Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[O:14])=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCc3ccccc3C2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 1,2,3,4-tetrahydroisoquinoline (6.6 mg, 0.050 mmol, 1.1 eq), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H18N2O2: 318.1368, found 318.1377.
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+].[C:14]([O:18][C:19](=[O:30])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[C:23]([CH3:29])[N:22]=1)([CH3:17])([CH3:16])[CH3:15].CCOC(C)=O>CN(C=O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:27][C:24]1[C:23]([CH3:29])=[N:22][C:21]([NH:20][C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:30])=[CH:26][CH:25]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)OCC
Reaction time: 0.75 h
Yield: 74 %

Procedure:
A solution of diethyl malonate (1.21 mL, 7.97 mmol) in DMF (2 mL) was added dropwise to a suspention of NaH (348 mg, 7.97 mmol, 55% in mineral oil) in DMF (5 mL) at 0 ° C. under argon. The reaction mixture was stirred for 45 min and a solution of (5-bromomethyl-6-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (2.0 g, 6.64 mmol) in DMF (5 mL) was added dropwise. The mixture was stirred over night (0° C.→20° C.). EtOAc was added and the solution was washed with water and brine, dried and concentrated under reduced pressure. Flash chromatography (heptane/EtOAc, 4:1) gave 2-(6tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.87 g, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c2cc(Br)ccc12
Reactant: Nc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-3-methylindazole (300 mg, 1.42 mmol) in DMF (6 mL) was added NaH (60% oil suspension) (91 mg, 2.27 mmol) at 0° C. The mixture was stirred at RT for 10 min before addition of 4-chloropyrimidin-2-amine (368 mg, 2.84 mmol). Stirring continued at 60° C. for 2 hr. After standing at RT overnight the reaction mixture was quenched by addition of water (10 mL). The mixture was extracted with EtOAc (2×15 mL). During the process of extraction solid formed was removed by suction filtration. The organic layer was washed with water (2×5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc-heptane (1:1) to give the title intermediate as a white solid: 1H NMR (250 MHz, DMSO) δ 2.53-2.64 (3H, m), 6.69-7.21 (3H, m), 7.43-7.62 (1H, m), 7.76-7.89 (1H, m), 8.18-8.38 (1H, m), 8.92-9.15 (1H, m); LC-MS: m/z=+303.95/305.65 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=[O:14].Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[Cl:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:14]
Reactant: O=C1C(=O)N(CCCl)c2ccccc21
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: O=C1Cc2ccccc2N1CCCl

Procedure:
1-(2-Chloroethyl)-1H-indole-2,3-dione [C.A. Reg no. 77218-99-6] was suspended in acetic acid and hydrogenated at 60 p.s.i., at room temperature, in the presence of 70% perchloric acid and 5% palladium on charcoal for 24 h. The clear solution was filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluent chloroform, to give 1-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one as a white solid, melting point 74° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.I[CH2:12]I.C[Li]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:12])[CH2:9][O:10]2)=[CH:4][CH:3]=1
Reactant: ICI
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Li]C
Solvent: C1CCOC1
Product: CC1(c2ccc(Br)cc2)CO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(4-Bromo-phenyl)-2-methyl-oxirane was synthesized according to the scheme shown in FIG. 5. 4′-Bromoacetophenone (0.60 g, 3 mmol) and diiodomethane (1.6 g, 6 mmol) were dissolved in 12 mL dry THF. Methyllithium (5.6 mL, 1.6M in ether) was added via syringe in 10 min at 0° C. The resulting clear yellow solution was stirred at 0° C. for 30 min and was then warmed up to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was quenched with ice. The resulting mixture was extracted with EtOAc, washed with brine and dried over Na2SO4. After removing the solvent, fairly pure product (0.62 g) was obtained as yellow solid, which was directly used for next step without further purification. ESI MS m/z 213, 215 (M+H).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]\[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.I[CH3:25]>CS(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:13]=[CH:14]\[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:25])[CH:19]=[CH:18]3)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: CI
Reactant: COc1cc(/C=C\c2ccc3[nH]ccc3c2)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(/C=C\c2ccc3c(ccn3C)c2)cc(OC)c1
Reaction time: 0.08 h

Procedure:
A suspension of KOH (2 mmol, 112 mg) in DMSO (5 mL) is stirred for 5 min. Then, compound 12a (1 mmol, 279 mg) and iodomethane (1.2 mmol, 75 μL) are added to the solution. The mixture is stirred at room temperature for 30 min, poured into water/ice, and extracted with ethyl acetate. The combined organic extracts are washed with brine (5 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure affords a residue, which is chromatographed on silica gel (20% ethyl acetate/light petroleum).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].C(Cl)Cl>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:6]1[CH:7]=[C:2]([CH3:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cn(CCCCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
5-methyl-2,4(1H,3H)-pyrimidinedione (commercially available, 0.55 g, 3.97 mmol) was dissolved in dry DMF (15 mL). K2CO3 (0.548 g, 3.97 mmol) was added and the mixture stirred at room temperature for 1 hour. 1-bromo-5-chloropentane (0.526 ml, 3.97 mmol) was then added and the suspension was stirred at room temperature for 4 h. The volume of solvent was reduced, then DCM was added and the organic layer was washed with water, the organic phase was evaporated and the crude purified by FC (DCM/MeOH 98/2-95/5) to afford 0.1 g of the title compound (y=11%).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=[O:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.C1CCN2C(=NCCC2)CC1.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1>C(#N)C>[CH3:19][C@H:14]1[O:15][C@@H:16]([CH3:18])[CH2:17][N:12]([C:9]2[C:8]([CH:20]=[O:21])=[CH:7][C:6]3[C:2]([N:33]4[CH:37]=[N:36][CH:35]=[N:34]4)=[N:3][O:4][C:5]=3[C:10]=2[F:11])[CH2:13]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@@H]1CN(c2c(C=O)cc3c(-n4cncn4)noc3c2F)C[C@H](C)O1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde (Intermediate 534, 0.2 g, 0.68 mmol) in acetonitrile was added DBU (0.19 mL, 1.28 mmol) followed by 1,2,4-triazole (0.053 g, 0.76 mmol), and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography using EtOAc in pet. ether to give title product.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37]1.CCOCC>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:36](=[O:42])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: O=C1CCC(=O)O1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(NCCCCNC(=O)CCC(=O)O)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 108.5 %

Procedure:
To a solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (25 mg, 0.05 mmol) in dichloromethane (4 mL) was added succinic anhydride (6 mg, 0.6 mmol). The resultant solution was stirred overnight and then ether was added. The precipitated solids were recovered by filtration to give 4-[(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]-4-oxobutanoic acid (31 mg, 99%) as a white solid. 1H NMR (CDCl3/CD3OD): δ 7.71 (m, 2 H), 7.47 (d, 2 H), 7.32 (m, 1 H), 6.97 (d, 2 H), 6.15 (d, 1 H), 6.04 (d, 1 H), 4.30 (m, 1 H), 3.88 (s, 3 H), 3.38–3.27 (m, 4 H), 2.62 (m, 2 H), 2.45 (m, 2 H), 2.10–2.00 (m, 2 H), 1.84–1.55 (m, 10 H); MS m/z 572 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[N:3]=1.[CH3:27]C(C)([O-])C.[K+].CI>CO>[CH3:27][N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]1[C:12]1[CH:13]=[CH:14][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:25][CH:26]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOP(=O)(Cc1ccc(-c2nc(O)c3ccccc3n2)cc1)OCC
Agent: [K+]
Solvent: CO
Solvent: CI
Product: CCOP(=O)(Cc1ccc(-c2nc3ccccc3c(=O)n2C)cc1)OCC
Temperature: 40 °C

Procedure:
A 5.9 g quantity of diethyl 4-(4-hydroxyquinazolin-2-yl)benzylphosphonate, 1.8 g of potassium tert-butoxide and 2.3 g of methyl iodide were suspended in 100 ml of anhydrous methanol and stirred with heating at 40° C. for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride: methanol=100:1) and the crude crystals thus obtained were recrystallized from methylene chloride-n-hexane to provide 3.0 g of the title compound as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]([NH2:22])=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1>CN(C=O)C.P(Cl)(Cl)(Cl)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]#[N:22])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:17]=1
Reactant: NC(=O)C=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 10.5 %

Procedure:
A solution of 3-[5-hydroxy-2-(4-hydroxyphenyl)-benzofuran-7-yl]-acrylamide 61 (0.07 g, 0.24 mmol) in DMF (5 mL) and phosphorous oxychloride (0.11 mL) was heated at 65° C. for 2 hours. Then ice was added to the reaction mixture and the product extracted into ethyl acetate. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The crude product was submitted for reverse phase prep HPLC. The product was isolated to give 0.007 g of 3-[5-hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-yl]-acrylonitrile 64: 1H NMR (DMSO-d6) δ 9.90 (s, 1 H), 9.48 (s, 1 H), 7.82 (d, 2 H, J=8.6 Hz), 7.79 (d, 1 H, J=16.7 Hz), 7.13 (s, 1 H), 7.03 (d, 1 H, J=2.3 Hz), 6.92 (d, 1 H, J=2.4 Hz), 6.88 (d, 2 H, J=8.7 Hz), 6.71 (d, 1 H, J=16.8 Hz); MS 276 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:29]([F:34])([F:35])[C:30]([F:33])([F:31])[F:32])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCn2c(C(F)(F)C(F)(F)F)nc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(Cc1ccc(OCCn2c(C(F)(F)C(F)(F)F)nc3ccccc32)cc1)C(=O)O

Procedure:
The ethyl ester (200 mg, 0.4 mmol) from Step B was hydrolysed using NaOH (64 mg, 1.6 mmol) in ethanol (10 ml) and water (5 ml) by the procedure described in Step C of Example 1 (141 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH3:16])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[OH-].[Na+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH2:12][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)([OH:11])[C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CCCC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 20.5 g (0.077 mol) of 2-(4-chlorophenylethyl)-2-(1,1-dimethylbutyl)-oxirane, 5.3 g (0.077 mol) of 1,2,4-triazole, 1.0 g (0.025 mol) of sodium hydroxide, 1 ml of water and a spatula tipful of α,α'-azoisoutyronitrile in 50 ml of N-methylpyrrolidone is heated at 120° C. for 5 hours. After this, the solution is cooled to room temperature and concentrated by stripping off the solvent under reduced pressure, the remaining residue is dissolved in acetic acid and washed three times with water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel; dichloromethane:ethyl acetate=4:1). In this manner 16.0 g (61.9% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl-methyl)-3-heptanol are obtained in the form of a yellow oil.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.Cl.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([NH:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)=[O:15])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)[C@@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1.0 g (3.22 mmol) Boc-D-Phe(4-NO2)—OH (Iris Biotech) and 0.84 g (3.22 mmol) H-Phe(4-NO2)—OMe.HCl (Aldrich) were suspended in 25 ml of DMF and stirred on the ice bath. After addition of 1.66 g (3.22 mmol) of PyBOP and 1.67 ml (9.66 mmol) of DIPEA (pH 7-8), the mixture was stirred at 0° C. for 2.5 h. The solvent was removed in vacuo and the yellow oil was taken up in 5% KHSO4 soln./EtOAc. The organic phase was washed 3× with 5% KHSO4 soln., 1× with sat. NaCl soln., 3× with sat. NaHCO3 soln. and 3× with sat. NaCl soln. The organic phase was dried with MgSO4, filtered, and the solvent was removed in vacuo.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O1CCOCC1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCCCC3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and piperidine (0.14 mL, 1.42 mmol) in THF (20 mL) was stirred at room temperature for 4 hrs. 1,4-Dioxane (20 mL) was added and the mixture was refluxed for 18 hrs. After cooled to room temperature, the solvents were removed under vacuum. The residue was partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous phase extracted with CH2Cl2 (1×). The combined organic extracts were dried (Na2SO4) and the solvent removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2) gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(1-piperidinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (147 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26](O)=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:41][S:42]([NH2:45])(=[O:44])=[O:43]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 30 %

Procedure:
A mixture of 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol), 4-dimethylaminopyridine (46 mg, 0.38 mmol), methane sulfonamide (47.5 mg, 0.50 mmol) in dichloromethane (4 mL) was heated for at 65° C. for 12 hours. Removal of the solvent to afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (35.8 mg, 30%) as a light yellow solid: LC/MS m/e calcd for C23H28ClN3O4S (M+H)+: 479.1, observed: 478.2.
Reaction SMILES: [NH2:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(OCC)(=O)C>[CH2:18]([O:17][C:15]([NH:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10]1)=[O:16])[CH3:19]
Reactant: NC1(C(=O)O)Cc2ccccc2C1
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 15 h
Yield: 44 %

Procedure:
To a stirred refluxing mixture of 2-aminoindan-2-carboxylic acid (1.90 g, 10.7 mmol, Pinder, R. M.; Butcher, B. H.; Buxton, D. A.; and Howells, O. J. J. Med. Chem. 1971, 14, 892) in ethyl acetate (200 ml) ws added ethyl chloroformate (1.16 g, 10.7 mmol). After 15 hours, the mixture was cooled, filtered, evaporated, and vacuum dried to give 1.17 g (44%) of a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[C:7]=1[OH:8])[CH3:2].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][N:6]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)[C:7]=1[O:8][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCc1cnn(-c2cc(C#N)ccn2)c1O
Reactant: OCc1ccc(F)cc1
Product: CCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(4-ethyl-5-hydroxypyrazol-1-yl)pyridine-4-carbonitrile and 4-fluorobenzyl alcohol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C18H15FN4O, 323. Found, 323.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1.[CH3:17][O:18]C1C2C(=CC=CC=2)C(O)=CC=1>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[C:9]([O:18][CH3:17])[CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1
Reactant: COc1ccc(O)c2ccccc12
Reactant: O=c1cc(O)c2ccc3ccccc3c2o1
Product: COc1cc2c(O)cc(=O)oc2c2ccccc12
Yield: 18 %

Procedure:
The procedure was identical to that used for the preparation of 10a: 18% yield (starting with 4-methoxy-1-naphthol 9e); 1H NMR (DMSO) δ 4.02 (3H, s, OCH3-6), 5.69 (1H, s, H-3), 7.12 (1H, s, H-5), 7.74 (2H, m, H-8, 9), 8.23 (1H, m, H-7), 8.33 (1H, m, H-10).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:14][CH2:13]1
Reactant: OCCCBr
Reactant: Fc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1.1 mmol) and 3-bromo-1-propanol (0.185 ml, 2.0 mmol). Yield: 0.16 g (29%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 259-261° C. MS m/z (relative intensity, 70 eV) 305 (M+, 4), 261 (16), 260 (bp), 217 (5), 177 (9).