Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]3[C:19]([N:20]=2)=[CH:18][CH:17]=[C:16]([C:21]2([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:23][CH2:22]2)[N:15]=3)=[C:8]([F:30])[CH:7]=1)=O.CI.[CH:35]([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[F:30][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[C:12]1[S:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[C:16]([C:21]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22]1)[N:15]=2)[N:5]([CH3:3])[CH3:35]
Reactant: O=C(Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(F)(F)F
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CI
Product: CN(C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,2,2-Trifluoro-N-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)acetamide (80 mg, 0.175 mmol) was dissolved in THF (1.7 mL) before methyl iodide (13 μl, 0.210 mmol) and lithium diisopropylamide (175 μl, 0.350 mmol) were added and stirred at 0° C. for 30 min. The reaction mixture was diluted with 75 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after flash chromatography. MS (ESI) m/z: Calculated: 389.1; Observed: 390.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][CH2:12][CH2:13][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[CH2:15][C:16]([CH3:18])=[CH2:17])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[CH2:12][CH2:13][C:14]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:19][C:34]2=[O:36])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)CC(O)(CCNC(C)(C)c1ccc(Br)cc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(Br)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-(4-bromophenyl)propan-2-ylamino)-5-methyl-3-phenylhex-5-en-3-ol (60 mg, 149.3 μmol) in CH2Cl2 (15 mL) was added Et3N (75.5 mg, 746.3 μmol). The mixture was cooled to 0° C. and triphosgene (44.3 mg, 149.3 μmol) was added under nitrogen. The solution was stirred at 0° C. for 1 h. The reaction was quenched with water (15 mL) and extracted with CH2Cl2 (15 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrate under vacuum. The residue was purified by preparative TLC (petroleum ether: EtOAc =3:1) followed by preparative HPLC to afford 3-(2-(4-bromophenyl)propan-2-yl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one. 1H NMR δ 7.45-7.26 (m, 7H), 6.78-6.73 (d, 2H), 4.81 (s, 1H), 4.59 (s, 1H), 3.33-3.27 (m, 1H), 3.05-2.95 (m, 1H), 2.60-2.44 (m, 3H), 2.28-2.18 (m, 1H), 1.65 (s, 3H), 1.59 (s, 3H), 1.41 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@@H:32]([C:34]([OH:36])=O)[CH3:33])[N:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:64]([O:71][C:72](=[O:78])[C@@H:73]1[CH2:77][CH2:76][CH2:75][NH:74]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:43])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C@H:32]([CH3:33])[C:34]([N:74]3[CH2:75][CH2:76][CH2:77][C@H:73]3[C:72]([O:71][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:78])=[O:36])[N:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)O)n(-c3ccccc3)n2)CC1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.000 g 4-((S)-4-tert-Butoxycarbonyl-2-{[5-((R)-1-carboxy-ethoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 15 ml DMF were added 0.509 g HOBt, 1.4 ml DIPEA and 0.804 g L-proline benzyl ester hydrochloride at RT. Then 0.637 g EDC were added portionwise and the suspension stirred at RT for 12 h. The reaction mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[CH3:12]OS([O-])(=O)=O.C[S+](C)C.[OH-].[Na+]>C(Cl)Cl>[O:10]1[C:7]2([CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)[CH2:12]1
Reactant: COS(=O)(=O)[O-]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C1COC2(CCC3(CC2)CO3)O1
Yield: 93 %

Procedure:
12.00 g (76.83 mmol, 1.0 equiv.) of 1,4 Cyclohexanedione ethylene ketal was added to 120 ml methylene chloride along with 18.8 g (99.88 mmol, 1.3 equiv.) of trimethyl sulfonium methyl sulfate. 40 ml 50% sodium hydroxide (NaOH) was added last and the reaction was refluxed for 24 hours. The methylene chloride was removed, 200 ml ether was added and the ether layer was washed with water. The organic layer was dried with sodium sulfate and concentrated down, leaving a yellow oil, 1,7,10-trioxa-dispiro[2.2.4.2]dodecane. (12.13 g, 93% yield). No further purification was necessary.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCC(=O)Cl
Reactant: c1ccc(C2CCNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath and pentanoyl chloride (301 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(3-phenylpyrrolidin-1-yl)pentan-1-one are collected and the solvent is removed in vacuo to give 378 mg of colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)C1CCNC(Cc2ccccc2F)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccccc2F)C1
Reaction time: 1.5 h
Yield: 111.6 %

Procedure:
To a solution of methyl 2-(2-fluorobenzyl)piperidine-4-carboxylate (4.49 g, 17.85 mmol) and DIPEA (9.35 mL, 53.55 mmol) in DCM (100 mL) was added methyl chloroformate (1.798 mL, 23.21 mmol) in DCM (50 mL). The reaction mixture was stirred for 1.5 h. The organic phase was washed with satd NaHCO3. The phases were separated and the organic phase dried using a phase separator to yield crude dimethyl 2-(2-fluorobenzyl)piperidine-1,4-dicarboxylate (6.16 g, 112%). MS m/z 310 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][O:29][CH3:30])=[CH:23][CH:22]=2)[CH:12]([CH2:13][CH:14]=[CH2:15])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][O:18][CH3:19])=[CH:9][CH:10]=2)[O:5][C:4]1=[O:20])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:3]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][O:29][CH3:30])=[CH:23][CH:22]=1)([CH:12]([C:11]1[CH:10]=[CH:9][C:8]([O:16][CH2:17][O:18][CH3:19])=[CH:7][C:6]=1[OH:5])[CH2:13][CH:14]=[CH2:15])[CH2:4][OH:20])[CH3:2]
Reactant: C=CCC1c2ccc(OCOC)cc2OC(=O)C1(CC)c1ccc(OCOC)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC(c1ccc(OCOC)cc1O)C(CC)(CO)c1ccc(OCOC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
A solution of (3RS,4RS)-3-ethyl-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)chroman-2-one (9.4 g) in dry tetrahydrofuran (50 ml) was added dropwise to an ice-cold suspension of lithium aluminum hydride (2.2 g) in dry tetrahydrofuran (50 ml) over 25 minutes under nitrogen atmosphere, and the reaction mixture was then stirred on ice for 1 hour and 15 minutes. Ethyl acetate (30 ml) and saturated aqueous ammonium chloride (30 ml) were added to stop the reaction, followed by stirring for 1 hour at room temperature. The reaction mixture was filtered through cellite and the resulting filtrate was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure to give (2RS,3RS)-2-ethyl-3-(2-hydroxy-4-methoxymethoxyphenyl)-2-(4-methoxymethoxyphenyl)-5-hexenol (9.5 g, quantitative) as a crude product, which was then used for the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:1]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Nc1ccccc1

Procedure:
Aniline, ethyl 2-bromoisobutyrate and potassium carbonate were reacted in DMF at 90° C. to obtain ethyl 2-anilino-2-methylpropanoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[N:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=1)[C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22]([C:25]4[CH:26]=[N:27][C:28]([O:33][CH3:34])=[C:29]([C:30]#[N:31])[CH:32]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Reactant: COc1ncc(Br)cc1C#N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C#N
Temperature: 110 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
To a glass vial was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 7) (630 mg, 1.97 mmol), 5-bromo-2-methoxynicotinonitrile (419 mg, 1.97 mmol), cesium carbonate (1281.0 mg, 3.93 mmol), tris(dibenzylideneacetone)dipalladium(0) (180 mg, 0.20 mmol), X-Phos (319 mg, 0.67 mmol) and anhydrous dioxane (10.0 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 1 h at 110° C. and then stirred at room temperature for 18 h. Diluted with CH2Cl2 (100 mL) and water (30 mL) and filtered through a celite pad. The organic phase was separated by filtering through a phase separation tube and concentrated in vacuo. Purified by flash chromatography on silica gel with heptanes/EtOAc, 80/20 to 0/100 to give (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester as a brown gum (350 mg, 39% yield) LCMS: [M+H]+=453.6, Rt(7)=1.29 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:23]2)=[N:19][CH:20]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:24]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:23]2)=[N:19][CH:20]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cn2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
After a mixture of ethyl 3-[1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]propionate (930 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (830 mg, yield: 94%). This was recrystallized from acetone-hexane. Melting point: 175–176° C.
Reaction SMILES: O1CCCC1.[CH3:6][CH:7]1[NH:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:13]([O-:17])(=[O:16])(=[O:15])=[O:14].CS[C:20]1[S:24][CH:23]=[CH:22][S+:21]=1>C(OCC)C>[Cl:13]([O-:17])(=[O:16])(=[O:15])=[O:14].[S:21]1[CH:22]=[CH:23][S:24][C:20]1=[N+:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH3:6]
Reactant: CSc1scc[s+]1
Reactant: CC1CCCCN1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CCCC[N+]1=c1sccs1
Temperature: 25 °C

Procedure:
To 50 ml of tetrahydrofuran, 1.1 g of α-pipecoline was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and then 50 ml of ethyl ether was added thereto, whereby 1.5 g (yield: 80%) of 1-(1,3-dithiol-2-ylidene)-2-methylpiperidinium perchlorate (Compound No. 51) was obtained as yellow oily precipitates.
Reaction SMILES: Cl[C:2]1[N:17]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH2:21][CH2:20]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([N:22]5[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]5)[CH:26]=4)[N:17]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(F)cc5)cccn4n3)c2)CC1

Procedure:
[8-(4-Fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-(4-fluoro-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.185 g, 0.747 mmol) and 3-(4-methylpiperazin-1-yl)aniline (0.171 g, 0.896 mmol) in a manner analogous to Example 311a and 311b with purification method from 313 to give product (0.155 g, 52%): MP=194-196° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.78 (d, 1H), 8.20 (m, 2H), 7.85 (d, 1H), 7.50 (s, 1H), 7.35 (m, 2H), 7.10 (m, 3H), 6.45 (m, 1H), 3.12 (m, 4H), 2.46 (m, 4H), 2.23 (s, 3H). MS=403 (MH)+.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Br:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([OH:15])=[CH:7][CH:6]=1>C(OCC)C.CO>[Br:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([O:15][CH3:3])=[CH:7][CH:6]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1nc(Br)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of diazomethane in diethyl ether (about 0.4 M) is added in excess to a solution of 2.3 mmol of methyl 6-bromo-3-hydroxypyridine-2-carboxylate [321601-48-3] in 30 ml of methanol at 0° C. The mixture is stirred at 0° C. for 2 hours, then quenched with magnesium sulphate, filtered and evaporated. The crude title compound is identified by means of the Rf.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:32])/[CH:15]=[CH:16]/[C:17]3[CH:18]=[C:19]4[C:24](=[N:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH:21]([C:28](OC)=[O:29])[CH2:20]4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:36]>N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:32])/[CH:15]=[CH:16]/[C:17]3[CH:18]=[C:19]4[C:24](=[N:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH:21]([C:28]([NH2:36])=[O:29])[CH2:20]4)[CH2:10][CH2:9]2)=[CH:33][CH:34]=1
Reactant: COC(=O)C1Cc2cc(/C=C/C(=O)N3CCC(COc4ccc(F)cc4)CC3)cnc2NC1=O
Reactant: [NH4+]
Agent: N
Agent: [OH-]
Product: NC(=O)C1Cc2cc(/C=C/C(=O)N3CCC(COc4ccc(F)cc4)CC3)cnc2NC1=O
Yield: 12 %

Procedure:
A solution of methyl 6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (13 mg, 0.028 mmol) in ammonium hydroxide (33% in water, 0.5 mL) and in ammonia (2M in ethanol, 0.5 mL) was stirred at 90° C. for 1 h30. The mixture was concentrated to dryness and the residue was purified on preparative TLC (eluent: dichloromethane/MeOH 90/10) to give 6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxamide (1.6 mg, 12%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C(OCC)(=O)C>O1CCCC1.CCO.CCCCCC>[O:23]=[C:21]1[C:22]2[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:30]=[CH:31][C:2]([CH3:1])=[CH:3][CH:4]=3)=[C:10]([NH:25][C:26](=[O:29])[CH2:27][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH:11]=[CH:12][C:13]=2[C:14](=[O:24])[C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCCCC3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 43 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and piperidine (0.79 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a kelly green compound CC-39. Mol. Wt.: 481.5424 (C29H27N3O4); Rf: 0.36 (ethyl acetate:n-hexane=1:2); Yield: 43%; Mp.: 213-214° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 481.2002 (C29H27N3O4+). Found, 481.2000. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 1.08 (d, J=3.6 Hz, 2H, —CH2—), 1.19 (br, 4H, —CH2—), 2.33 (br, 4H, —CH2—), 2.43 (s, 3H, —CH3), 3.07 (s, 2H, —CH2N—), 7.43 (d, J=7.8 Hz, 1H, Ar—H), 7.87-7.91 (m, 2H, Ar—H), 8.07-8.19 (m, 4H, Ar—H), 8.27 (d, J=8.7 Hz, 1H, Ar—H), 8.78 (d, J=8.7 Hz, 1H, Ar—H), 10.13 (s, 1H, Ar—NH—), 10.52 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.85, 22.80, 24.79, 54.13, 62.39, 125.19, 126.27, 126.53, 126.89, 127.84, 127.92, 128.02, 129.00, 129.22, 130.57, 132.31, 134.13, 134.36, 134.42, 140.63, 142.40, 166.25 (NCO), 169.55 (NCO), 181.42 (CO), 183.67 (CO).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])=[CH:10][C:5]2=[CH:4][C:3]=1[CH2:29][NH:30]C(=O)OC(C)(C)C.F[C:39](F)(F)[C:40](O)=O>ClCCl>[NH2:30][CH2:29][C:3]1[CH:4]=[C:5]2[CH:10]=[C:9]([C:11]([NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:15])[F:16])=[O:28])[N:8]([CH2:39][CH3:40])[C:6]2=[N:7][C:2]=1[CH3:1]
Reactant: Cc1nc2[nH]c(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2cc1CNC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(CN)c(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
tert-Butyl {[6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}carbamate (274 mg, 0.46 mmol) was initially charged in dichloromethane (5.0 ml), trifluoroacetic acid (526 mg, 4.61 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed completely under reduced pressure, giving 210 mg (86% of theory) of 5-(aminomethyl)-1-ethyl-6-methyl-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, which were directly reacted further. HPLC-MS: log P=1.94; mass (m/z): 460.1.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=2[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6](=[O:17])[CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:8]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[N:44][CH:45]=2)O1.[OH-].[Cs+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:46][C:42]1[CH:41]=[C:40]([C:2]2[C:3]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=3[N:5]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:6](=[O:17])[CH:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[N:8]=2)[CH:45]=[N:44][CH:43]=1
Reactant: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3cncc(N)c3)c3cc(Cl)ccc32)cc1
Temperature: 90 °C
Yield: 33.4 %

Procedure:
5,7-Dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (240 mg) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (134 mg, 1.2 eq) were suspended in dioxane/water (6 mL/2 mL), and then cesium hydroxide (170 mg, 2 eq) was added and the mixture was degassed by pulling vacuum until bubbling occurred, and then introducing nitrogen gas. The degassing procedure was repeated twice, and then tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.05 eq) was added. The degassing procedure was repeated once, and then the reaction was heated to 90° C. for three hours. The crude mixture was then diluted with EtOAc (20 mL) and then washed with water, then brine, and then it was dried over sodium sulfate, and concentrated onto silica gel. The product was purified by chromatography (gradient: 75:25 hexanes:EtOAc to EtOAc) delivering the product as a solid (90 mg, 33% yield). MS (ES+) m/z 531.0 (M+1).