Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH:6]([N:20](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([F:19])[CH:8]=1)[CH3:2]>CCO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH:6]([NH2:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([F:19])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccc(-c2ccccc2)c(F)c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC(N)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 12 h

Procedure:
A solution of the dibenzylamine 13-3 (5.65 gm, 11.75 mmol) in EtOH/HOAc (90/10 mL) was purged with argon and treated with Pd(OH)2 (3 g) and placed under 1 atm of H2 gas for 12 h. Additional portions (2.5 g) or Pd(OH)2 were added after 24 h, 48 h and 144 h. The reaction mixture was purged with argon, filtered through Celite, and the filtrate dissolved in aq HCl (pH=1) The aqueous solution was washed with EtOAc, neutralized with satd aq NaHCO3, and extracted with EtOAc (3×30 mL). The combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated to give the desired product 13-4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[CH3:9][C:4]1[CH:5]=[C:6]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:11]([F:22])([F:21])[F:10])[CH:17]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Cl)nc(N)n1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(N)n1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 2.0 g (14 mmol) 2-amino-4-chloro-6-methylpyrimidine and 3.4 g (18 mmol) 3-trifluoromethyl-phenyl boronic acid. Yield after extraction: 5.0 g (99%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and thiophene-2-sulfonyl chloride (80 mg, 0.437 mmol), the title compound was obtained as a white solid (93 mg, 65% yield). MS (ESI): 489.9 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([N:14]([CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:35]1[CH:40]=[C:39]([C:41]2[C:50]3[C:45](=[CH:46][C:47]([O:53][CH3:54])=[C:48]([O:51][CH3:52])[CH:49]=3)[CH:44]=[C:43]([CH2:55][OH:56])[C:42]=2[CH2:57][OH:58])[CH:38]=[CH:37][N:36]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:1]=[C:2]1[CH:11]=[C:10]([C:12]([N:14]([CH2:25][CH2:26][OH:27])[CH2:15][CH2:16][OH:17])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:35]1[CH:40]=[C:39]([C:41]2[C:50]3[C:45](=[CH:46][C:47]([O:53][CH3:54])=[C:48]([O:51][CH3:52])[CH:49]=3)[CH:44]=[C:43]([CH2:55][OH:56])[C:42]=2[CH2:57][OH:58])[CH:38]=[CH:37][N:36]=1
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)cc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)c5ccccc54)c3)c2cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)cc(C(=O)N(CCO)CCO)c5ccccc54)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 1-{2-(2-oxo-4-bis(2-tert-butyldimethylsilyloxyethyl)aminocarbonyl-1,2-dihydroquinolin-1-yl]-4-pyridyl}-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (1.9 g) in tetrahydrofuran (20 ml) is added a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2.8 ml) under ice-cooling, and the mixture is stirred at room temperature for one hour. After the reaction is complete, the mixture is concentrated under reduced pressure to remove the solvent, and to the resultant are added methylene chloride and an aqueous sodium hydrogen carbonate solution. The methylene chloride layer is separated, washed, dried, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=10:1~5:1), and triturated with ether to give 1-{2-(2-oxo-4-bis(2-hydroxyethyl)aminocarbonyl-1,2-dihydroquinolin-1-yl)-4-pyridyl}-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.68 g) which is listed in Table 7.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].Cl.C1C(O)=CC=CC=1C.[CH3:19][NH:20][C:21]#[N:22].[OH-].[Na+]>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:21]([NH:20][CH3:19])=[NH:22]
Reactant: CNC#N
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: CNC(=N)Nc1c(Cl)cccc1Cl

Procedure:
To 51 g (0.315 mole) of 2,6-dichloroaniline is added 0.4 moles of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 17.7 g (0.315 mole) of methyl cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2×1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dichlorophenyl)-3-methylguanidine hydrochloride.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:15][CH:16]=1)=O)(C)(C)C>O1CCOCC1.ClCCl>[NH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:23])[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:15][CH:16]=1
Reactant: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)c1ccc(CN)cn1
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Add 4N hydrogen chloride in dioxane (1 mL) to a solution of 5-tert-butoxycarbonylaminomethyl-2-(3,3-dimethyl-butyryl)-pyridine (104 mg, 0.339 mmol) in anhydrous dichloromethane (4 mL) and stir the solution overnight. Concentrate in vacuo and partition the residue between saturated aqueous NaHCO3 and dichloromethane. Extract the aqueous phase with dichloromethane (2×15 mL) and EtOAc (2×15 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound as an oil (62 mg, 88%) that was used without any further purification. MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][NH2:21]>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:21][CH2:20][C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccccc2c1Cl
Reactant: NCc1cccs1
Solvent: O
Product: N#Cc1c(N)nc2ccccc2c1NCc1cccs1

Procedure:
5 g of 2-amino-3-cyano4-chloroquinoline, prepared as described in Example 1, is stirred with 11 ml of 2-thienylmethylamine at 130° C. for 3 hours. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale yellow material is recrystallized from 25 ml of ethanol to obtain 5.2 g of title compound, mp.: 208° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30]Cl>CS(C)=O.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(NCCCCOc2ccc3ccccc3c2)cc1
Temperature: 130 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and p-anisidine (0.4 gm, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 130° C. for 7 hrs. and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get as oily compound which was later crystallized by benzene hexane to get N-(4-methoxyphenyl)-[4-(naphthalen-2-yloxy)butyl]amine, yellow solid, m.p 95° C., (yield 0.67 gm, 97.8%).
Reaction SMILES: Br[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:12]([B-](F)(F)F)=[CH2:13].[K+].C(N(CC)CC)C>CC(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:12]([C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH2:13]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1ncccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=Cc1cccnc1C(=O)OC
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Methyl 3-bromopyridine-2-carboxylate (1.0 g, 4.63 mmol) and potassium vinyltrifluoroborate (CAS number 13682-77-4; 0.744 g, 5.56 mmol) were dissolved in IPA (15 ml). To this was then added triethylamine (0.467 g, 4.63 mmol) and the mixture was degassed under nitrogen atmosphere for 15 minutes. [1,1′-Bis(diphenyl phosphino)ferrocene]dichloropalladium(II) (0.075 g, 0.092 mmol) was added and the reaction was stirred at 100° C. for 4 hours. The reaction was diluted with water (75 ml) and filtered through diatomaceous earth (commercially sold under the trade mark “Celite”). The organics were extracted with ethyl acetate (3×50 ml), washed with water (25 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-18% ethyl acetate/n-hexane to afford the title compound.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:36][CH3:37])[C@@H:33]([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:36][CH3:37])[C@@H:33]([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)[C@H](C)O
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1)[C@H](C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.2 mL, 10.96 eq, 1.14 mmol) followed by (2S,3R)-3-amino-pentan-2-ol (60 mg, 5.5 eq, 0.58 mmol). The reaction mixture was placed in a preheated oil bath at 160° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSo4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 36.1 mg (93%). (80% de 3R,2S: 20% de 3R,2R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.91 & 1.06 (2×t, 3H, J=7.11 & 7.42 Hz, —NHCH(CH2CH3)CH(CH3)OH), 1.16 & 1.29 (2×d, 3H, J=6.48 & 3.48 Hz, —NHCH (CH2CH3)CH3)OH) 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.71-2.01 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 3.98 (m, 2H, —NHCH(CH2CH3)CH(CH3)OH), 4.58-4.69 (m, 1H, —CH(CH3)2), 4.83-5.00 (m, 2H, —HNCH2-Pyr), 6.75-6.91 (m, 1H, —HNCH2-Pyr), 7.19-7.25 (m, 1H, Pyr-H), 7.37 (d, 1H, J=8.05 Hz, Pyr-H), 7.57 (s, 1H, —N═CH—N), 7.64-7.71 (m, 1H, Pyr-H), 8.61 (d, 1H, J=4.58 Hz, Pyr-H). FABMS m/z (relative intensity): 370 ([M+H]+, 100), 324 (40). Accurate Mass (M+H): Actual: 370.2355, Measured: 370.2347.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH3:17])=[O:15]>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3]
Reactant: COC(=O)C1CCCCC1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCC[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
MsCl (0.543 mL, 6.97 mmol) was added to a solution of methyl 2-(hydroxymethyl)cyclohexanecarboxylate (1.0 g, 5.8 mmol, Rieke) in DCM (4 mL) at about 0° C. TEA (0.971 mL, 6.97 mmol) was then added. The mixture was stirred at rt for about 4 h. The mixture was washed with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give (trans)-methyl 2-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (1.4 g, 100%). LC/MS (Table 2, Method c) Rt=1.35 min; MS m/z 251 (M+H)+.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14]([C:26]#[N:27])=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[F:37][CH:38]([F:50])[O:39][C:40]1[CH:41]=[N:42][C:43](S(C)(=O)=O)=[N:44][CH:45]=1.CCOC(C)=O>CN1C(=O)CCC1>[F:37][CH:38]([F:50])[O:39][C:40]1[CH:41]=[N:42][C:43]([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:15]3[C:14]([C:26]#[N:27])=[N:13][N:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=4)[C:17](=[O:18])[CH:16]=3)[CH2:21][CH2:22]2)=[N:44][CH:45]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1
Reactant: CS(=O)(=O)c1ncc(OC(F)F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-n2nc(C#N)c(OC3CCN(c4ncc(OC(F)F)cn4)CC3)cc2=O)cc1
Temperature: 100 °C
Yield: 15.4 %

Procedure:
To a stirring solution of 1-(4-(methylsulfonyl)phenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl (example 47 step A) (41 mg, 0.10 mmol) in NMP (3 mL) at room temperature under argon was added DIPEA (38.8 mg, 0.30 mmol) and 5-(difluoromethoxy)-2-(methylsulfonyl)pyrimidine (22.4 mg, 0.1.0 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. After cooling to room temperature, 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜3 ml) and loaded onto a 24 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 8 mg (15% for two steps) of 4-(1-(5-(difluoromethoxy)pyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile was obtained as a tan solid 1H NMR (400 MHz, CDCl3) δ ppm 1.75-2.27 (m, 4H) 3.08 (s, 3H) 3.66-3.97 (m, 2H) 3.97-4.24 (m, 2H) 4.54-4.95 (m, 1H) 6.34 (s, 1H) 7.84 (d, J=8.79 Hz, 2H) 8.07 (d, J=8.79 Hz, 2H) 8.24 (s, 2H). MS (ESI) 519 (M+H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C[O-].[K+].Cl[CH2:11][CH2:12][CH2:13][Si:14]([O:19][CH3:20])([O:17][CH3:18])[O:15][CH3:16]>CO.C1C=CC(NC2C=CC(NC3C=CC=CC=3)=CC=2)=CC=1.[Cl-].C(C(CCCC)C[N+]1C=CC(N(C)C)=CC=1)C>[C:1]([O:6][CH2:11][CH2:12][CH2:13][Si:14]([O:19][CH3:20])([O:17][CH3:18])[O:15][CH3:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: C=C(C)C(=O)O
Agent: CCCCC(CC)C[n+]1ccc(N(C)C)cc1
Agent: C[O-]
Agent: [Cl-]
Solvent: CO
Product: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Temperature: 125 °C
Yield: 92.6 %

Procedure:
86 g (1 mol) of methacrylic acid was neutralized, while stirring, with 280 g of a 25% solution of potassium methylate in methanol. Thereafter, 0.6 g of N,N'-diphenyl-p-phenylenediamine, 2.8 g (0.009 mol) of 1-(2'-ethylhexyl)-4-dimethylaminopyridinium chloride and 198.5 g (1 mol) of 3-chloropropyltrimethoxysilane were added while continuously stirring, and the methanol was distilled off. The reaction mixture was maintained at 125° C. for 1.5 hours and, after cooling, it was separated from the precipitated potassium chloride by filtration. The potassium chloride was washed with methanol. The methanol was evaporated from the combined filtrates, and the residue was distilled under reduced pressure. 230 g of 3-methacryloxypropyltrimethoxysilane having a boiling of 82° C. (0.4 mbar) were obtained, which corresponds to a yield of 92.7% of theory, based on the amount of methacrylic acid used. The purity of the product was 98.5%. In the gas chromatogram only traces of 4-dimethylaminopyridine and 0.01% of 2-ethylhexyl methacrylate were detectable.
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)N.C([O:20][C:21](=[O:39])[C@H:22]([CH3:38])[NH:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)C(C)C>>[F:31][C:30]([F:32])([F:33])[C:28]1[CH:29]=[C:24]([NH:23][C@H:22]([C:21]([OH:39])=[O:20])[CH3:38])[CH:25]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:27]=1
Reactant: CC(C)COC(=O)[C@H](C)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: C[C@H](Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O

Procedure:
Following General Procedure J and using 3,5-di(trifluoromethyl)aniline (Aldrich) and isobutyl R-(+)-lactate (Aldrich), N-[3,5-di(trifluoromethyl)phenyl]-L-alanine isobutyl ester was prepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.38 in 10% EtOAc/hexanes). Purification was by preparative plate thin layer chromatography using 10% EtOAc/hexanes as the eluant.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][CH2:10][P:11]([CH3:16])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[C:56]([O-])([OH:58])=[O:57].[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:56]([OH:58])=[O:57])=[CH:3][CH:4]=1)=[O:17])([CH3:16])=[O:15])[CH3:14]
Reactant: CCOP(C)(=O)CCC(=O)c1ccc(Br)cc1
Reactant: O=C([O-])O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(C)(=O)CCC(=O)c1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Ethyl [3-(4-bromophenyl)-3-oxopropyl]methylphosphinate (3 g, 9.40 mmol), palladium(II) acetate (0.106 g, 0.470 mmol) and 1,3-bis(diphenylphosphino)propane (0.194 g, 0.470 mmol) were taken up in DMF (24 mL)/water (8 mL). CO was bubbled through for 10 minutes before adding DIPEA (3.28 mL, 18.80 mmol) and stirring at 70° C. under a balloon of CO overnight. Room temperature was attained and saturated NaHCO3 was added. The aqueous phase was extracted with EtOAc (×2) before acidifying with 2N HCl and extracting again with EtOAc (×2). The combined organic extracts from the acidic aqueous were washed with brine, dried over MgSO4 and concentrated in vacuo to give 4-{3-[(ethyloxy)(methyl)phosphoryl]propanoyl}benzoic acid as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH:25]4[CH2:27][CH2:26]4)[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.CCO.O.CCOC(C)=O.[Cl-].[Na+].O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH:25]1([C:21]2[CH:20]=[C:19]([C:8]3([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:32]5[CH:33]=[N:28][CH:29]=[N:30][CH:31]=5)[CH:3]=4)[C:16]4[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:18])=[N:9]3)[CH:24]=[CH:23][N:22]=2)[CH2:27][CH2:26]1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(C3CC3)c2)c2cccc(F)c21
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: COCCOC
Product: NC1=NC(c2cccc(-c3cncnc3)c2)(c2ccnc(C3CC3)c2)c2cccc(F)c21
Temperature: 150 °C
Yield: 61.9 %

Procedure:
To a solution of 1-(3-bromophenyl)-1-(2-cyclopropylpyridin-4-yl)-4-fluoro-1H-isoindol-3-amine (97 mg, 0.23 mmol) in DME:EtOH:water (6:3:1) (5 mL) was added pyrimidin-5-ylboronic acid (37.0 mg, 0.30 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium (II) dichloromethane adduct (9.38 mg, 0.01 mmol) and cesium carbonate (225 mg, 0.69 mmol). The vial was sealed and heated in a microwave reactor at 150° C. for 20 minutes. The reaction was diluted with EtOAc and brine, the layers were separated and the aqueous layer was extracted with EtOAc. The organics were combined, dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The crude was purified by preparative HPLC, appropriate fractions combined and the MeOH removed by evaporation. The remaining aqueous phase was basified by addition of sat. aqueous NaHCO3 (pH˜9) and extracted with dichloromethane (×3). The organics were combined, washed once with sat. aqueous NaHCO3, dried (Na2SO4), filtered and evaporated to give 60 mg (62%) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.Cl[C:13]1[N:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.C1OCCOCCOCCOCCOCCOC1>[F:11][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([O:10][C:13]2[N:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Oc1ccnc(OC(F)F)c1
Reactant: COc1cnnc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: COc1cnnc(Oc2ccnc(OC(F)F)c2)c1
Temperature: 25 °C
Yield: 45 %

Procedure:
2-Difluoromethoxy-4-hydroxypyridine (123 g, 0.764 mol), 3-chloro-5-methoxypyridazine (110.47 g, 0.764 mol), potassium carbonate (211.18 g, 1.53 mol), CuBr (54.80 g, 0.382 mol) and 18-crown-6 (1 g) were mechanically stirred under nitrogen in diglyme (1.28 L) at 100° C. for 30 h. The mixture was cooled to RT and partitioned between ethyl acetate and 2 L of 3% HCl. The layers were separated. The aqueous layer was then adjusted to pH--1 with conc. HCl and extracted twice with additional ethyl acetate. The combined organics were filtered through silica gel and then extracted twice with 1.5 N NaOH. Solids were formed which were removed by filtering the organic layer through silica gel and celite. The organic layer was dried (MgSO4), filtered through silica gel and evaporated in-vacuo. The residue was triturated with ethyl acetate and filtered to give pure 3-[[2-(difluoromethoxy)-4-pyridinyl]oxy]-5-methoxypyridazine (92.5 g, 45% yield) as a light brown solid, mp=119° C. -120.5° C.