Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C@@H:24]1[CH2:29][N:28]([C:30]2[O:31][C:32]3[C:37]([C:38](=[O:40])[CH:39]=2)=[CH:36][C:35]([C:41]([OH:43])=O)=[CH:34][C:33]=3[CH:44]2[CH2:48][CH2:47][CH2:46][N:45]2[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:27][CH2:26][O:25]1.CCN(C(C)C)C(C)C.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>CC(N(C)C)=O>[CH3:23][C@@H:24]1[CH2:29][N:28]([C:30]2[O:31][C:32]3[C:37]([C:38](=[O:40])[CH:39]=2)=[CH:36][C:35]([C:41]([N:64]2[CH2:69][CH2:68][O:67][CH2:66][CH2:65]2)=[O:43])=[CH:34][C:33]=3[CH:44]2[CH2:48][CH2:47][CH2:46][N:45]2[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:27][CH2:26][O:25]1
Reactant: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4ccccc4)c3o2)CCO1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)N4CCOCC4)cc(C4CCCN4c4ccccc4)c3o2)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
TBTU (148 mg, 0.46 mmol) was added to a stirred solution of 2-((R)-2-methylmorpholino)-4-oxo-8-(1-phenylpyrrolidin-2-yl)-4H-chromene-6-carboxylic acid (80 mg, 0.18 mmol), DIPEA (0.080 mL, 0.46 mmol) dissolved in DMA (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 30 min. Morpholine (0.048 mL, 0.55 mmol) was added to the mixture and stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC. The fractions containing the desired compound were evaporated to dryness to afford 2-((R)-2-methylmorpholino)-6-(morpholine-4-carbonyl)-8-(1-phenylpyrrolidin-2-yl)-4H-chromen-4-one (60 mg, 65%) as a gummy solid.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5]C)=[O:3].[CH3:7][C:8]1([CH3:18])[CH2:13][C:12]([CH2:15][NH2:16])([CH3:14])[CH2:11][CH:10](N)[CH2:9]1>>[CH3:5][O:4][C:2]([NH:16][CH2:15][C:12]1([CH3:14])[CH2:13][C:8]([CH3:18])([CH3:7])[CH2:9][CH:10]([NH:1][C:2]([O:4][CH3:5])=[O:3])[CH2:11]1)=[O:3]
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Reactant: CCOC(N)=O
Product: COC(=O)NCC1(C)CC(NC(=O)OC)CC(C)(C)C1
Yield: 98.1 %

Procedure:
The thus-prepared crude reaction solution was analyzed by gas chromatography and it was confirmed that a urethane compound corresponding to IPDA, that is, 3-methoxycarbonylaminomethyl-3,5,5-trimethyl-1-methoxycarbonylaminocyclohexane, was produced in a yield of 98.1% based on IPDA.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[Mg]Br.[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:21]([Sn:12]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)cc(C)cc1C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To 2,4,6-trimethylphenylmagnesium bromide (1.0 M in THF, 10.0 mL, 10 mmol, 1.0 equiv) in THF (30 mL) at −78° C. was added nBu3SnCl (3.25 g, 10.0 mmol, 1.00 equiv). After stiffing for 1.0 hr at 23° C., the solvent was removed in vacuo and the residue was purified by fractional distillation to afford 3.68 g of the title compound as a colorless oil (90% yield).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH2:14][P:15]([O:19]Cl)([O:17]Cl)=[O:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])=[O:4].[CH2:23]([NH2:26])[CH:24]=[CH2:25]>CCOCC>[F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH2:14][P:15]([O:19][NH:26][CH2:23][CH:24]=[CH2:25])([O:17][NH:26][CH2:23][CH:24]=[CH2:25])=[O:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])=[O:4]
Reactant: C=CCN
Reactant: CCCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: C=CCNOP(=O)(CN(CC(=O)OCCCC)C(=O)C(F)(F)F)ONCC=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of butyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (7.9 g, 0.022 mole) in 200 ml. of ether was added slowly with good stirring allylamine (5.02 g, 0.088 mole) in 50 ml. of ether. The reaction was stirred overnight at room temperature, then was filtered, and the filtrate concentrated in vacuo. The residue was dissolved in ether, washed with water, dried over MgSO4, and concentrated in vacuo to yield butyl N-trifluoroacetyl-N-(bis(allylamino)phosphonomethyl)glycinate (6.8 g), ND =1.4624.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:18]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2C)cc1OC
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(CCl)cc3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
4-(Chloromethyl)benzoyl chloride (0.73 g) was added dropwise to a stirred mixture of N-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide (1 g), triethylamine (0.98 ml) and methylene chloride (80 ml) and the mixture was stirred at ambient temperature for 16 hours. A 1N hydrochloric acid solution (10 ml) was added and the resultant solution was stirred at ambient temperature for 1 hour. The resultant white solid was filtered off, washed with water and with diethyl ether, dried under vacuum at 40° C. to give the title compound (1.35 g); NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.82 (s, 6H), 4.82 (s, 2H), 7.06 (d, 1H). 7.21 (d, 1H). 7.58 (m, 5H), 7.81 (s, 1H), 7.94 (d, 2H), 9.76 (s, 1H), 10.23 (s, 1H);
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1.O>C1COCC1>[Cl:11][C:12]1[N:13]=[N:14][C:15]([O:3][CH2:4][CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(OCCN2CCCC2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
175 mg (4.01 mmol, 55%) NaH are added to a solution of 0.50 mL (4.04 mmol) N-(2-hydroxyethyl)pyrrolidine in 50 mL THF at 0° C. The reaction solution is stirred for 60 min and heated to RT. 500 mg (3.26 mmol) 3,6-dichloro-pyridazine are added. The solution is stirred for 5 h at RT. 50 mL water are added and the aqueous phase is extracted with 100 mL EtOAc. The organic phase is extracted once with saturated NaCl solution and dried over Na2SO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (gradient: EtOAc to EtOAc/MeOH/NH3 9:1:0.1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]#[C:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:3]=1.[F:24][C:25]([F:31])([F:30])[CH2:26][N:27]=[C:28]=[S:29]>CN(C=O)C>[F:24][C:25]([F:31])([F:30])[CH2:26][NH:27][C:28](=[S:29])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]#[C:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[N:3]=1
Reactant: Nc1ccnc(SCC#CCN2C(=O)c3ccccc3C2=O)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC#CCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 72 h
Yield: 23.2 %

Procedure:
A mixture of 4-amino-2-(4-phthalimidobut-2-ynylthio)pyrimidine (1.2 g.), 2,2,2-trifluoroethylisothiocyanate (0.85 g.) and DMF (10 ml.) was stirred at 70° for 72 hours. The mixture was evaporated to dryness, and the residue stirred with N aqueous HCl and then filtered to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobut-2-ynylthio)pyrimidine (0.4 g.), m.p. 124-127°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](O)=[O:11]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11]
Reactant: O=C(O)Cc1ccc(F)cc1Br
Solvent: C1CCOC1
Product: OCCc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of (2-bromo-4-fluorophenyl)acetic acid (1.5 g, 6.44 mmol) in tetrahydrofuran (10 mL) was added 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (9.66 mL, 9.66 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched by the addition of 2N hydrochloric acid (50 mL), extracted with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL) dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/ethyl acetate (5/1) to afford 1.30 g (92%) of the title compound as colorless oil:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([N:11]3[CH2:19][C:18]4[C:13](=[C:14]([Cl:20])[CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])=[CH:9][N:8]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:49]2[CH:54]=[CH:53][C:52]([S:55]([CH:58]3[CH2:63][CH2:62][N:61]([C:64]([O:66]C(C)(C)C)=[O:65])[CH2:60][CH2:59]3)(=[O:57])=[O:56])=[CH:51][CH:50]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:21])[N:11]([C:10]1[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:49]4[CH:50]=[CH:51][C:52]([S:55]([CH:58]5[CH2:59][CH2:60][N:61]([C:64]([O:66][C:13]([CH3:18])([CH3:14])[CH3:12])=[O:65])[CH2:62][CH2:63]5)(=[O:56])=[O:57])=[CH:53][CH:54]=4)[N:3]=3)[N:8]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:9]=1)[CH2:19]2
Reactant: O=C1c2c(Cl)cccc2CN1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(-c3cnc4c(n3)c(N3Cc5cccc(Cl)c5C3=O)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)CC1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
2-(2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl)-7-chloro-isoindolin-1-one (150 mg, 0.2476 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (112 mg, 0.2476 mmol) and Na2CO3 (371 μL of a 2.0 M aqueous solution, 0.7428 mmol) combined in 1,4-dioxane (3 mL) under N2. Mixture de-gassed (×3 vacuum-N2 cycles) then Pd(PPh3)4 (14 mg, 0.01238 mmol) added. Reaction mixture de-gassed (×3 cycles) and stirred overnight at 110° C. Reaction cooled and partitioned between DCM and water. Aqueous phase extracted with DCM and combined organics dried and concentrated. Residue purified by chromatography (silica, 0-100% EtOAc-petroleum ether gradient elution). Title compound obtained as a yellow solid (186 mg, 88%), taken directly on to deprotection reaction; MS (ES+) 850.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](F)[N:17]=2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH:23]1([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CS(C)=O>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:30][CH2:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:17]=2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: NCC1CCCCC1
Reactant: N[C@H]1CC[C@H](Nc2ncc(Cl)c(-c3cccc(F)n3)n2)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2ncc(Cl)c(-c3cccc(NCC4CCCCC4)n3)n2)CC1
Temperature: 105 °C
Reaction time: 24 h

Procedure:
A mixture of trans-N1-(5-chloro-4-(6-fluoropyridin-2-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (12 mg, 0.037 mmol), cyclohexylmethanamine (42.2 mg, 0.373 mmol), and DMSO (0.35 ml) was stirred at about 105° C. for about 24 hours. The excess cyclohexylmethanamine was removed under vacuum to yield a residue. The residue was mixed with 0.5 ml DMSO, filtered, purified by prep HPLC and then lyophilized to yield 9.4 mg of the title compound as a TFA salt. LCMS (m/z): 415.3 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, METHANOL-d4, 45° C.) δ ppm 0.89-1.07 (m, 2 H) 1.10-1.30 (m, 3 H) 1.30-1.54 (m, 4 H) 1.55-1.65 (m, 2 H) 1.69 (d, J=12.91 Hz, 2 H) 1.76 (d, J=12.91 Hz, 2 H) 1.96-2.14 (m, 4 H) 2.98-3.10 (m, 1 H) 3.18 (d, J=6.65 Hz, 2 H) 3.71-3.82 (m, 1 H) 7.03 (d, J=9.00 Hz, 1 H) 7.49 (br. s., 1 H) 7.83 (t, J=8.22 Hz, 1 H) 8.35 (s, 1 H)
Reaction SMILES: O.[NH2:2][NH2:3].C([O:6][C:7]([CH:9]1[CH2:17][CH2:16][C:12]2[O:13][CH:14]=[CH:15][C:11]=2[C:10]1=O)=O)C>C(O)C>[OH:6][C:7]1[C:9]2[CH2:17][CH2:16][C:12]3[O:13][CH:14]=[CH:15][C:11]=3[C:10]=2[NH:3][N:2]=1
Reactant: CCOC(=O)C1CCc2occc2C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Oc1n[nH]c2c1CCc1occc1-2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Hydrazine monohydrate was added to an ethanol (50 ml) solution of 3.00 g 5-ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]furan, and the mixture was stirred at room temperature for 14 hours. The solvent was evaporated under a reduced pressure, and the residue was washed with hexane/ethyl acetate and dried under a reduced pressure to give 4,5-dihydro-3-hydroxy-1H-furo[2,3-g]indazole. Diazomethane (2 eq.) was added to a mixed solution of 1,4-dioxane (10 ml) and methanol (20 ml) containing 1.50 g of the thus obtained compound, and the mixture was stirred at room temperature for 1 hour. Acetic acid was added to the reaction mixture until gas evolution stopped, and then the solvent was evaporated under a reduced pressure. The residue was extracted with chloroform and washed with saturated sodium bicarbonate aqueous solution, and the thus obtained organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent, the solvent was evaporated and the residue was purified by a silica gel column chromatography to give 0.80 g of 4,5-dihydro-3-methoxy-1H-furo[2,3-g]indazole. From this compound, 3-methoxy-1H-furo[2,3-g]indazole was obtained in the similar manner as described in Reference Example 60.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1([CH:19]=[CH:20][C:21](O)=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl.Cl>>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([CH:19]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][CH:10]=3)[CH2:20][C:21](=[O:22])[O:5]2)=[CH:7][CH:8]=1
Reactant: O=C(O)C=Cc1cccc2ccccc12
Reactant: Oc1cccc(O)c1
Agent: Cl
Product: O=C1CC(c2cccc3ccccc23)c2ccc(O)cc2O1
Yield: 64 %

Procedure:
Condensation of resorcinol with 3-(1-naphthyl)acrylic acid in the presence of hydrochloric acid/hydrogen chloride (method of J. D. Simpson and H. Stephen, J. Chem. Soc. (London) 1936, 1382) gave the desired dihydrocoumarin, m.p. 203.5°-206.5°, in 64% yield.
Reaction SMILES: BrCCBr.Cl[C:6]1([F:24])[C:11](Cl)([F:12])[O:10][C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:8]([F:23])([C:19]([F:22])([F:21])[F:20])[O:7]1>[Zn].CN(C=O)C>[F:18][C:9]1([C:14]([F:15])([F:16])[F:17])[C:8]([F:23])([C:19]([F:22])([F:21])[F:20])[O:7][C:6]([F:24])=[C:11]([F:12])[O:10]1
Reactant: FC(F)(F)C1(F)OC(F)(Cl)C(F)(Cl)OC1(F)C(F)(F)F
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: FC1=C(F)OC(F)(C(F)(F)F)C(F)(C(F)(F)F)O1
Temperature: 105 °C
Yield: 43.1 %

Procedure:
A mixture of 16.4 g (0.25 mol) of zinc dust, 200 mL of dry DMF, and 2 mL of 1,2-dibromoethane was stirred under N2 while a small portion of 41 g (0.112 mol) of 20 was added. The mixture was heated until reaction had started (ca. 90° C.), then the remainder of 20 was added dropwise at a rate sufficient to maintain temperature up to 105° C. in the pot while product was taken overhead as formed, bp 60°-65° C. When the addition had been completed, the pot temperature was increased until distillate was being collected at 135° C. The distillate was washed with water, dried over CaSO4, filtered and distilled to afford 14.2 g (43%) of perfluoro-2,3-dimethyl-2,3-dihydro-1,4-dioxin (21), bp 65°-67.5° C.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[N:17][CH:18]=[C:19]([CH:21]([N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH3:22])[CH:20]=3)[N:12]=[C:11]([CH3:42])[N:10]=2)=CC=1.FC(F)(F)C(O)=O>>[CH3:41][O:40][C:37]1[N:36]=[CH:35][C:34]([NH:33][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:42])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25][CH2:24]3)[CH3:22])=[CH:18][N:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
N,N-Bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (499.0 mg, 0.6744 mmol) was dissolved in trifluoroacetic acid (10.4 mL, 140 mmol) and the flask was fitted with a reflux condenser, placed in a preheated oil bath (75° C.) and stirred overnight. Then, the reaction was cooled to room temperature, concentrated, diluted with DCM (40 mL) and treated with saturated sodium bicarbonate, water, and 5 N NaOH until the pH of the aqueous phase was about 7. Then, the layers were separated, and the aqueous phase was extracted with DCM and 10:1 DCM/MeOH. During these extractions, 5 N NaOH was added to the aqueous phase to raise the pH from about 5 to about 11. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 75:1 DCM/MeOH to 50:1 DCM/MeOH to 35:1 DCM/2 N ammonia in MeOH to 20:1 DCM/2 N ammonia in MeOH to 10:1 DCM/2 N ammonia in MeOH) to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (241.9 mg, 72% yield) as a yellow powder. 1H NMR (CDCl3, 400 MHz) δ 11.68 (s, 1H), 8.71 (s, 1H), 8.36 (d, J=2.74 Hz, 1H), 8.27 (d, J=2.35 Hz, 1H), 8.13 (dd, J=8.80 Hz, 2.74 Hz, 1H), 6.79 (d, J=8.80 Hz, 1H), 5.42 (br s, 2H), 3.95 (s, 3H), 3.60-3.52 (m, 1H), 3.30-3.20 (m, 4H), 2.77 (s, 3H), 2.70-2.53 (m, 7H), 1.45 (d, J=6.06 Hz, 3H). m/z (ESI, +ve ion) 500 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][OH:32])[C:6]=2[CH:33]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][O:32][C:34](=[O:36])[CH3:35])[C:6]=2[CH:33]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(CCO)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in pyridine (6 ml) is added acetic anhydride (0.09 ml), and the mixture is stirred at 80° C. for 2 hours. The reaction solution is poured into water, and extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid, water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-(2-acetyloxyethyl)-1-[6-(2-chlorobenzoylamino )nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (230 mg) as white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.O>C1COCC1>[OH:21][C:18]1([C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C2(O)CCOCC2)c1
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of 5-bromo-m-xylene (5.55 g) in THF (60 ml) was added n-butyl lithium (17.8 ml) at −78° C. under an atmosphere of argon. The mixture was stirred for 1 hour. To the reaction solution was added tetrahydropyran-4-one (2.0 g) and the mixture was stirred for additional 3 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane=1:3) to give the title compound (2.6 g) having the following physical data.