Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].ClC1C=NC=C(Cl)C=1CO>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)cncc1Br
Agent: OCc1c(Cl)cncc1Cl
Product: OCc1c(Cl)cncc1Br

Procedure:
A solution of LDA (7.94 mL, 1.8 M in THF/heptane/ethylbenzene, 14.3 mmol) in anhydrous THF (30 mL) at −78° C. under Ar was treated dropwise with a solution of 3-bromo-5-chloro-pyridine (2.5 g, 13.0 mmol) in anhydrous THF (30 mL) The solution was stirred at −78° C. for 30 min, then a solution of ethyl formate (10.46 mL, 130 mmol) in anhydrous THF (30 mL) was added dropwise. The resulting solution was stirred at −78° C. for 1.5 h and then treated with saturated NaHCO3 with vigorous stirring. The quenched mixture was extracted with EA (2×25 mL) and the combined organic extracts were washed with saturated NaHCO3 (15 mL) and dried over Na2SO4. The residue was purified by flash chromatography on silica gel with EA/hexane to provide 3-bromo-5-chloro-pyridine-4-carbaldehyde as a yellow solid. Reduction of the aldehyde according to the synthesis of (3,5-dichloro-pyridin-4-yl)-methanol yielded the title compound. MS (m/z): 224.0 [M+H+].
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(S)CCS.B(F)(F)F.S1CCCCS1.[Li]CCCC.[C:31](OC)(=[O:40])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN1CCN(C)C1=O>C(Cl)Cl>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[CH2:1][CH:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:32][C:31]2=[O:40]
Reactant: COC(=O)C=Cc1ccccc1
Reactant: COc1ccccc1C=O
Agent: C1CCSSC1
Agent: FB(F)F
Agent: SCCCS
Solvent: CN1CCN(C)C1=O
Solvent: ClCCl
Product: COc1cccc2c1CC(c1ccccc1)CC2=O

Procedure:
o-Anisaldehyde (20.5 g) was treated with 1,3-propanedithiol (24 ml) in the presence of BF3 etherate (4 ml) and CH2Cl2 (300 ml). This dithiane derivative (4.7 g) was reacted with n-BuLi (2.5 M hexane solution) (7.3 ml), methyl cinnamate (3.4 g) and 1,3-dimethyl-2-imidazolidone-(4.6 ml) affording the desired product (M+H)+ 389. Desulfurization was accomplished with Raney Nickel and EtOH, followed by hydrolysis to the desired carboxylic acid. Cyclization to the desired 5 methoxy 3 phenyl 1 tetralone was accomplished by heating with polyphosphoric acid, (M+H)+ 253.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[N:5][CH:4]=1.C([N:18]=[C:19]=[S:20])(=O)C1C=CC=CC=1>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:19]([NH2:18])=[S:20])[CH:6]=[N:5][CH:4]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cncc(N)n1
Solvent: CCO
Product: COc1cncc(NC(N)=S)n1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
6-Methoxy-pyrazin-2-ylamine (0.85 g, 6.8 mmol) is dissolved in ethanol (7 ml) and benzoylisothiocyanate (0.91 ml) is added dropwise. The mixture is heated to 80° C. with stirring for 10 minutes then allowed to cool to room temperature. The solvent is removed in vacuo and the resulting solid dissolved in 1M sodium hydroxide (15 ml) and heated under reflux for 1 hour. The resultant suspension is filtered and the solid washed with water and a little cold ethanol. The solid is dried in vacuo to yield the title compound.
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH:12]1([CH2:11][CH2:10][NH:9][CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N(CCC(N)=O)CCC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)CCNCCC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Next, a 4 N solution of hydrogen chloride in 1,4-dioxane (3.1 ml) was added to 3-[N-(t-Butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionamide (0.37 g, 1.2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diisopropyl ether was added to the resulting solid, and the solid was filtered off to give 0.30 g (quantitatively) of the titled compound as colorless crystals.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]1[CH:6]=[CH:7][C:8]([CH3:24])=[C:9]([NH:11][C:12]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[S:13])[CH:10]=1)[CH2:2][CH3:3].BrBr>C(Cl)(Cl)(Cl)Cl.O>[C:20]1([CH3:21])[CH:19]=[C:18]([CH3:22])[CH:17]=[C:16]([CH3:23])[C:15]=1[NH:14][C:12]1[S:13][C:10]2[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:25][CH2:26][CH3:27])=[CH:6][CH:7]=[C:8]([CH3:24])[C:9]=2[N:11]=1
Reactant: CCCN(CCC)c1ccc(C)c(NC(=S)Nc2c(C)cc(C)cc2C)c1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCN(CCC)c1ccc(C)c2nc(Nc3c(C)cc(C)cc3C)sc12
Yield: 39.2 %

Procedure:
To a mixture of 1-(5-dipropylamino-2-methylphenyl)-3-mesitylthiourea (100 mg, 0.261 mmol) in carbon tetrachloride (10 ml) was added dropwise bromine (0.015 ml, 0.287 mmol) in carbon tetrachloride (5 ml) over 30 min. The mixture was refluxed for 18 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water and brine and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 39 mg of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[S:10]([CH:13]([CH3:16])[CH:14]=O)[C:11]#[N:12]>>[ClH:9].[Cl:9][C:6]1[N:7]=[CH:8][C:3]([N:2]2[CH:14]=[C:13]([CH3:16])[S:10][C:11]2=[NH:12])=[CH:4][CH:5]=1
Reactant: CC(C=O)SC#N
Reactant: Nc1ccc(Cl)nc1
Agent: Cl
Product: Cc1cn(-c2ccc(Cl)nc2)c(=N)s1

Procedure:
The title compound was prepared from 5-amino-2-chloropyridine hydrochloride and 2-thiocyanatopropanal as described for Example 160A. The title compound was used without additional purification.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1c(F)cccc1Cl
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3c(F)cccc3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-6-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])(=[O:3])[CH3:2].C(OCCCCC=CCCCCOC(=O)C)(=O)C.ClCCC=CCCCl>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][Cl:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCCl
Agent: CC(=O)OCCCCC=CCCCCOC(C)=O
Agent: ClCCC=CCCCl
Product: CC(=O)OCCCCC=CCCCl

Procedure:
FIG. 24A shows a synthesis of 8-chlorooctan-1-yl acetate, in which 1,10-diacetoxy-5-decene is cross-metathesized with 1,6-dichloro-3-hexene to yield 8-chloro-5-octen-1-yl acetate, which is reduced to yield 8-chlorooctanyl acetate.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonarnide (61.2 mg) in acetonitrile (10 mL) were added sodium iodide (49.3 mg) and chloro(trimethyl)silane (0.166 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate to give the title compound (53.4 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=5)(=[O:27])=[O:26])=[CH:19][CH:20]=4)[C:15](=[N:36][NH:37]C(OC(C)(C)C)=O)[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[N:36](=[C:15]1[C:14]2[CH:13]=[C:12]([S:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)(=[O:10])=[O:11])[CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][C:18]([S:25]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=1)(=[O:27])=[O:26])=[CH:19][CH:20]=2)[NH2:37]
Reactant: CC(C)(C)OC(=O)NN=C1c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc2-c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: NN=C1c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc2-c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
The product from Example 4A (218 mg, 0.34 mmol) in absolute ethanol was treated with three crystals of p-toluenesulfonic acid and heated at reflux. After 3 hours, the mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (85% ethyl acetate/hexanes) to provide the title compound as a yellow solid (36 mg, 20% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.41 (d, 2H), 8.78 (bs, 2H), 8.63 (bs, 1H), 8.28 (d, 1H), 8.02-8.1 (m, 2H), 7.81 (dd, 1H), 7.70 (dd, 1H), 6.91-7.01 (m, 2H), 6.49-6.61 (m, 4H), 6.33-6.42 (m, 2H); MS (ESI) 535 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][P:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:21][CH3:22])[CH:15]=1)(=[O:12])[O:6][CH2:7][C:8]([F:11])([F:10])[F:9].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=2[C:35]([NH:37][CH3:38])=[O:36])[C:29]([C:43]([F:46])([F:45])[F:44])=[CH:28][N:27]=1>>[F:24][C:2]([F:1])([F:23])[CH2:3][O:4][P:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:26]2[N:31]=[C:30]([NH:32][C:33]3[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=3[C:35](=[O:36])[NH:37][CH3:38])[C:29]([C:43]([F:46])([F:44])[F:45])=[CH:28][N:27]=2)=[C:16]([O:21][CH3:22])[CH:15]=1)(=[O:12])[O:6][CH2:7][C:8]([F:9])([F:10])[F:11]
Reactant: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1N
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)cc2OC)ncc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure for Example 102 bis(2,2,2-trifluoroethyl)(4-amino-3-methoxybenzyl)phosphonate (Compound 114A, 38 mg, 0.1 mmol) and 2-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-methylbenzamide (33 mg, 0.1 mmol). The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=2.73 (s, 3H), 3.52 (d, J=21.6 Hz, 2H), 3.73 (s, 3H), 4.60-4.65 (m, 4H), 6.81 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 7.05 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.2 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.65 (dd, J=1.2, 7.6 Hz, 1H), 8.34 (s, 1H), 8.38 (s, 1H), 8.68 (d, J=4.4 Hz, 1H), 8.71 (s, 1H), 11.42 (s, 1H). MS (ES+): m/z 676.05 [MH+]; HPLC: tR=3.69 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Oc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, phenol and DBU in DME. EI-MS m/e (%): 278 (M+, 100), 277 ([M—H]+, 22), 250 (68), 249 (89).
Reaction SMILES: C([O:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:14]2)=[CH:9][CH:8]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:36])([F:34])[F:35])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([O:18][C@H:15]4[CH2:16][CH2:17][N:13]([C:10]5[CH:11]=[CH:12][C:7]([C:6]([OH:43])=[O:5])=[CH:8][CH:9]=5)[CH2:14]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](Oc3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(N2CC[C@H](Oc3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
The above 4-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-benzoic acid tert-butyl ester (150 mg) was dissolved in a mixture of methylene chloride (2 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 1 hr and solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was dried and solvents were evaporated. The residue was triturated with ethyl acetate and hexanes to give a tan solid as 4-((S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-benzoic acid (75 mg). LC-MS for C28H22F3N3O5 (m/e) calcd 537, obsd 538 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N+:4]=1[O-:30]
Reactant: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(C(F)(F)F)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Nc1nc(N)[n+]([O-])c(C(F)(F)F)c1-c1cccc(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 14 by reaction with MCPBA in CHCl3 at room temperature. Mp. 275°-278° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29]([C:32](O)=[O:33])[CH:30]=[N:31][C:23]1=2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:32]([C:29]3[CH:30]=[N:31][C:23]4[N:22]([CH3:21])[CH2:27][CH2:26][O:25][C:24]=4[CH:28]=3)=[O:33])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: CN1CCOc2cc(C(=O)O)cnc21
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CN1CCOc2cc(C(=O)Nc3cnc(OCC(F)(F)F)c(-c4ccc(Cl)cc4)c3)cnc21

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 3,4-dihydro-4-methyl-2H-pyrido[3,2-b]-1,4-oxazine-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 479.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:22][CH:23]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Product: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cn1
Yield: 6.8 %

Procedure:
Following general procedure D, (6-bromo-4-(6-(2-(dimethylamino)ethylamino)pyridin-3-ylamino)quinolin-3-yl)(cyclopropyl)methanone (75 mg, 0.17 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (69 mg, 0.25 mmol) to afford the desired product (6 mg, 7%) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.25 (dd, J=8.8, 1.9 Hz, 1H), 8.22-8.15 (m, 2H), 8.03 (d, J=8.8 Hz, 1H), 7.69 (dd, J=9.1, 2.6 Hz, 1H), 7.27-7.18 (m, 2H), 6.95 (d, J=9.1 Hz, 1H), 3.87-3.81 (m, 2H), 3.46-3.39 (m, 2H), 2.97 (s, 6H), 2.89-2.78 (m, 1H), 1.28-1.17 (m, 4H); ESI MS m/z 520 [C28H27ClFN5O2+H]+; HPLC>99% (AUC), tR=10.34 min.
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:10]=[CH:9][N:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>O.[Cl-].C([N+](CC)(CC)CC)C.CCOC(C)=O.[Cl-].[Na+].O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]=[C:16]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[O:13][CH2:14][CH2:15]1
Reactant: C=CCCOc1cccnc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C1CCOc2cccnc21
Temperature: 25 °C
Yield: 67.5 %

Procedure:
An anhydrous DMF solution (120 mL) of 2-bromo-3-but-3-enyloxy-pyridine (6.43 g, 28.2 mmol) in a round bottom schlenk flask was degassed with argon using the freeze/pump/thaw method. To this freshly degassed solution was added triphenylphosphine (2.66 g, 10.2 mmol), palladium acetate (696 mg, 3.10 mmol), potassium acetate (13.84 g, 141 mmol), and tetraethylammoniumchloride hydrate (9.35 g, 56.4 mmol). The resultant mixture was heated at 110 IC under argon for 18 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (300 mL), brine (120 mL) and H2O (60 mL). The organic phase was separated and washed with brine (3×120 mL) and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatograph on silica gel (Hexanes/EtOAc, 95:5) afforded 4-methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine (2.8 g, 67%) as a white solid. 1H NMR (CDCl3) δ 2.79-2.86 (m, 2H), 4.25 (t, 2H, J=5.7 Hz), 5.08 (d, 1H, J=1.6 Hz), 6.19 (d, 1H, J=1.6 Hz), 7.08-7.17 (m, 2H), 8.20 (dd, 1H, J=4.7, 1.6 Hz).
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:22][C@H:23]([OH:40])[CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:28][CH:27]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)C.C([O-])=O.[NH4+]>CO.[Pd]>[OH:40][C@H:23]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:28][CH:27]=1)[CH2:22][NH:21][CH2:20][CH:17]1[CH2:16][CH2:15][N:14]([C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:41])=[O:3])=[CH:6][CH:7]=2)=[O:13])[CH2:19][CH2:18]1
Reactant: CCOC(=O)c1ccc(NC(=O)N2CCC(CNC[C@H](O)COc3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)N2CCC(CNC[C@H](O)COc3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
A mixture of 4-[(4-{[(2S)-2-hydroxy-3-(4-benzyloxy-phenoxy)-propylamino]-methyl}-piperidine-1-carbonyl)-amino]-benzoic acid ethyl ester (0.11 g, 0.43 mmol) and ammonium formate (0.063 g, 1 mmol) in 5 mL of methanol over 0.110 g of 10% palladium on carbon was stirred at ambient temperature overnight. The catalyst was filtered (solka floc) and the filtrate concentrated in vacuo. Trituration of the crude solid foam with Et2O provided 0.061 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:36]>C(Cl)Cl.CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH2:36])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(N)=O)cc2)CC(C)(C)C1
Reaction time: 1 h
Yield: 15 %

Procedure:
To a stirred suspension of (2E)-3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoic acid (16) (0.18 g, 0.46 mmol) in CH2Cl2 (6 mL) at room temperature was added oxalyl chloride (0.15 mL, 0.218 g, 1.72 mmol, 3.7 eq) followed by several drops of DMF (Note: vigorous bubbling occurred upon addition of DMF). The reaction mixture was stirred under a nitrogen atmosphere for 1 h and concentrated in vacuo. Toluene was added to the crude acid chloride and the solvent was removed in vacuo. To the crude acid chloride was added ammonia (0.5 M in 1,4-dioxane) (6 mL) and the turbid reaction mixture stirred at room temperature under a nitrogen atmosphere for 3 h. Ammonia (0.5 M in 1,4-dioxane) (2 mL) was added to the reaction mixture and stirring was continued overnight at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo. Ammonia (0.5 M in 1,4-dioxane) (8 mL) and CH2Cl2 (8 mL) were added to the residue. The flask was equipped with a rubber septum and the reaction mixture was stirred at room temperature for 2 d. The reaction mixture was transferred to a separatory funnel and partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous phase was extracted with CH2Cl2. The organic extracts were combined, washed with brine, dried (MgSO4) filtered, and the filtrate was concentrated to give the crude product as an amorphous solid. The crude product was purified by flash chromatography on silica gel with CH2Cl2:MeOH (100:0 to 19:1) as eluant to provide the product which was dried to give 0.026 g (15%) of compound 17 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (s, 6H), 0.88 (s, 6H), 1.25 (s, 2H), 1.89 (s, 2H), 1.92 (s, 2H), 6.53 (d, J=15.8 Hz, 1H), 6.66 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 7.06 (br s, 1), 7.14 (d, J=8.1 Hz, 2H), 7.35 (d, J=15.9 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.50 (br s, 1H), 9.30 (s, 1). HRMS (ESI) Calcd for C26H32NO2: 390.2433 (M+H)+. Found: 390.2427.