Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=4[CH3:33])[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3)CCCCC2)CC1

Procedure:
Example 92 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.46–7.43 (m, 3H), 7.26–7.22 (m, 2H), 7.10 (d, 1H, J=8.4 Hz), 7.06–7.01 (m, 2H), 6.74 (brs, 1H), 3.31 (dd, 2H, J=6.0, 12.0 Hz), 2.96 (d, 2H, J=11.6 Hz), 2.68 (m, 1H), 2.52 (m, 1H), 2.36–2.32 (m, 4H), 2.29 (s, 3H), 2.03–1.90 (m, 4H), 1.74–1.61 (m, 12H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 522.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1.N1C=CC=CC=1.BrN1C(=O)CCC1=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:18])[CH3:19])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[CH:23]=1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(=O)[nH]1)-c1cc(Br)ccc1CC2
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1

Procedure:
A mixture of N-(9-bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (1.09 g, 2.9 mmoles) and pyridine (0.28 ml, 3.5 mmoles) in dry benzene (100 ml) was stirred and heated to reflux under a nitrogen atmosphere. N-Bromosuccinimide (0.57 g, 3.2 mmoles) was added in a single portion, and the mixture was vigorously stirred and refluxed for 1.5 hours. After cooling, benzene and excess pyridine were removed under reduced pressure, leaving a light yellow residue which was then triturated with methanol:methylene chloride (1:1), filtered and dried to give N-(9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. (0.4 g, 37%) 1H NMR(DMSO-d6, 200 MHz) δ: 1.26(s, 9H, t-butyl); 7.58(d, J=9.0 Hz, 1H, Ar); 7.74(dd, J=8.7, 2.1 Hz, 1H, Ar); 7.98(d, J=8.8 Hz, 1H, Ar); 8.25(d, J=9.0 Hz, 1H, Ar); 9.92(d, J=2.0 Hz, 1H, Ar); 11.35(br s, 1H, NH); 12.35(br s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH:4][C:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1cc(OCCN2CCOCC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C=Cc1ccccc1)Nc1cc(OCCN2CCOCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
2-chloro-5-(2-morpholinoethoxy)aniline (1.9 g, 7.4 mmol, 1 eq.) was placed in a mixture of acetone (2.5 mL) and water (3.2 mL) in the presence of K2CO3 (2.1 g, 14.4 mmol, 2 eq.). Cinnamoyl chloride (1.2 g, 7.4 mmol, 1 eq.) was then added at 0° C. The reaction mixture was allowed to warm-up to room temperature, stirred for 2 hours and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford N-(2-chloro-5-(2-morpholinoethoxy)phenyl)cinnamamide (1.7 g, 60%).
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].C(OCC)(=O)C>C(Cl)Cl>[C:16]([NH:20][S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[CH:2][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Powdered isoquinoline-5-sulfonyl chloride hydrochloride (1.00 g, 3.79 mmol) is added in small portions to a stirred solution of tert-butylamine (2.00 mL, 18.9 mmol) in CH2Cl2 (10 mL) at 0° C. under nitrogen. The resultant mixture is allowed to stir at ambient temperature for 1 hour. Ethyl acetate (50 mL) is added to the mixture and the mixture is washed with saturated aqueous NaHCO3 (20 mL). The organic layer is dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 0-2% CH3OH in CH2Cl2) to give 857 mg (3.24 mmol, 86% yield) of the title compound as a white solid. ESIMS: m/z 265 (M+H)+. Analysis for C13H16N2O2S: calcd: C, 59.07; H, 6.10; N, 10.60; found: C, 59.21; H, 6.01; N, 10.67.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:17]1[C:22]([O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:10][CH:11]=2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1nccnc1Cl
Reactant: Oc1ccc(Nc2ncccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cccnc1Nc1ccc(Oc2nccnc2Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-fluoropyridin-2-ylamino)phenol (1.0 g, 0.048 mol) and 2,3-dichloropyrazine (1.01 g, 0.006 mol) in DMF (10 mL) was added potassium carbonate (1.32 g, 0.0096 mol). The reaction mixture was heated to 100° C. for overnight. After cooling to RT, the reaction mixture was concentrated under high vacuum and diluted with water to get precipitate. After stirring for 1 h, the solid was collected by filtration, washed with water and ether, dried to give desired product as tan solid. MS (ESI, pos. ion) m/z: 317.05 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[CH2:27][CH2:28][N:29]=[C:30]=[O:31].[H-].[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:27][CH2:28][NH:29][C:30]2=[O:31])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C=NCCCl
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cnc(CN(CCCCN2CCNC2=O)Cc2ncccc2C(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a cold (0° C.) solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-{3-isopropyl-pyridin-2-ylmethyl}-butane-1,4-diamine (163 mg, 0.48 mmol) in CH2Cl2 (5 mL) was added 2-chloroethylisocyanate (50 μL, 0.59 mmol) and the resultant mixture was stirred for 80 minutes then concentrated to provide a yellow oil. To a cold (0° C.) solution of the yellow oil in THF (5 mL) was added NaH (95% dry, 39 mg, 0.98 mmol). The cooling bath was removed and the resultant mixture was stirred at room temperature overnight. The mixture was treated with brine (10 mL) and extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 82 mg (41%) of COMPOUND 151 as a colorless oil. 1H NMR (CDCl3) δ 0.98 (d, 6H, J=6.9 Hz), 1.26-1.36 (m, 2H), 1.42-1.52 (m, 2H), 2.19 (s, 3H), 2.28 (s, 3H), 2.53 (dd, 2H, J=7.2, 7.2 Hz), 2.90-3.06 (m, 3H), 3.27-3.39 (m, 4H), 3.72 (s, 4H), 4.21 (br s, 1H), 7.—(dd, 1H, J=7.2, 4.8 Hz), 7.25 (s, 1H), 7.51 (dd, 1H, J=7.8, 1.5 Hz), 8.19 (s, 1H), 8.33 (dd, 1H, J=4.8, 1.5 Hz); 13C NMR (CDCl3) δ 18.27, 18.30, 23.51 (2 carbons), 24.36, 25.98, 27.46, 38.56, 43.75, 45.40, 54.47, 58.99, 59.59, 123.06, 132.12, 133.16, 133.61, 138.92, 144.24, 145.99, 146.57, 154.48, 156.29, 163.37; ES-MS m/z 410 (M+H). Anal. Calcd. For C24H35N5O.0.7H2O: C, 68.28; H, 8.69; N, 16.59. Found: C, 68.24; H, 8.52; N, 16.36.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25](Br)=[CH:24][C:23]=1[CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O>[CH2:14]([O:21][C:22]1[C:23]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:24][C:25]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c(C2CCCC2)cc1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1cc(C2CCCC2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 45.4 %

Procedure:
Diethyl malonate (1059 mg, 1.0 mL, 6.6 mmol) was added dropwise to a suspension of NaH (265 mg, 6.6 mmol) in DMSO (3.3 mL). The reaction mixture was warmed to 60° C. for 30 min. A solution of 1-benzyloxy-4-bromo-2-cyclopentyl-5-nitro-benzene (995 mg, 2.6 mmol) in DMSO (3 mL) was added dropwise and the reaction mixture heated at 100° C. for 2 h. The cooled solution was poured into ice water, and the aqueous layer extracted with dichloromethane (3×20 mL). The organic layer was dried down to an orange residue. Purification by silica gel chromatography (0-40% ethyl acetate/hexane) provided diethyl 2-(4-(benzyloxy)-5-cyclopentyl-2-nitrophenyl)malonate as a yellow oil (538 mg, 45% yield). LC/MS m/z 456.2 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH:7](C)[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].C(N(CC)CC)C>C1COCC1>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(N)C(O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NCC(O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A solution of 0.33 ml (0.975 g, 4.2 mmol) chloroacetyl chloride in 10 ml THF was cooled to 0° C. To this was added a solution of 0.8 g (3.98 mmol) 2-amino-1,1-diphenylpropanol and 0.6 ml (0.436 g, 4.31 mmol) triethylamine in 10 ml THF. The resulting solution was stirred at 0° C. for 2 hours before it was filtered and the residue washed with THF. The combined filtrate was concentration and the residue crystallized from ethyl acetate-hexane to afford 0.986 g (78%) of 2-(2-chloroacetylamino)-1,1-diphenylethanol, m.p. 178°-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9][CH2:10][C:11]([O:13]C)=O)[CH:5]=[N:6][CH:7]=1.[NH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9][CH2:10][C:11]([NH2:15])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)CSCc1cncc(Br)c1
Reactant: N
Product: NC(=O)CSCc1cncc(Br)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of methyl 2-((5-bromopyridin-3-yl)methylthio)acetate (1.2 g, 4.5 mmol) in NH3 (2.0 M in MeOH, 40 mL) was heated at 80° C. in a sealed vessel for 2 h. After this time, the reaction mixture was allowed to cool to room temperature and then the solvent was evaporated under reduced pressure. The resulting residue was recrystallized from EtOAc/hexanes to provide 2-((5-bromopyridin-3-yl)methylthio)acetamide (0.8 g, 72% yield). LCMS Method W: retention time 1.08 min; [M+1]=263.0.
Reaction SMILES: [Cl:1][C:2]1[C:12]([NH2:13])=[C:6]2[CH2:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]2=[C:4]([C:14]2[O:18][N:17]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:15]=2)[CH:3]=1.Br[CH2:26][CH2:27][CH2:28][C:29]#[N:30].C(N(CC)CC)C>CN(C)C=O>[NH2:13][C:12]1[C:6]2[CH2:7][C:8]([CH3:10])([CH3:11])[O:9][C:5]=2[C:4]([C:14]2[O:18][N:17]=[C:16]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH2:28][C:29]#[N:30])[CH2:23][CH2:24]3)[N:15]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: N#CCCCBr
Reactant: CC1(C)Cc2c(N)c(Cl)cc(-c3nc(C4CCNCC4)no3)c2O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)Cc2c(N)c(Cl)cc(-c3nc(C4CCN(CCCC#N)CC4)no3)c2O1
Temperature: 70 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
A mixture of intermediate 5 (4 g), 4-bromobutanenitrile (2.2 g) and triethylamine (4.2 ml) in dimethylformamide (70 ml) was stirred for 2 hours at 70° C. The mixture was cooled and the solvent evaporated. The residue was partitioned between CH2Cl2 and NH3 /H2O. The organic layer was separated, dried over MgSO4, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated. The residue was solidified in DIPE at 0° C., filtered and dried, yielding 1.89 g (38%) of 4-[5-(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)-1,2,4-oxadiazol-3-yl]-1-piperidinebutanenitrile (compound 3; mp. 151.4° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][N:4]=1)[CH3:2].[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][Br:11])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1cc(CO)ccn1
Solvent: ClCCl
Product: CCc1cc(CBr)ccn1
Temperature: 20 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
A solution of 0.3 g of 2-ethyl-4-(hydroxymethyl)pyridine in 3.5 ml of dichloromethane is added dropwise to a solution of 1.25 g of dibromotriphenylphosphorane in 4 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 0° C. The mixture is stirred to a temperature in the region of 20° C. over about 1 hour. The reaction medium is taken up in 50 ml of dichloromethane and then washed with 3×50 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 20 mm in diameter packed with 10 g of 20-40 μm conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate) (9/1) (v/v), at a flow rate of 8 ml/minute. The fractions between 80 and 120 ml are concentrated under reduced pressure. 0.062 g of 2-ethyl-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:22]=2[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[O:24])[CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[C:41]([C:38]1[CH:39]=[CH:40][C:21]([NH:20][C@@H:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)=[C:22]([CH:37]=1)[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:24])#[N:42]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H]2CCNC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of (R)-2-[1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (918 mg) in chloroform (5 mL). The mixture was stirred for 4 hours at ambient temperature and concentrated in vacuo. The residue was partitioned between chloroform and an aqueous saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give (R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide (610 mg) as amorphous powders.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
1-Methylpiperidin-4-ol (4 g, 34.7 mmol) was dissolved in CH2Cl2 (70 ml) at 0° C. followed by the addition of Et3N (10 ml, 69.4 mmol, 2 eq.) and methanesulfonyl chloride (2.7 ml, 34.7 mmol, 1 eq.). The mixture was stirred at RT for 3 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the crude product (6.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:42][CH2:41][N:40]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=5)[CH2:45][CH2:44]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: COc1cccc(N2CCN(C(=O)c3cccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)c3)CC2)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(3-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=622.01 (M+H+); retention time=0.97 minutes.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(C)(C)C.C([N:27]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[CH:40]=O)C(=O)C(C)(C)C)=O.[OH-].[Na+]>C(O)C>[C:16]1([C:15]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][OH:6])=[CH:13][CH:12]=3)=[N:27][C:34]3[C:39]([CH:40]=2)=[CH:38][CH:37]=[N:36][CH:35]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: CC(C)(C)C(=O)N(C=O)c1cnccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(-c2nc3cnccc3cc2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a partial suspension of 1-[4-({[t-butyl-(dimethyl)silyl]oxy}methyl)phenyl]-2-phenylethanone (1.03 gm, 3.0 mmol) and N-formyl-N-(4-formylpyridine-3-yl)-2,2-dimethylpropanamide (704 mg, 3.0 mmol) in absolute ethanol (8 mL) was added dropwise 5N NaOH (2.5 mL, 12.5 mmol). This mixture was heated at 70° C. over night. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and aqueous sodium carbonate. The organic layer was dried (Na2SO4), the solution filtered, and the solvent evaporated. This residue was chromatographed on a column of silica gel eluting with 40-100% ethyl acetate/hexane and then 0.5-1.5% methanol/ethyl acetate (sat'd with ammonia). The appropriate fractions were combined and the solvents evaporated. The residue was triturated with diethyl ether to give crystalline title compound. 1H-NMR (500 MHz, CDCl3): δ 9.60 (1H, s), 8.65 (1H, d, J=5.5 Hz), 8.17 (1H, s), 7.71 (1H, d, J=5.6 Hz), 7.48 (2H, d, J=6.5 Hz), 7.25-7.36 (7H, m), 4.72 (2H, s). m/e (m+1): 313.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CC(C)=O>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14]
Reactant: BrCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCBr
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a stirred solution of 1,6-dibromohexane (9) (16.5 g, 67.5 mmol) in acetone (100 mL) was added potassium phthalimide (5.00 g, 27.0 mmol). The resulting mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. MPLC purification of the residue (Hexanes:EtOAc/70:30) gave 10 as a colorless oily liquid (6.3 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.85-7.83 (m, 2H), 7.72-7.70 (m, 2H), 3.68 (t, J=7.2 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H), 1.89-1.82 (m, 2H), 1.73-1.66 (m, 2H), 1.52-1.45 (m, 2H), and 1.41-1.33 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[N:4][NH:5][C:6]=1[CH3:7].F[C:16]1[CH:31]=[CH:30][C:19]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:18][C:17]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:1][C:2]1[C:3]([N:8]([CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH3:14])=[N:4][N:5]([C:16]2[CH:31]=[CH:30][C:19]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[CH:18][C:17]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:6]=1[CH3:7]
Reactant: CCCN(CCC)c1n[nH]c(C)c1Cl
Reactant: CCOC(=O)c1cc(C(=O)OCc2ccccc2)ccc1F
Product: CCCN(CCC)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)OCC)c(C)c1Cl
Yield: 47.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 4-chloro-5-methyl-N,N-dipropyl-1H-pyrazol-3-amine (290 mg, 1.34 mmol) and 1-benzyl 3-ethyl 4-fluoroisophthalate (Intermediate 91B, 447 mg, 1.48 mmol) were converted to the title compound (315 mg, 47%). 1H NMR (CDCl3) δ 8.55 (d, J=2.0 Hz, 1H), 8.27 (dd, J=8.3, 2.1 Hz, 1H), 7.54-7.32 (m, 6H), 5.43 (s, 2H), 4.20 (q, J=7.0 Hz, 2H), 3.32-3.17 (m, 4H), 2.17 (s, 3H), 1.69-1.54 (m, 6H), 1.21 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 498.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:33])[C:27]([F:32])([F:31])[CH:28]([Cl:30])[F:29])[CH:20]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C>C(O)(=O)C.Br.C(Cl)Cl>[Cl:30][CH:28]([F:29])[C:27]([F:31])([F:32])[C:26]([NH:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4]([OH:34])=[O:3])=[O:33]
Reactant: CCCCCCCCCCCCC(Oc1cccc(NC(=O)C(F)(F)C(F)Cl)c1)C(=O)OCC
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCCCCCCCCC(Oc1cccc(NC(=O)C(F)(F)C(F)Cl)c1)C(=O)O
Temperature: 100 °C

Procedure:
An amount of 76.2 g (0.15 mol) of 2-[m-(3-chloro-2,2,3-trifluoropropionamido)-phenoxy]-myristic acid ethyl ester is dissolved in a mixture of 300 ml of acetic acid and 37.5 ml of 40% aqueous hydrobromic acid. The reaction mixture is heated for 15 min at 100° C., next poured out in 500 ml of methylene chloride, and finally extracted with methylene chloride. The extract is rinsed with water until neutral, dried over magnesium sulphate, and heated to remove any remaining solvent by evaporation.