Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][S:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20])=[O:13].C(OO)(=[O:23])C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][S:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20])(=[O:23])=[O:13]
Reactant: CC(=O)OO
Reactant: O=[N+]([O-])c1ccc(CS(=O)c2cccc[n+]2[O-])c(Cl)c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CS(=O)(=O)c2cccc[n+]2[O-])c(Cl)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of 16.1 g (0.055 mole) of 2-[[(2-chloro-4-nitrophenyl)-methyl]sulfinyl]-pyridin-1-oxide and 60 ml of acetic acid was added, dropwise at room temperature over 0.5 hours, 13.5 g (1.3 mole) of peracetic acid in acetic acid (40%). The mixture was heated at 70° C. for six hours. The reaction was worked up in the usual fashion, but the product proved to be a mixture of the starting material and desired sulfone. The isolated material (10 g), estimated to contain about 16% sulfoxide, was subsequently redissolved in 40 ml of acetic acid and 1.33 g of 40% peracetic acid in acetic acid was added. The mixture was heated for seven hours at 70° C. and then stirred at room temperature overnight. The excess peracetic acid was destroyed with sodium bisulfite, the mixture was then poured into ice water and then neutralized with potassium carbonate. The solid was filtered off and dried, having a melting point of 199-201 ° C. An NMR spectrum supported the proposed structure.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CCc5ccccc54)CC3)nn2)n1

Procedure:
The object product (175 mg, 76%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (130 mg) obtained in Example 43(2), 2,3-dihydrospiro[indene-1,4′-piperidine] hydrochloride (180 mg) and potassium carbonate (110 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[C:5]2[CH:16]=[CH:17][N:18]([CH2:19][CH2:20][OH:21])[C:4]=2[N:3]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[CH3:28][S:29]([O:21][CH2:20][CH2:19][N:18]1[C:4]2[N:3]=[C:2]([NH2:1])[N:7]3[N:8]=[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[C:6]3[C:5]=2[CH:16]=[CH:17]1)(=[O:31])=[O:30]
Reactant: Nc1nc2c(ccn2CCO)c2nc(-c3ccco3)nn12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the title C compound, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethanol (15 g, 5.28 mmol) in 45 mL of dry THF is added 75 mL of TEA, 75 mL of pyridine and methanesulfonyl chloride (0.6 mL, 7.75 mmol) at 0° C. The mixture is stirred at RT under N2 for 12 h. The solvent is evaporated in vacuo and the residue is purified by flash chromatography using EtOAc as eluent to give 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate as a white solid: LC/MS (M+1=363.4). 1H NMR (DMSO-d6, 400 MHz) δ 3.07 (s, 3H), 4.47 (t, 2H, J=5.2 Hz), 4=59 (t, 2H) J=5.2 Hz), 6.65 (d, 1H, J=3.6 Hz), 6.72 (dd, 1H, J=3.2 Hz and 1.6 Hz), 7.18 (d, 1H, J=3.6 Hz), 7.20 (d, 1H, J=3.2 Hz), 7.60 (s, 2H), 7.92 (d, 1H, J=1.2 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:24][C:25]1[CH:26]=[C:27]([C:28]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccc(F)c(F)c2)n1
Temperature: 150 °C
Yield: 48 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.050 g, 0.154 mmol) in anhydrous acetonitrile (2.0 mL) under N2, was added 3,4-difluorobenzoyl chloride (0.121 g, 0.177 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.033 g (48% yield) of pure product: MS (ES) m/z 446 (M+).
Reaction SMILES: [C:1]([O:9]C(C)(C)C)(=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH:6]=[CH2:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCC/C=C/C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCC=CC(=O)O
Reaction time: 12 h
Yield: 68 %

Procedure:
To a solution of oxalyl chloride (3.36 mL, 39.2 mmol) in CH2Cl2 (100 mL) at −78° C. was added DMSO (5.56 mL, 78.3 mmol). After stirring for 5 min, 4-penten-1-ol (2.00 mL, 19.6 mmol) was added, and after another 15 min Et3N (13.6 mL, 97.9 mmol) was added. The reaction mixture was warmed to rt and then treated with 0.1M HCl. The organic layer was separated, washed with saturated aqueous NaCl solution, dried (MgSO4), and treated with Ph3PCHCO2t-Bu (7.38 g, 19.6 mmol) at rt. The reaction mixture was stirred for 5 h and then treated with saturated aqueous NH4Cl solution and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was filtered through a silica plug (CH2Cl2/pentane 1:1) to give t-butyl(E)-2,6-heptadienoate. To a solution of this ester in CH2Cl2 (40 mL) was added TFA (5 mL) at rt. After stirring for 12 h, the reaction mixture was concentrated under reduced pressure. Purification of the crude product by FC (hexane/EtOAc 15:1→5:1) afforded 2,6-heptadienoic acid 6 (1.67 g, 68%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ7.12-7.05 (m, 1H), 5.88-5.76 (m, 2H), 5.08-5.02 (m, 2H), 2.37-2.32 (m, 2H), 2.26-2.21 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([O:7][CH3:8])=[O:6])[CH3:4].Br[CH:10]([CH3:14])[C:11]([OH:13])=[O:12].[OH-].[Na+]>O1CCOCC1.O>[C:5]([CH:3]([NH:2][C@H:10]([C:11]([OH:13])=[O:12])[CH3:14])[CH3:4])([O:7][CH3:8])=[O:6]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(C)N[C@@H](C)C(=O)O
Reaction time: 0.5 h

Procedure:
Neutralize a solution of 1.4 g of methyl L-alaninate HCl and 3.1 g of α-bromopropionic acid in a dioxane-water mixture to pH 9 with sodium hydroxide. Warm to 70° and hold for 30 minutes, keeping the pH at 8 to 9 by addition of sodium hydroxide as necessary. Cool, apply to a column of Dowex 50 (H+) ion exchange resin, wash with water, and elute with 2% pyridine in water. Combine the product fractions and freeze dry. Purify this crude by chromatography on an ion-exchange column of Dowex 50 (Na+) in 0.5 M sodium citrate buffer pH 3.3. Collect the product fractions, concentrate to a small volume in vacuo, and repeat the Dowex 50 (H+) chromatography. Freeze dry the product fractions to obtain the pure N-(1-carbomethoxyethyl)-alanine.
Reaction SMILES: [N:1]1([CH:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:37])=[CH:22][N:21]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:37][C:23]1[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:21][CH:22]=1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
Into a microwave vial was placed 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (66 mg, 0.00027 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (70 mg, 0.0002 mol) in isopropyl alcohol (4 mL, 0.05 mol). To this mixture was added 4N HCl-dioxane (0.03 g, 0.0002 mol) and the contents subjected to microwaves at 120° C. for 10 min. HPLC showed starting materials remaining so the reaction mixture was subjected to an additional 10 min reaction time using the same conditions. A solid had precipitated out of solution and was collected by filtration. The solid was resuspended in methylene chloride and washed with aqueous sat. sodium bicarbonate followed by water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a pale yellow foam (46 mg, 40% yield). 1HNMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 9.32 (s, 1H), 7.73 (m, 2H), 8.20 (m, 2H), 7.75 (d, 1H, J=7.8 Hz), 7.49 (m, 2H), 7.33 (d, 1H, J=7.8 Hz), 7.15 (t, 1H, J=7.6), 7.01 (d, 1H, J=8.3), 3.55 (s, 4H), 2.81 (d, 3H), 2.76 (m, 1H), 2.60 (m, 3H), 2.47 (s, 4H), 1.98 (m, 2H), 1.32 (m, 3H); MS (m/e) 507 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:22][CH3:23])[CH3:21]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:22]([CH2:20][CH3:21])[CH3:23])[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1Cl
Solvent: CS(C)=O
Product: CCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B8) (3.5 g, 12.2 mmol) and N-ethylmethylamine (5.5 ml, 61.0 mmol) in DMSO (35 mL) at 55° C. according to the general procedure C. Obtained as a yellow solid (3.58 g, 95%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:44]([O:46][C:47](=[O:50])[CH2:48][NH2:49])[CH3:45]>CN(C=O)C.O>[CH2:44]([O:46][C:47](=[O:50])[CH2:48][NH:49][C:18](=[O:20])[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=1)[CH3:45]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 106.6 %

Procedure:
DIPEA (441 mg, 0.6 ml, 3.41 mmol) was added to a stirred solution of 4-hydroxyphenyl acetic acid (104 mg, 0.68 mmol) in DMF (4 mL). HOBT (101 mg, 0.748 mmol) and EDCI.HCl (245 mg, 1.28 mmol) were added at room temperature. After 2 minutes glycine ethyl ester hydrochloride (114.5 mg, 0.82 mmol) was added. The resulting mixture was stirred at room temperature for 24 hours. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 172 mg of [2-(4-hydroxy-phenyl)-acetyl amino]-acetic acid ethyl ester). LC-MS purity: 81.298%, HPLC purity 93.36%. 1H NMR (CDCl3): δ 7.1 (d, 2H), 6.8 (d, 2H), 6.0 (bs, 1H), 4.15 (q, 2H), 4.0 (d, 2H), 3.5 (s, 2H), 1.2 (t, 3H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:14](Br)([F:16])[F:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N#N>CN(C)C(=O)C.C(Cl)Cl.[Zn]>[F:15][C:14]([F:16])=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: FC(F)(Br)Br
Agent: N#N
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1CCC(=C(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.5 %

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (0.47 mL, 2.94 mmol) and dibromodifluoromethane (0.54 mL, 5.88 mmol) in N,N-dimethylacetamide (3.5 mL) was added triphenylphosphine (1.54 g, 5.88 mmol) in N,N-dimethylacetamide (3.5 mL) dropwise under N2 at 0° C. over 15 min. The reaction mixture was stirred at ambient temperature for 1 h, then zinc (0.384 g, 5.88 mmol) was added over 1 min. The mixture was stirred at rt for 20 min and then heated at 70° C. for 16 hr. The reaction was diluted with DCM, filtered through diatomaceous earth (Celite®) and the filtrate was washed with sat. NaHCO3, water and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to an oil. The crude product was charged to a 40 g silica gel cartridge which was eluted with a 20 min gradient of 0-20% EtOAc in hexane to yield ethyl 4-(difluoromethylene)cyclohexanecarboxylate (0.015 g). 1H NMR (400 MHz, CDCl3) ppm 4.10-4.20 (2H, m), 2.35-2.52 (3H, m), 1.95-2.05 (2H, m), 1.79-1.93 (2H, m), 1.48-1.63 (3H, m), 1.25-1.31 (3H, m).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[N:15]([CH2:16][C@H:17]([NH:28][C:29](=[O:32])[O:30][CH3:31])[CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.Cl>[Pd].CO>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C@@H:17]([NH:28][C:29](=[O:32])[O:30][CH3:31])[CH2:16][N:15]2[CH:10]3[CH2:11][CH2:12][CH:13]2[CH2:14][NH:8][CH2:9]3)=[CH:25][CH:24]=1)#[N:27]
Reactant: COC(=O)N[C@H](COc1ccc(C#N)cc1)CN1C2CCC1CN(Cc1ccccc1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)N[C@H](COc1ccc(C#N)cc1)CN1C2CCC1CNC2
Yield: 86 %

Procedure:
Methyl (1S)-2-(3-benzyl-3,8-diazabicyclo[3.2.1]oct-8-y)-1-[(4-cyanophenoxy)methyl]ethylcarbamate (2.9 g, 6.7 mmol; from step (g) above) was mixed with MeOH (55 mL) and 1 M HCl (13 mL). The mixture was hydrogenated over 5% Pd/C. Filtration through a pad of Celite® and evaporation gave the title compound in 86% yield.
Reaction SMILES: F[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)[C:7]([F:20])=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([NH2:39])[CH3:38])=[N:35][CH:36]=1>CCCCO.O>[F:20][C:7]1[C:8]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[N:9][C:2]([NH:39][C@H:37]([C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]=2)[CH3:38])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(F)c(C#N)cc2F)n[nH]1
Solvent: O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)c(C#N)cc2F)n[nH]1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of 2,5-difluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile (Method 42, 0.30 g, 1.07 mmol), DIEA (0.16 g, 1.29 mmol), and (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 0.22 g, 1.6 mmol) in n-BuOH (3 ml) was heated to 130° C. for 18 hours. The reaction was then cooled to room temperature, diluted with water (20 ml), and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (hexanes-EtOAc=3:1) to give the title compound (0.25 g, 58%). 1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 7.56-7.55 (m, 2H), 7.45 (d, J=10.5 Hz, 1H), 5.42 (s, 1H), 5.25-5.22 (m, 1H), 4.63 (br s, 1H), 1.60 (d, J=7.0 Hz, 3H), 1.34 (d, J=6.1 Hz, 6H). MS: Calcd.: 399. Found: [M+H]+ 400.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(C(F)(F)F)ccc3F)cccc2c1N
Yield: 77.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro-5-(trifluoromethyl)phenylboronic acid (208 mg, 1.000 mmol) were reacted to afford the title compound (148 mg, 78% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:22])[CH2:20][C:19](=O)[O:18][C:16](=[O:17])[CH2:15]1.C(Cl)(=O)C>ClCCCl.ClCCl>[CH3:13][C:14]1([CH3:22])[CH2:15][C:16](=[O:17])[N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[C:19](=[O:18])[CH2:20]1
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CCOC(=O)c1ccc(N2C(=O)CC(C)(C)CC2=O)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-aminobenzoate (1.0 g, 6.1 mmol) and 3,3-dimethylglutaric anhydride (0.95 g, 6.7 mmol) in 1,2-dichloroethane (15 mL) was heated to reflux for 1 hour, cooled to room temperature, and treated dropwise with acetyl chloride (0.88 mL, 12.5 mmol). The mixture was heated to reflux for 1 hour, cooled to room temperature, diluted with dichloromethane, washed sequentially with water, saturated NaHCO3, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS(DCI(+)) m/e 290 (M+H)+.
Reaction SMILES: COC1C=CC(CC#N)=CC=1.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.CI.C(OC1C=CC(C(C)C#N)=CC=1)C.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([CH3:53])([CH3:52])[C:50]#[N:51])=[CH:45][CH:44]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.[Cl-].[NH4+]>[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([CH3:53])([CH3:52])[CH2:50][NH2:51])=[CH:45][CH:44]=1
Reactant: COc1ccc(C(C)(C)C#N)cc1
Agent: CC(C)[N-]C(C)C
Agent: CCOc1ccc(C(C)C#N)cc1
Agent: COc1ccc(CC#N)cc1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(C(C)(C)CN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of (4-methoxy-phenyl)-acetonitrile [5 g, 34 mmol] in THF (40 mL), is added a 1.5 M solution of lithium diisopropylamide in cyclohexane (36 mL, 54 mmol) at −78° C. After 2 hours at −78° C., methyl iodide (3.4 g, 54 mmol) is added, and the mixture is allowed to warm to room temperature over 3 hours. After additional 12 hours at 20° C., the mixture is diluted with aqueous ammonium chloride solution, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 40% EtOAc in heptane to afford a mixture of 2-(4-ethoxy-phenyl)-propionitrile and 2-(4-methoxy-phenyl)-2-methyl-propionitrile. To above mixture (5 g) in THF (20 mL) is add a 2 M solution of lithium aluminum hydride (35 mL, 70 mmol) at 0° C. After 12 hours at 20° C., the mixture is carefully quenched with 10% sodium hydroxide solution, and the white slurry is diluted with ether. The mixture is dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica to afford 2-(4-methoxy-phenyl)-2-methyl-propylamine [2 g, 33%, Intermediate (35)]. MS: 180 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([Cl:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Cl)nc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc([N+](=O)[O-])c(Cl)nc1Cl
Temperature: 110 °C
Yield: 86 %

Procedure:
A mixture of 2,6-dichloro-3-methylpyridine (2.20 g, 13.6 mmol) in concentrated sulfuric acid (11.3 mL) was treated with fuming nitric acid (6.65 mL) and heated to 110° C. for 3 hours. The reaction mixture was poured into ice-water and neutralized with 2N sodium hydroxide. The mixture was extracted with dichloromethane (3×70 mL) and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 2,6-dichloro-3-methyl-5-nitropyridine (2.43 g, 86%). 400 M Hz 1H NMR (DMSO-d6) δ: 8.66 (s, 1H), 2.39 (s, 3H).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:17][NH2:18]>N1C=CC=CC=1>[F:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:18][N:17]=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1cc(F)ccc1F
Solvent: c1ccncc1
Product: Fc1ccc2[nH]nc(-c3ccccc3)c2c1
Yield: 40 %

Procedure:
A solution of 2,5-difluorobenzophenone (0.655 g, 3.0 mmol) and hydrazine (1.0 mL) in dried pyridine (10 mL) was heated at 130° C. for 5 hours and then concentrated and purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide the title compound (0.254 g, 40% yield): mp 124–125° C.; 1N NMR (CDCl3) δ 10.89 (br s, 1H), 7.94 (d, 2H), 7.65 (dd, 1H), 7.42–7.54 (m, 3H), 7.33 (dd, 1H), 7.21 (dt, 1H); EL-MS (m/z) 212 [M]+.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: O=C(Nc1ccc(C2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(C2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 72.6 %

Procedure:
A mixture of intermediate (9) (0.025 mol) in methanol (250 ml) was hydrogenated at 50° C. overnight with palladium on carbon (10%; 2 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 7.7 g of N-[4-(4-piperidinyl)phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 10).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1[N:28]([CH3:29])[N:27]=[C:26]([C:30]#[N:31])[CH:25]=1>ClCCCl.ClC(Cl)C>[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:25]1[C:26]([C:30]#[N:31])=[N:27][N:28]([CH3:29])[C:24]=1[C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[F:16])=[O:9]
Reactant: Cn1nc(C#N)cc1-c1c(F)cccc1F
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: Cn1nc(C#N)c(C(=O)c2ccc(F)cc2Cl)c1-c1c(F)cccc1F
Temperature: 180 °C

Procedure:
To a mixture of aluminum chloride (0.18 g, 1.36 mmol) in 1,2-dichloroethane (2 mL) was added a mixture of 2-chloro-4-fluorobenzoyl chloride (0.26 g, 1.36 mmol) and 5-(2,6-difluorophenyl)-1-methyl-1H-pyrazole-3-carbonitrile (i.e. the product of Step B) (0.15 g, 0.68 mmol) in dichloroethane (1 mL). The reaction mixture was heated at 180° C. in a Biotage Initiator™ microwave apparatus for 30 minutes. The resulting mixture was poured directly onto a Varian Bond Elute SIC) column and eluted with methylene chloride followed by 30% ethyl acetate in hexanes to provide the title compound, a compound of the present invention, as a solid (0.07 g).