Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][N:2]3[CH2:3][CH2:4][CH:5]([C:6]1=2)[CH2:15][CH2:16]3
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Reactant: Brc1ccc2ccccc2n1
Product: c1ccc2nc(-n3c4c(c5ccccc53)CN3CCC4CC3)ccc2c1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 2-bromoquinoline (312 mg, 1.5 mmol; Alfa Aesar) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.97-2.12 (m, 2H) 2.19-2.32 (m, 2H) 3.11-3.29 (m, 5H) 4.36 (s, 2H) 7.11-7.19 (m, 2H) 7.40-7.48 (m, 2H) 7.60 (d, J=9 Hz, 1H) 7.66 (t, J=8 Hz, 1H) 7.79-7.87 (m, 1H) 8.03 (t, J=7 Hz, 2H) 8.55 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][N:9]=[C:10]3[C:15]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20](I)[CH3:21].O>CN(C)C=O>[CH2:20]([O:18][C:17](=[O:19])[CH2:16][C:15]1[C:10]2[C:11](=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][N:9]=2)[CH:12]=[CH:13][CH:14]=1)[CH3:21]
Reactant: CCI
Reactant: O=C(O)Cc1cccc2c(-c3ccccc3)onc12
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc2c(-c3ccccc3)onc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.9 %

Procedure:
To a stirred slurry of 0.7 g (0.014 mole) of washed (petroleum ether), 50% sodium hydride/oil in 5 ml of dry dimethylformamide was added a solution of 2.9 g (0.012 mole) of 3-phenyl-2,1-benzisoxazol-7-acetic acid in 15 ml of dimethylformamide. The mixture was stirred at ambient temperature for 10 minutes and then 2.0 g (0.013 mole) of ethyl iodide was added. The dark solution was stirred at ambient temperature for 1 hr and then poured into 500 ml of water and let stand overnight. The mixture was filtered and the collected solid was recrystallized from 2-propanol to give 0.2 g (6%) of solid, m.p. 97°-98° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:7][NH2:8].[Cl:14][C:15]1[C:16](=[O:25])[N:17]([CH2:22][CH2:23][CH3:24])[N:18]=[CH:19][C:20]=1Cl.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:14][C:15]1[C:16](=[O:25])[N:17]([CH2:22][CH2:23][CH3:24])[N:18]=[CH:19][C:20]=1[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([O:3][CH3:2])[CH:5]=1
Reactant: CCCn1ncc(Cl)c(Cl)c1=O
Reactant: COc1ccc(CN)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCn1ncc(NCc2ccc(OC)c(OC)c2)c(Cl)c1=O
Reaction time: 5 h

Procedure:
A mixture comprising 1.52 g of 3,4-dimethoxybenzylamine hydrochloride prepared in Reference Example 1, 0.62 g of 4,5-dichloro-2-n-propyl-3(2H)pyridazinone, 1.66 g of potassium carbonate, 10 ml of 1,4-dioxane and 30 ml of water was refluxed under stirring for 5 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained, and the mixture was extracted with ethyl acetate. The extract was washed successively with 2% diluted hydrochloric acid, water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off to obtain a pale yellow oily substance. This substance was crystallized from diethyl ether-n-hexane to obtain 522 mg of the above identified compound having a melting point of from 139 to 140° C. as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:14])[C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].[P:15](Cl)(Cl)([Cl:17])=[O:16]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([CH3:12])([CH3:13])[CH2:10][O:11][P:15](=[O:16])([Cl:17])[O:14]1
Reactant: CC(C)(CO)C(O)c1ccccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)COP(=O)(Cl)OC1c1ccccc1Cl
Yield: 98.3 %

Procedure:
1-(2-Chlorophenyl)-2,2-dimethyl-1,3-propanediol (1.0 g, 4.66 mmol) was diluted with dichloromethane (5 ml) and, under reflux, a solution of phosphorus oxychloride (0.65 g, mmol) in dichloromethane (3 ml) was added dropwise over 40 min. After the dropwise addition, the mixture was refluxed for 6 h. The mixture after completion of the reaction was concentrated, and after addition of ether (dry, 5 ml), concentrated again to dryness to give the title compound (1.23 g, 90%) as colorless crude crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:6][C:5]2=O.[C:19](=[N:25][Si](C)(C)C)=[N:20][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:6][C:5]2=[N:25][C:19]#[N:20]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(c2ccccn2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(c2ccccn2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 6-bromo-2-pyridin-2-yl-chroman-4-one (303 mg, 1 mmol) in DCM (10 mL) was added TiCl4 (4 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.5 mL, 2.2 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (50 g). The aqueous layer was extracted with CHCl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude 6-bromo-2-pyridin-2-yl-chroman-4-ylidene-cyanamide (300 mg, 92%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:26])=[C:5]2[C:9](=[C:10]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]=1[CH2:12][CH:13]=[C:14]([CH3:17])[CH2:15]O)[C:8](=[O:25])[O:7][CH2:6]2)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:15][C:14]([CH3:17])=[CH:13][CH2:12][C:11]1[C:10]([O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:24])[CH3:22])=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:25])=[C:4]([CH3:26])[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CO)C(=O)OC2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CBr)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
5-Ethyl-6-(4-hydroxy-3-methyl-but-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (57.2 mg, 0.152 mmol) was dissolved in DCM (3.5 mL). Polymer-bound triphenylphosphine (3 mmol/g, 152.1 mg) was added and the mixture was mechanically stirred at room temperature. Carbon tetrabromide (151.3 mg, 0.456 mmol) was added and the solution was stirred at room temperature. After 2 hours, the reaction was filtered and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography to provide 58.0 mg (87%) of the desired product. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H), 1.25 (m, 2H), 1.95 (s, 3H), 2.20 (s, 3H), 2.70 (q, J=7.8 Hz, 2H), 3.52 (d, J=6.3 Hz, 2H), 3.94 (s, 2H), 4.28 (m, 2H), 5.14 (s, 2H), 5.50 (m, 1H) ppm.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]2=[N:3][N:2]=1)=[CH:10][C:9]([C:14]1[CH:15]=[C:16]([C:20]2([C:23](OC)=[O:24])[CH2:22][CH2:21]2)[CH:17]=[N:18][CH:19]=1)=[CH:8][CH:7]=3.[C:27](=[N:30]O)([NH2:29])[CH3:28].[O-]CC.[Na+]>C(O)C>[CH3:28][C:27]1[N:30]=[C:23]([C:20]2([C:16]3[CH:15]=[C:14]([C:9]4[CH:10]=[C:11]5[C:6](=[CH:7][CH:8]=4)[N:5]4[CH:1]=[N:2][N:3]=[C:4]4[CH2:13][CH2:12]5)[CH:19]=[N:18][CH:17]=3)[CH2:21][CH2:22]2)[O:24][N:29]=1
Reactant: CC(N)=NO
Reactant: COC(=O)C1(c2cncc(-c3ccc4c(c3)CCc3nncn3-4)c2)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(C2(c3cncc(-c4ccc5c(c4)CCc4nncn4-5)c3)CC2)n1
Temperature: 150 °C

Procedure:
To a vial containing the title compound from Example 71 Step D (75 mg, 0.217 mmol), acetamide oxime (32.1 mg, 0.433 mmol) and sodium ethoxide (73.7 mg, 1.083 mmol) was added ethanol (2.2 mL). The vial was capped tightly and heated to 150° C. for 15 minutes in the microwave. The reaction solution was then concentrated under reduced pressure. The resulting material was diluted with acetonitrile and then purified by HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid). Fractions containing product were combined, aqueous 1 N HCl solution was added, and the resulting solution concentrated to provide the title compound: LCMS m/z 370.97 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 10.1 (s, 1H), 9.28 (s, 1H), 9.13 (s, 1H), 8.1-8.01 (m, 4H), 3.49-3.46 (m, 2H), 3.39-3.36 (m, 2H), 2.29 (s, 3H), 2.04-2.02 (m, 2H), 1.94-1.91 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:22][C@H:20]1[NH:21][C:32](=[O:34])[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:7]3[C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH:10]=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[C:19]1=[O:23]
Reactant: Cc1noc2cccc(Oc3ccc(NC(=O)[C@@H](C)N)cc3)c12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1noc2cccc(Oc3ccc(N4C(=O)N[C@H](C)C4=O)cc3)c12
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
N1-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-D-alaninamide (Intermediate 14, 337 mg) was dissolved in 8.0 ml of ethyl acetate. Triethylamine (0.33 ml, 2.38 mmol) was added followed by a solution of triphosgene (161 mg, 0.54 mmol) in 2.0 ml of ethyl acetate. After 5 minutes stirring, DMAP (66 mg, 0.54 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with a saturated aqueous solution of NaHCO3, the reaction mixture was extracted two times with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with a gradient Cy-Hex/EtOAc from 100/0% to 0/100%. This afforded the title compound (160 mg).
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[Si:45]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][O:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>>[Si:45]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][O:59][CH:60]1[CH2:65][CH2:64][N:63]([C:11]([C:13]2[CH:14]=[C:15]([S:19]([C:22]3[CH:23]=[C:24]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]4[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:62][CH2:61]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCOC1CCNCC1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCC(OCCCCCCO[Si](C)(C)C(C)(C)C)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 23 in place of 8-aminooctanol. ES/MS calcd. for C42H57N4O7SSi+ 789.4. Found m/z=789.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: N#Cc1cccnc1-c1ccccc1C(F)(F)F
Yield: 30 %

Procedure:
Prepared in 30% yield from 2-chloro-3-cyanopyridine and 2-trifluoromethylphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 249.0 (M+H)+; 1H NMR (CDCl3) δ 7.45-7.50 (m, 2H), 7.62-7.72 (m, 2H), 7.83-7.86 (m, 1H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.87 (dd, J=5.7, 1.7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:26]1[CH2:28][CH2:27]1)[CH:9]([C:11]1[CH:12]=[C:13]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:25])[O:23][CH3:24])[C:14](Cl)=[N:15][CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](B1OC(C)(C)C(C)(C)O1)=[CH2:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([CH:26]1[CH2:28][CH2:27]1)[CH:9]([C:11]1[CH:12]=[C:13]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:25])[O:23][CH3:24])[C:14]([CH:29]=[CH2:30])=[N:15][CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)NCCCc1cc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cnc1Cl
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ncc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cc1CCCNC(=O)OC
Temperature: 85 °C
Reaction time: 17 h

Procedure:
to a solution of methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-chloropyridin-3-yl)propyl]carbamate (380 mg) in dimethoxyethane (8 mL) were added vinyl boronic acid pinacol ester (235 μL), 2M sodium carbonate (1.38 mL) and dichlorobis(triphenylphosphine)palladium (II) (65 mg), and the mixture was stirred at 85° C. for 17 hours. The reaction solution was cooled, and then an insoluble was filtered off through Celite, and to the filtrate was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1→1/4) to give methyl [3-(5-{1-[(tert-butoxycarbonyl)(cyclopropyl)amino]ethyl}-2-vinylpyridin-3-yl)propyl]carbamate [REx(113-6)] (282 mg) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7]CC)=O.[C:13]1([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:29]=[C:28]([NH2:30])[NH:27][N:26]=3)[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:10][C:3]1([C:2]([F:1])([F:11])[F:12])[CH2:4][C:5](=[O:7])[NH:30][C:28]2[NH:27][N:26]=[C:25]([CH:22]3[CH2:21][CH2:20][N:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:24][CH2:23]3)[C:29]1=2
Reactant: Nc1cc(C2CCN(c3ccccc3)CC2)n[nH]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CC(O)(C(F)(F)F)c2c(C3CCN(c4ccccc4)CC3)n[nH]c2N1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Ethyl trifluoroacetoacetate (1.50 g, 8.15 mmol) was added to a solution of 3-(1-phenylpiperidin-4-yl)-1H-pyrazol-5-amine (648 mg, 2.67 mmol) produced in Reference Example 3 in acetic acid (10 mL), and the mixture was stirred at 60° C. for 2 hours and 30 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elute: ethyl acetate/methanol=100/0-96/4 (gradient)] and further purified by silica gel chromatography [elute: hexane/ethyl acetate=60/40-0/100 (gradient)] to obtain the title compound (430 mg, yield: 42%).
Reaction SMILES: [C:1](=[O:20])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([C:1]([O:2][CH:3]3[CH2:4][CH2:5][N:6]([CH3:9])[CH2:7][CH2:8]3)=[O:20])[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: CN1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Cc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(C(=O)OC3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 1-methylpiperidin-4-yl 4-nitrophenyl carbonate (1.81 g, 6.44 mmol) and DIPEA (0.76 mL, 4.4 mmol) in DMF (20 mL) was added 4-(4-methylphenyl)piperazine (1.53 g, 6.14 mmol). The reaction mixture was stirred at room temperature for 3 hours, the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (250 mL) and washed with 1M aq Na2CO3 (5×150 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) to give 1-methyl-piperidin-4-yl 4-(4-methylphenyl)piperazine-1-carboxylate (1.54 g, 79%) as a cream solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:26]([F:29])([F:28])[F:27])=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>CO>[Cl:25][C:22]1[S:21][C:20]([C:18]2[CH:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=[N:16][C:17]=2[C:26]([F:29])([F:27])[F:28])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(Cl)s3)c(C(F)(F)F)nn2)CC1
Solvent: CO
Product: FC(F)(F)c1nnc(N2CCNCC2)cc1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyridazin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (D15) (0.114 g, 0.25 mmol) in methanol (10 ml) was added Amberlyst® 15 ion exchange resin, acidic form (4.1 mmol/g) (0.305 g, 1.25 mmol) and the reaction mixture was shaken at room temperature for 18 h. After this period, the mixture was filtered and then a saturated solution of ammonia in methanol was added. The mixture was shaken for 1 h, filtered and the filtrate evaporated in vacuo. The residue was then purified by column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The crude product was dissolved in a 2 M solution of hydrochoric acid in diethyl ether and the mixture stirred at room temperature for 16. The solvent was evaporated in vacuo. The solid obtained was triturated from diethyl ether to yield E27 (0.062 g, 87%). C13H12ClF3N4S requires 348; Found 349 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[F:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:14]2[CH:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]([F:9])[CH:15]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
N-Ethylpiperazine (4.8 mL, 37.7 mmol, 1.2 equiv) is added to a mixture of 2,4-difluoronitrobenzene (5 g, 31.4 mmol) and potassium carbonate (8.7 g, 62.9 mmol, 2 equiv) in DMF (50 mL). The reaction mixture is stirred at 100° C. for 6 h, allowed to cool to RT, diluted with H2O and extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) to provide the title compound as a yellow oil: ES-MS: 254.1 [MH]+; TLC: Rf=0.67 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:14](=[O:16])[O:13][C:12](=O)[C:11]=2[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[NH2:18]C(N)=O>>[CH3:1][O:2][C:3]1[C:15]2[C:14](=[O:16])[NH:18][C:12](=[O:13])[C:11]=2[CH:10]=[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=12
Reactant: NC(N)=O
Reactant: COc1c2c(cc3ccccc13)C(=O)OC2=O
Product: COc1c2c(cc3ccccc13)C(=O)NC2=O

Procedure:
Prepared as described in Intermediate 33 from 4-methoxynaphtho[2,3-c]furan-1,3-dione (229 mg) and urea (120 mg). M.p. 216°-220°. NMR (DMSO-d6) δ 10.6 (1H, s), 7.52 (1H, d), 7.39 (1H, d), 7.34 (1H, s), 6.92 (2H, m), 3.43 (3H, s).
Reaction SMILES: N1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21](C)=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=4)[N:13]=3)=[CH:8][CH:7]=2)=[N:4]N=N1.[OH-:25].[Na+].OO>CS(C)=O>[CH3:24][O:23][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH2:4])=[O:25])=[CH:7][CH:8]=1)[CH:21]=[CH:20]2
Reactant: [OH-]
Reactant: COc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)c(C)cc2c1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2nc(-c3ccc(C(N)=O)cc3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(6-methoxyquinolin-2-yl)benzonitrile (5.00 g, 15.4 mmol, prepared following Scheme 2, Step 1 starting from Intermediate 1 and 4-cyanophenylboronic acid) in DMSO (40 mL) was added aqueous NaOH (1M, 10 mL). The mixture was cooled to 0° C. The aqueous H2O2 (30%, 30 mL) was added dropwise. After addition, the mixture was stirred at 0° C. for 30 minutes. The mixture was quenched with saturated Na2SO3 (100 mL) and filtered. The precipitate was washed with H2O (50 mL) and MeOH (50 mL). The filter cake was dried via high vacuum to give the desired (5.50 g, yield: 99+%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14](O)=[O:15])=[C:8]([CH3:20])[C:6]=2[N:7]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:14]([N:31]4[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]4)=[O:15])[CH:17]=[CH:18][CH:19]=3)=[C:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: Cc1c(-c2cccc(C(=O)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: OC1CCNCC1
Product: Cc1c(-c2cccc(C(=O)N3CCC(O)CC3)c2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 4-hydroxypiperidine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperadin-1-yl)methanone. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperadin-1-yl)methanone (72 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 29.5 mg of 425. MS (Q1) 555.2 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].[CH2:11]1[O:13][CH2:12]1>[Cl-].C[N+](C)(C)C.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH:12]([OH:13])[CH3:11]
Reactant: Oc1c(Br)cc(Br)cc1Br
Reactant: C1CO1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(O)Oc1c(Br)cc(Br)cc1Br

Procedure:
2,4,6-Tribromophenol (94.9 parts), ethylene oxide (14.7 parts) and tetramethylammonium chloride (2.0 parts) were charged into the same type of reactor as described in Example I. Reactants were heated to 95°-100° C. over 21/2 hours and allowed to react at this temperature for an additional 41/2 hours for the completion of reaction. The product was then dissolved in benzene, washed with water three times, dried with anhydrous sodium sulfate, filtered, and benzene stripped off under vacuum at 40° C. The final product was a slightly colored pasty material having a hydroxyl number of 150.