][CH:11]=2)=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@H]1N[C@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)[C@@H](c2cccc(Cl)c2F)[C@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@H]1N[C@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@@H](c2cccc(Cl)c2F)[C@]1(C#N)c1ccc(Cl)cc1F

Procedure:
4-{[(2S,3R,4S,5R)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (made above, 255 mg, 0.397 mmol) was treated with 50% TFA/methylene chloride (10 mL) overnight. Removal of solvent and treating the residue with acetonitrile and water gave a white solid after filtration and dying. 239 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[O:9])[CH:7]=1.Cl[C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[N:25]=1>>[CH3:31][C:26]1[N:25]=[C:24]([N:14]2[CH2:15][CH:16]3[CH2:17][N:10]([C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:18]4[N:22]=[CH:21][CH:20]=[N:19]4)=[O:9])[CH2:11][CH:12]3[CH2:13]2)[CH:29]=[C:28]([CH3:30])[N:27]=1
Reactant: Cc1cc(Cl)nc(C)n1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC2CNCC2C1
Product: Cc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 21 and 4-chloro-2,6-dimethyl-pyrimidine. MS (ESI): mass calculated for C21H22FN7O, 407.45, m/z found 408.2 [M+H]+. 1H NMR (CDCl3) 7.97 (dd, J=9.0, 4.8 Hz, 1H), 7.73 (s, 2H), 7.25-7.19 (m, 1H), 7.16-7.10 (m, 1H), 5.94 (s, 1H), 3.95-2.88 (m, 10H), 2.50 (s, 3H), 2.34 (s, 3H).