Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH:11]=O)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[CH:11][C:9]1[NH:10][C:6]2[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=2[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Yield: 31.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 41 with 4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-phenyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (22 mg, 31.9%) as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].O.Cl>N1C=CC=CC=1>[C:1]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:15]2([CH:12]3[CH2:13][CH2:14][CH:9]([CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:22]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCCC1CCC(C2(c3cccc(O)c3)CCCCC2)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCC1CCC(C2(c3cccc(OC(=O)CC)c3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
Under a nitrogen atmosphere, 1.7 g of propanoyl chloride was added to 5.0 g of 3-((4-propylcyclohexyl)cyclohexyl)phenol (3) dissolved in 10 mL of pyridine under cooling with iced water, and after completing dropwise addition, the mixture was stirred at ambient temperature for 2 hours. The resulting solution was added to 20 mL of 3N hydrochloric acid. The aqueous layer was extracted with diethyl ether, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 6.52 g of 3-((4-propylcyclohexyl)cyclohexyl)phenyl propanoate (4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]([F:19])[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:18]=1
Reactant: COc1ccc(-c2cc3cc(F)cc(F)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(-c2cc3cc(F)cc(F)c3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Compound 86 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried, and the product was purified by column chromatography (eluent 25% EtOAc/hex) to give a solid (0.12 g, 13%): Mp=152-154° C.; 1H NMR (DMSO-d6) δ 10.01 (br s, 1 H), 7.77 (d, 2 H, J=8.9 Hz), 7.32-7.25 (m, 3 H), 6.91 (d, 2 H, J=8.9 Hz); MS 245 [M−H]−
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:20])[NH:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].[F:27][C:28]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C)(=O)=O.O>C1COCC1>[F:27][C:28]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:16]1[CH:17]=[CH:18][N:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[C:15]1=[O:20]
Reactant: CS(=O)(=O)OCCCCOc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccn(CCCCOc3cc(F)c(F)cc3F)c2=O)CC1
Reaction time: 0.17 h

Procedure:
A mixture of 3-(4-tert-butoxycarbonyl-1-piperazinyl)-2(1H)-pyrazinone (1.20 g, 4.30 mmol; from Example 48, Step 1) and t-BuOK (730 mg, 6.50 mmol) in THF (10 mL) was stirred for 10 min, and then added to a solution of methanesulfonic acid 4-(2,4,5-trifluoro-phenoxy)butyl ester (1.23 g, 4.3 nmol; from Step 2) in THF (50 mL). After being stirred at room temperature for 1 day, HPLC showed about 30% conversion. After 3 days, the reaction was worked up: water was added, THF was evaporated off and the aqueous mixture was extracted twice with EtOAc, dried and concentrated to yield 2.21 g of the crude product as a yellow oil. HPLC analysis showed a 5/1 ratio between the title product and the isomeric O-alkylated product.* Purification by chromatography on silica gel using EtOAc/hexane (1/2 to 1/1) as eluent gave 870 mg (42%) of the title product as a colorless oil. HPLC purity: 95%. MS m/z 483 (M+H)+. *Assignments were based on NMR analysis.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]([NH:18][C:19]1[C:28]2[C:23](=[C:24]([C:37](=[O:39])[NH2:38])[CH:25]=[C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:22]=[CH:21][N:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)C)(C)(C)C.C1COCC1.Cl>O1CCOCC1>[CH2:30]([O:29][C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([C:37]([NH2:38])=[O:39])[CH:25]=1)[N:22]=[CH:21][N:20]=[C:19]2[NH:18][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:9][NH:7][CH3:6])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(CC(Nc1ncnc2c(C(N)=O)cc(OCc3ccccc3)cc12)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNCC(Nc1ncnc2c(C(N)=O)cc(OCc3ccccc3)cc12)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 97 %

Procedure:
A scintillation vial equipped with a stir bar was charged with [2-(6-benzyloxy-8-carbamoyl-quinazolin-4-ylamino)-2-(3-chloro-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (20 mg, 0.035 mmol) and THF, (3 mL). Then, 4 M HCl in dioxane, (3 mL) was added at RT and the mixture was stirred overnight. After 18 h, a white precipitate had formed and LCMS indicated consumption of SM. The mixture was diluted with Et2O (30 mL) and the precipitate was filtered through a filter paper and washed with Et2O, (30 mL). The solid was dried under vacuum. Amount obtained: 15 mg, 0.034 mmol, 97% yield. LCMS (ESI) 462 (M+H).
Reaction SMILES: [Mg].Br[CH2:3][CH:4]1[CH2:6][CH2:5]1.[Br:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[C:11](N(OC)C)=[O:12]>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([C:11](=[O:12])[CH2:6][CH2:5][CH:4]=[CH2:3])[CH:17]=[CH:18][CH:19]=1
Reactant: CON(C)C(=O)c1cccc(Br)c1
Reactant: BrCC1CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(=O)c1cccc(Br)c1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A mixture of magnesium (0.48 g, 20.29 mmol) in THF was treated dropwise with (bromomethyl)cyclopropane (2.49 g, 18.45 mmol) in THF, heated at reflux temperature for 1 hour, poured into a cold (0° C.) mixture of 3-bromo-N-methoxy-N-methylbenzamide (2.5 g, 10.24 mmol) and THF, allowed to come to room temperature, stirred for 10 min, quenched with aqueous NH4Cl and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue on silica gel (ISCO) using hexanes/EtOAc 10/1 as the eluting solvents gave a clear oil (2.4 g, 54% yield), MS m/e (M−H)+ 239; 1H NMR (400 MHz, DMSO-d6) 2.3 (m, 2H), 3.1 (t, J=7.19 Hz, 2H), 5.02 (m, 2H), 5.8 (m, 1H), 7.47 (t, J=7.93 Hz, 2H), 7.77 (dd, J=7.08, 2.2 Hz), 7.94 (dd, J=7.81, 1.58 Hz), 8.04 (t, J=1.83 Hz, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH:27]([CH3:29])[CH3:28])=[C:20](C(OCC)=O)[N:21]=4)=[C:13]([NH:30][CH:31]([CH3:33])[CH3:32])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C[Mg]Br>O1CCCC1>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH:27]([CH3:29])[CH3:28])=[C:20]([C:19]([OH:18])([CH3:27])[CH3:20])[N:21]=4)=[C:13]([NH:30][CH:31]([CH3:33])[CH3:32])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)oc1C(C)C
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nc(C(C)(C)O)c(C(C)C)o1
Temperature: 25 °C

Procedure:
To a solution ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate (29) (150 mg, 0.34 mmol) in dry Tetrahydrofuran (10 mL) was added methyl magnesium bromide (2.132 mmol) (3.0 M in diethyl ether) at −78° C. Reaction mixture was allowed to warm up to 25° C. over 2 h. The reaction mixture was cooled to 0° C. and quenched by the addition of saturated aqueous NH4Cl solution dropwise. Extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated to get the crude product, which was purified by flash column using ethyl acetate/hexanes as eluent to furnish 2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazol-4-yl)propan-2-ol. 1H NMR: 400 MHz, DMSO-d6: δ 1.26-1.27 (m, 13H), 1.48 (s, 6H), 3.63-3.71 (m, 2H), 5.06 (s, 1H), 6.13 (s, 1H), 7.57 (dd, J=2.00, 8.80 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.28 (d, J=6.80 Hz, 1H), 8.51 (s, 1H), 8.75 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.28 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.842 min; LCMS (ES-API), m/z 452.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 7.608 min; Purity: 97.8%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=1.C(N(C(C)C)CC)(C)C.[Br:39][CH2:40][C:41](Cl)=[O:42]>O1CCCC1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=[C:2]3[NH:1][C:41](=[O:42])[CH2:40][Br:39])[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CBr
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1nc(NC(=O)CBr)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of Example 64A (500 mg, 1.28 mmol) in tetrahydrofuran (12 mL) was added diisopropylethylamine (0.22 mL, 1.28 mmol). The reaction mixture was stirred at ambient temperature for about 15 minutes then 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred at ambient temperature for about 16 hours then additional 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred for an additional 15 minutes then concentrated under reduced pressure to provide the title compound as a brown solid. This material was used without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:20](/[CH:38]=[CH:39]/[CH2:40][O:41][CH3:42])=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[CH3:42][O:41][CH2:40]/[CH:39]=[CH:38]/[C:20]1[C:21]([NH:23][CH2:24][CH:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)=[CH:22][C:17]([NH:16][C:13]2[N:14]=[CH:15][C:10]([C:8]#[N:9])=[N:11][CH:12]=2)=[N:18][CH:19]=1
Reactant: COC/C=C/c1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC/C=C/c1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCNCC1
Reaction time: 0.33 h
Yield: 51.4 %

Procedure:
TFA (0.2 mL) was added at room temperature to a solution of (E)-tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-methoxyprop-1-enyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (0.020 g, 0.041 mmol) in dichloromethane (2 mL). The reaction mixture was stirred for 20 min. Solvent was removed in vacuo and the mixture was purified by ion exchange on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude product was purified by preparative thin layer chromatography, eluting with methanol/dichloromethane/NH3 (9%/90%/1%) to give the title compound as a yellow solid (0.008 g, 51%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][CH2:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:6])[CH3:5])[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Product: CC(O)(CCN1CCOCC1)c1ccccc1-c1ccccc1

Procedure:
2.6 g of 1-chloro-3-p-biphenylyl-butan-3-ol are boiled with 30 ml of morpholine for 1.5 hours and the mixture is cooled and worked up in the customary manner to give 1-morpholino-3-p-biphenylyl-butan-3-ol, m.p. 116° -118°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:8][CH:7]=1
Reactant: Nc1ccc(OCCCCl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCCCCl)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
To a cooled (0° C.), stirred solution of 1-chloro-3-(4-aminophenoxy)propane (680 mg, 3.66 mmol) and pyridine (319 mg, 4.03 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (461 mg, 4.03 mmol). After 18 hours, the mixture was washed with 1N HCl and brine, dried (MgSO4), and concentrated to give 865 mg (90%) of product as an off-white solid m.p. 120°-122° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>CO.[OH-].[Na+]>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([OH:24])=[O:3])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (348 mg, 1 mmol) in methanol (25 ml), 10 N NaOH (10 ml) was added. The reaction mixture was stirred at room temperature for 48 hours. At the end, the reaction mixture was concentrated and carefully neutralized with dilute HCl. The residue obtained was extracted with chloroform, washed well with water, dried and concentrated. The product obtained was purified by silica-gel column chromatography by eluting with ethyl acetate: methanol (95:5) to afford 2-(4-methoxy-benzenesulfonyl)3-phenyl-propionic acid as a colorless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH3:20])[O:14][N:13]=1.[C:21](OC)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C1COCC1>[CH3:11][C:12]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH2:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:14][N:13]=1
Reactant: COC(=O)c1ccccc1
Reactant: Cc1noc(C)c1C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O

Procedure:
A solution of lithium bis(trimethylsilyl)amide (10 g, 60 mmol, 3 eq) in toluene (60 mL) was added drop wise during 15 min to a solution of 3,5-dimethylisoxazole-4-carboxylic acid (2.82 g, 20 mmol) and methyl benzoate (2.5 mL, 1 eq) in THF (20 mL) at a temperature not exceeding 40 deg. After 1 h the reaction was quenched by the addition of a water solution of 0.1M HCl (0.3 L) leaving the water phase still basic and the phases was separated. The water phase was washed with toluene and then reduced in volume by evaporation until most of the residual organic solvents were removed. 1M HCl was added dropwise with stirring. The resulting crystals were filtered and dried in vacuum to yield the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.45 (s, 3H) 4.75 (s, 2H) 7.43-7.51 (m, 2H) 7.55-7.63 (m, 1H) 7.86-8.12 (m, 2H)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[F:18][C:19]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:20]=1[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([C:27]([C:24]2[CH:23]=[C:22]([CH2:21][C:20]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:19]=3[F:18])[O:26][N:25]=2)=[O:28])[CH2:14][CH2:13]1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2cc(F)ccc2F)on1)N1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.4 %

Procedure:
The mixture of 5-chloro-3-(piperidin-4-yl)-1H-indole hydrochloride (0.070 g; 0.258 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.062 g; 0.258 mmol), HART (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.098 g: 0.258 mmol) and N,N-diisopropylethylamine (0.113 mL; 0.634 mmol) in DMF (3 mL) was stirred for 72 hours at room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) to give 0.0428 g (36%) of (4-(5-chloro-1H-indol-3-yl)piperidin-1-yl)(5-(2,5-difluorobenzyl)isoxazol-3-yl)methanone as a white solid.
Reaction SMILES: [CH2:1]([NH:8]CCC1C2C(=CC=C(F)C=2OC)N(C)C=1)C1C=CC=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:28]([O:38][CH3:39])=[C:29]2[C:33]=1[N:32]([CH3:34])[CH:31]=[C:30]2[CH2:35][CH2:36]O>>[F:24][C:25]1[CH:26]=[C:27]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:28]([O:38][CH3:39])=[C:29]2[C:33]=1[N:32]([CH3:34])[CH:31]=[C:30]2[CH2:35][CH2:36][NH:8][CH3:1]
Reactant: COc1c(CCc2ccccc2)cc(F)c2c1c(CCO)cn2C
Reactant: COc1c(F)ccc2c1c(CCNCc1ccccc1)cn2C
Product: CNCCc1cn(C)c2c(F)cc(CCc3ccccc3)c(OC)c12
Yield: 62 %

Procedure:
Following the procedure (step 6, scheme 17) used to prepare compound 17-7, compound 23-3 was used as starting material, giving compound 23-4 in 62% yield as a colorless oil, which was converted to the hydrochloride salt. 1H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt): 8.62 (br, 2H), 7.18-7.31 (m, 5H), 7.15 (s, 1H), 6.87 (d, J=13.4 Hz, 1H), 3.85 (d, J=1.7 Hz, 3H), 3.69 (s, 3H), 3.05-3.13 (m, 4H), 2.88 (br, 4H), 2.57 (s, 3H). LRMS: calc 340.2 found 341.1[MH]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=[O:30])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[ClH:31].[CH2:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:30])=[CH:32][CH:33]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 72.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 0.93 ml (4.96 mmol) of 4-n-butylbenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minute. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.10 g of the desired compound (free base) (80.7%, colorless wax), mp: 46.0°-47.0° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([C:10]([NH:12][C:13]3[CH:17]=[C:16]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[O:19])[N:15]([CH3:27])[CH:14]=3)=[O:11])=[CH:8][C:7]([NH:28][C:29]([C:31]3[N:32]([CH3:39])[CH:33]=[C:34]([N+:36]([O-])=O)[CH:35]=3)=[O:30])=[CH:6]2)[CH2:3][CH2:2]1.[CH2:40]([OH:42])C>[Pd]>[CH:1]1([CH2:4][N:5]2[C:9]([C:10]([NH:12][C:13]3[CH:17]=[C:16]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[O:19])[N:15]([CH3:27])[CH:14]=3)=[O:11])=[CH:8][C:7]([NH:28][C:29]([C:31]3[N:32]([CH3:39])[CH:33]=[C:34]([NH:36][CH:40]=[O:42])[CH:35]=3)=[O:30])=[CH:6]2)[CH2:3][CH2:2]1
Reactant: CN(C)CCCNC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2CC2CC2)cn1C
Reactant: CCO
Agent: [Pd]
Product: CN(C)CCCNC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc(NC=O)cn3C)cn2CC2CC2)cn1C
Reaction time: 3 h
Yield: 42 %

Procedure:
N-[1-(Cyclopropylmethyl)-5-({[5-({[3-(dimethylamino)propyl]amino}-carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]-1-methyl-4-nitro-1H-pyrrole-2-carboxamide (100 mg, 0.186 mmol; see step (iv) above) was dissolved in ethanol (25 mL) to which Pd/C-10% (78 mg) was added at 0° C. under N2 with stirring. The reaction mixture was hydrogenated for 3 h at room temperature and atmospheric pressure. The catalyst was removed over Kieselguhr. Ethyl formate was added to the ethanolic solution of the amine and the reaction mixture was heated under reflux for 48 h. Ethanol and excess ethyl formate were removed under reduced pressure and the crude product was purified by HPLC. The product was obtained as pale yellow solid (52 mg, 42% yield) after freeze drying with no distinct melting point.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:22]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:40].[NH2:41][CH2:42][CH2:43][N:44]([CH3:52])[C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:41][CH2:42][CH2:43][N:44]([CH3:52])[C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:23])[CH:33]=[CH:34][C:35]=3[CH3:36])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:40]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(NCCN(C)C(=O)OC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(2-phenylethyl)benzamide (156 mg, 0.28 mmol) in dichloromethane (11 mL) was added 1,1-dimethylethyl (2-aminoethyl)methylcarbamate (75 μL, 0.42 mmol) and triethylamine (78.7 μL, 0.56 mmol). The reaction mixture was stirred at room temperature for 16 hours then applied to the flash chromatograph to afford the titled compound 147 mg (79%).