Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.C([BH3-])#N.[Na+]>CO.[Cl-].[Na+].O>[F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH:15]([N:34]3[CH2:35][CH2:36][N:31]([C:29]4[CH:30]=[C:21]([O:20][CH3:19])[CH:22]=[C:23]5[C:28]=4[N:27]=[CH:26][CH:25]=[CH:24]5)[CH2:32][CH2:33]3)[CH2:14][CH2:13]2)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(c2c(F)ccc3cccnc23)CC1
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N2CCN(C3CCN(c4c(F)ccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(7-fluoroquinolin-8-yl)piperidin-4-one (Step 3, 0.26 g) and 6-methyoxy-8-(1-piperazinyl)quinoline (Example A, Step 4; 0.26 g) in anhydrous methanol (10 mL) was added sodium cyanoborohydride (0.11 g). The resulting mixture was stirred at room temperature under nitrogen for 18 hours. An additional aliquot of sodium cyanoborohydride (0.11 g) was added and stirring at room temperature was continued for another 24 hours. The resulting reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/acetone to give the desired product, which was converted to its trihydrochloride salt in CH2Cl2 using 1M HCl/Et2O to provide 0.12 g of a yellow solid; MS (ES) m/z (relative intensity): 472 (M+H)+ (100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]3[NH:27][CH2:26][CH2:25][S:24]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30]>CC(C)=O>[CH3:28][S:29]([NH:32][C:33]([N:27]1[CH2:26][CH2:25][S:24][CH:23]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:9][CH2:10]1)=[O:34])(=[O:31])=[O:30]
Reactant: Fc1cccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Reactant: CS(=O)(=O)N=C=O
Solvent: CC(C)=O
Product: CS(=O)(=O)NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
1.94 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine are dissolved in anhydrous acetone, and 0.73 g of methanesulfonyl isocyanate is added thereto at room temperature. After the mixture is stirred for 30 minutes, the mixture is concentrated under reduced pressure to remove solvent. The residue is collected by filtration, and washed with water and ether, successively. The crude product thus obtained is recrystallized from a mixture of acetone and ether. 1.56 g of N-methanesulfonyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazollidine-3-carboxamide are obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[NH:2]1.CN(C)C=O.S(Cl)([Cl:18])=O>ClC1C=CC=CC=1>[Cl:18][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: O=c1[nH]sc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: Clc1nsc2ccccc12
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 75.6 g (0.5 mol) of 1,2-benzisothiazol-3-one, 54.8 g (0.75 mol) of N,N-dimethylformamide and 100.0 g of chlorobenzene. While stirring, 71.4 g (0.6 mol) of thionyl chloride was added dropwise thereto over 1 hour at 70° to 80° C., and the mixture was reacted at the same temperature for 8 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was distillated under reduced pressure of 0.93 kPa at 128° C. to give 75.1 g (0.45 mol) of 3-chloro-1,2-benzisothiazole. The yield based on the 1,2-benzisothiazol-3-one was 90%.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH3:1][C:2]1([CH2:13][CH2:12][C:11]([O:10][CH3:9])=[O:14])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: C=CC(=O)OC
Reactant: CC1C(=O)CCC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)CCC1(C)C(=O)CCC1=O
Reaction time: 72 h

Procedure:
A mixture of 0.3 g. of 2-methylcyclopentane-1,3-dione, 0.33 ml. of methylacrylate and 0.1 g. of potassium t-butoxide in 200 ml. of t-butanol is allowed to stand at about 20°C for 72 hours. The reaction mixture is washed with water, dilute sodium hydroxide and then water to neutral, dried and evaporated to give 2-methyl-2-(β-carbomethoxyethyl)cyclopentane-1,3-dione which is purified by distillation. ##SPC6##
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][CH2:14][OH:15].O[C:17]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[O:19][N:18]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[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][CH2:14][O:15][C:17]1[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[O:19][N:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: COC(=O)c1cc(O)no1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCc2nc(-c3ccccc3)oc2C)no1
Reaction time: 15 h
Yield: 104.3 %

Procedure:
To a mixture of 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (5.64 g), methyl 3-hydroxy-5-isoxazolecarboxylate (8.00 g), tributylphosphine (15.9 g) and tetrahydrofuran (200 mL) was added a solution (100 mL) of 1,1′-(azodicarbonyl)dipiperidine (19.9 g) in tetrahydrofuran at room temperature and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give crystals (9.50 g, 73%) of methyl 3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-isoxazolecarboxylate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 90-91° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:18]([O-:20])=[O:19])[CH:6]=[CH:7][C:8]=2[N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[C:3]1=[O:21].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH:14]2[CH2:15][CH2:16][N:11]([C:8]3[CH:7]=[CH:6][C:5]([N+:18]([O-:20])=[O:19])=[C:4]4[C:9]=3[CH2:10][N:2]([CH3:1])[C:3]4=[O:21])[CH2:12][CH2:13]2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CN1Cc2c(N3CCC(=O)CC3)ccc([N+](=O)[O-])c2C1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CN1Cc2c(N3CCC(N4CCN(C(=O)OC(C)(C)C)CC4)CC3)ccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
To a solution of 2-methyl-7-nitro-4-(4-oxo-piperidin-1-yl)-2,3-dihydro-isoindol-1-one (4.2 g, 14.5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (3.24 g, 17.4 mmol) in 1,2-dichloroethane is added sodium triacetoxy borohydride (3.69 g, 17.4 mmol) at 0° C. under nitrogen atmosphere. After the mixture is stirred at room temperature for 5 hours, 1N sodium hydroxide aqueous solution is added at 0° C. The mixture is extracted with dichloromethane and the organic layer is washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (AcOEt; AcOEt: MeOH=9: 1) to give 4-[1-(2-methyl-7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-piperidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (4.16 g, 62%). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.47 (s, 9H), 1.66-1.76 (m, 2H), 1.94-2.02 (m, 2H), 2.42-2.59 (m, 5H), 2.84-2.93 (m, 2H), 3.05 (s, 3H), 3.40-3.49 (m, 4H), 3.49-3.57 (m, 2H), 4.35 (s, 2H), 7.00 (d, 1H), 7.76 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[C:4]([OH:13])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(#N)C>[C:25]([O:24][C:22](=[O:23])[CH2:21][O:13][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=[C:2]([Br:1])[CH:3]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCCc2c(O)cc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1cc(Br)cc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a suspension of 7-bromo-5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (XIb, 158 mg, 0.65 mmol) and cesium carbonate (431 mg, 1.31 mmol) in acetonitrile (5 mL) was added tert-butyl bromoacetate (XII, 261 mg, 1.31 mmol) at room temperature under nitrogen. The resulting suspension was stirred for 15 h at room temperature and then concentrated under vacuum. The residue was diluted with water (10 mL) and ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL), and the combined organic extracts were washed with brine solution (50 mL), then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. Chromatography using an ISCO (40 g) column, (gradient elution with 5-25% ethyl acetate in hexanes) provided (3-bromo-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (150 mg, 64%) as a white solid: ES(+)-HRMS m/e calcd. for C16H19O4Br (M+Na)+377.0359, obsd. 377.0358.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([CH2:23][NH2:24])[OH:22].C(OCC)(=O)C>O>[OH:22][CH2:21][CH2:23][NH:24][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCO
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(NCCO)c2)c1
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 0.5 g, 0.0018 mol) and ethanolamine (15 mL) was heated at 100° C. for 18 hours. The reaction mixture was cooled and treated with ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate) to give 0.44 g (80% yield) of product as a yellow oil: Anal. Calc'd. for C18H20N4O: C, 70.11; H, 6.54; N, 18.17. Found: C, 69.89; H, 6.65; N, 18.35.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:22]([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:10][C:11]([O:13][CH3:22])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 15 mL of DMF charged with (3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid (8 mmol, 2.0 g), methyl iodide (15 mmol, 1.9 mL) and K2CO3 (15 mmol, 2.1 g), was stirred at ambient temperature for 16 h. The reaction mixture was poured into 50 mL of saturated NaHCO3, and the resulting solution was extracted with ether (3×50 mL). The combined organic phase was washed with 50 mL of H2O, dried with MgSO4, and the solvent removed under reduced pressure to yield the title compound as a slightly yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.26-7.38 (m, 5 H), 5.49 (br s, 1H), 5.13 (br s, 1H), 3.65 (s, 3H), 2.80-2.96 (m, 2H), 1.45 (s, 9H). MS (ESI): m/z 302 (M+Na).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([N:5]5[CH2:6][CH2:7][CH2:8][C@H:4]5[CH2:3][O:2][CH3:1])[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]
Reactant: COC[C@@H]1CCCN1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: COC[C@@H]1CCCN1c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using (s)-2-methoxymethyl-pyrrolidine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 481 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19](=[O:34])[CH2:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:4]=1>O1CCOCC1.CO>[CH3:41][N:38]1[CH2:37][CH2:36][N:35]([C:5]2[CH:6]=[C:7]([C:9]3[CH:18]=[C:17]4[C:12]([CH2:13][CH2:14][N:15]([C:19](=[O:34])[CH2:20][CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[CH2:16]4)=[CH:11][CH:10]=3)[N:8]=[C:3]([NH2:2])[N:4]=2)[CH2:40][CH2:39]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)CC4)nc(N)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNCC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.6 %

Procedure:
2 mL of 4.0 N HCl in 1,4-dioxane was added to a solution of tert-butyl 4-{2-[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}piperidine-1-carboxylate (25 mg, 0.045 mmol) in methanol (1.0 mL). The reaction mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford the product as an HCl salt (25 mg, 98%). Analytic LCMS (M+H)+: m/z=450.2.
Reaction SMILES: CO.C1C[O:6][CH2:5]C1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:18])[C:16]=1Br>O>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:18])[C:16]=1[O:6][CH3:5]
Reactant: C1CCOC1
Reactant: Brc1cncc(Br)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(Br)cncc1Br
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of MeOH (0.115 mL, 2.85 mmol) and THF (0.5 mL) at 0° C. was added sodium hydride (60% dispersion, 114 mg, 2.85 mmol). After stirring for 15 min, Intermediate 31B (600 mg, 1.900 mmol) was added, and the resulting mixture was stirred at room temperature for 19 hours, diluted with water (3 mL) and extracted with EtOAc (2×10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield Intermediate 31 (0.480 g, 1.798 mmol, 95% yield) as a beige color solid. MS (ES): m/z=267.9 [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 8.68 (2 H, s), 3.99 (3 H, s). Intermediate 31 was used in the synthesis of Example 185.
Reaction SMILES: Br.Br.[NH:3]1[CH2:6][CH:5]([NH:7][C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)[CH:9]=2)[CH2:4]1.[C:23](O)(=[O:32])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:23]([N:3]1[CH2:6][CH:5]([NH:7][C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)[CH:9]=2)[CH2:4]1)(=[O:32])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CNc1cc(-c2c[nH]c(=O)c(NC3CNC3)c2)ccn1
Reactant: O=C(O)C=Cc1ccccc1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(-c2c[nH]c(=O)c(NC3CN(C(=O)/C=C/c4ccccc4)C3)c2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
A solution of 5-(azetidin-3-ylamino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one di-hydrobromide (80.0 mg, 0.185 mmol) in DMF (1 mL) was added cinnamic acid (60 mg, 0.41 mmol), HATU (105 mg, 0.277 mmol), and DIPEA (120 mg, 0.924 mmol). The reaction mixture was stirred at RT under nitrogen for 16 h. The residue was purified by Prep HPLC (ethyl acetate/hexane) to afford (E)-5-((1-cinnamoylazetidin-3-yl)amino)-2′-(methylamino)-[3,4′-bipyridin]-6(1H)-one (41 mg, 55%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 11.25 (s, 1H), 8.11 (d, J=5.4 Hz, 1H), 7.69 (d, J=15.6 Hz, 1H), 7.52 (dd, J=6.7, 3.0 Hz, 2H), 7.37 (dd, J=5.0, 2.0 Hz, 3H), 7.09 (d, J=2.2 Hz, 1H), 6.63 (dd, J=5.4, 1.6 Hz, 1H), 6.48 (d, J=15.6 Hz, 1H), 6.38 (d, J=1.9 Hz, 2H), 5.48 (d, J=6.6 Hz, 1H), 4.80-4.65 (m, 2H), 4.63-4.50 (m, 1H), 4.46-4.32 (m, 1H), 4.26-4.05 (m, 2H), 2.98 (d, J=4.8 Hz, 3H); MS (ES) m/z 402 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][N:15]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([O:13][CH3:12])[CH:19]=1)=[O:5]
Reactant: COc1cc(N)ccn1
Reactant: O=C(Cl)c1cc(F)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2cc(F)ccc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A solution of 2,5-difluorobenzoyl chloride (2.0 mL, 16.14 mmol) and dichloromethane (14.25 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (2.0 g, 16.14 mmol), pyridine (3.9 mL, 48.42 mmol) and dichloromethane (57.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl and dichloromethane. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a tan solid. The solid was slurried in hexanes (150 mL) and was filtered to give 2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (2.61 g, 61%) as a tan solid. ESI-MS m/z calc. 264.07. found 265.3 (M+1)+; Retention time: 1.22 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.12-8.05 (m, 1H), 7.58 (ddd, J=8.3, 5.4, 2.9 Hz, 1H), 7.52-7.41 (m, 2H), 7.25-7.19 (m, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (98) and 3-fluorobenzyl bromide according to General Procedure B. Yield 428 mg (56%), MP 137° C.; 1H-NMR (DMSO-d6): δ 3.73 (m, 4H), 3.93 (m, 4H), 5.52 (s, 2H), 7.06-7.10 (m, 3H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.33 (m, 1H), 7.50 (d, J=3.6 Hz, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 8.17 (dd, J=2.8, 9.2 Hz, 1H), 8.77 (d, J=2.8 Hz, 1H); EIMS: 492 (M+1). Anal (C25H19F2N5O2S) C, H, N.
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)[CH:8]=[CH:9][C:10]=1[CH3:11].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>CCOCC>[C:20]([NH:24][CH2:19][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)[CH:8]=[CH:9][C:10]=1[CH3:11])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(C2=NNC(=O)CC2)cc1OCC1CO1
Solvent: CCOCC
Product: Cc1ccc(C2=NNC(=O)CC2)cc1OCC(O)CNC(C)(C)C

Procedure:
A stirred mixture of 6-[3-(2,3-epoxypropoxy)-4-methylphenyl]-4,5-dihydro-3(2H)-pyridazinone (3.3 g, 0.013 mole) methanol (33 ml) and t-butylamine (8 ml, 0.076 mole) was heated under reflux for 75 minutes. Evaporation of the solution under reduced pressure gave a gum which when treated with ether, solidified 4.27 g, 100%, m.p. 153°-158°C. 6-[3-(3-t-Butylamino-2-hydroxypropoxy)-4-methylphenyl]-4,5-dihydro-3(2H)-pyridazinone was purified as its hemisulphate m.p. 274°-276°C (decomposition), which recrystallised from aqueous ethanol had m.p. 275°-277°C (decomposition).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:34][CH2:33]1>C(Cl)Cl>[OH:19][C:20]1[C:21](=[O:22])[C:13]2[CH:8]3[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]3)[CH2:6][CH:5]([O:4][C:2](=[O:3])[CH3:1])[C:14]=2[C:15]2([CH3:30])[C:16]=1[C:17](=[CH:18][N:44]1[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][N:35]3[CH2:34][CH2:33][O:32][CH2:37][CH2:36]3)[CH2:46][CH2:45]1)[C:23](=[O:24])[O:25][CH:26]2[CH2:27][O:28][CH3:29]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: C(CN1CCNCC1)CN1CCOCC1
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCN(CCCN3CCOCC3)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 1-(3-morpholinopropyl)piperazine (99 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 645 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20]([NH:22]C(OC(C)(C)C)=O)=[N:19]C=3C)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1.[C:31](O)([C:33]([F:36])([F:35])[F:34])=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20]([NH2:22])=[N:19][C:31]=3[C:33]([F:36])([F:35])[F:34])=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:2]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)NCC1(c2cccnc2)CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(C(F)(F)F)c(C(=O)NCC2(c3cccnc3)CCCCC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-tert-butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid (1-pyridin-3-yl-cyclohexylmethyl)-amide (2.45 g) and TFA (10 mL) in methylene chloride (10 mL) is stirred at RT for 2 h and concentrated in vacuo. Water is added to the residue and the mixture is basified with Na2CO3 solution and extracted with EtOAc. The extract is washed with brine, dried and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[S:22](=[O:38])(=[O:37])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH:34]1[CH2:36][CH2:35]1)[N:29]=[CH:28]2)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[S:22](=[O:37])(=[O:38])[N:23]([CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH:34]1[CH2:36][CH2:35]1)[N:29]=[CH:28]2)[C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C3CC3)c2)c(Cl)c1
Reactant: Fc1ncc(Cl)cc1Cl
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C3CC3)c2)c2ncc(Cl)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and ethyl 3-chloro-4-(N-((1-cyclopropyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 31).