Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([NH:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25](/[CH:29]=[CH:30]/[O:31][CH3:32])[N:24]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.C1CCCCC=1>CCO.[Pd]>[CH3:1][C:2]1([CH3:33])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([NH:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][O:31][CH3:32])[N:24]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CO/C=C/c1cccc(Nc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COCCc1cccc(Nc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Temperature: 120 °C
Yield: 13.4 %

Procedure:
To a solution of Example 441 (100 mg, 0.2 mmol) in EtOH (4 mL) was added cyclohexene (1 mL) and palladium on carbon (120 mg, 10% wt). The reaction mixture was heated at 120° C. under microwave irradiation for 1 h. Additional palladium on carbon (40 mg, 10% wt) was added and the reaction mixture heated at 130° C. under microwave irradiation for 5 h. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (12.5 mg, 12.5%) as a brown solid. δH (CDCl3) 8.11 (1H, d, J 2.4 Hz), 7.42 (1H, dd, J 8.1 and 7.3 Hz), 7.01 (1H, dd, J 8.9 and 2.4 Hz), 6.92 (1H, d, J 8.7 Hz), 6.68 (1H, d, J 7.9 Hz), 6.64 (1H, d, J 7.3 Hz), 6.42 (1H, br. s), 5.15 (1H, br. s), 4.26-4.38 (2H, m), 4.18-4.08 (2H, m), 3.76 (2H, t, J 6.8 Hz), 3.36 (3H, s), 2.94 (2H, t, J 6.8 Hz), 2.87 (2H, s), 1.39 (6H, s). LCMS (ES+) 466.18 (M+H)+, RT 2.17 minutes (Method 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:24][CH3:25])=[C:11]([CH:17]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)O)[C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]1[C:10]([CH2:24][CH3:25])=[C:11]([C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=1)[CH2:17][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(OCc2ccccc2)c(CC)c1C(O)c1ncc[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(OCc2ccccc2)c(CC)c1Cc1ncc[nH]1

Procedure:
2-(3-Benzyloxy-2,6-diethyl-benzyl)-1H-imidazole was prepared from rac-(3-benzyloxy-2,6-diethyl-phenyl)-(1H-imidazol-2-yl)-methanol, triethylsilane and trifluoroacetic acid in analogy to Example 191e): off-white crystals; MS (ISP): 321.0 ([M+H]+, 100%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([O:20]C)=[CH:15][C:14]=3[Cl:22])[C:8]2=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=3[Cl:22])[C:8]2=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C(Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
Dissolve 1-cyclohexyl-3-(2,6-dichloro-4-methoxy-benzyl)-pyrrolidin-2-one (86 g, 241.4 mmol) in 1300 mL dichloromethane then cool to 0° C. under nitrogen. Slowly add BBr3 (120.9 g, 482.75 mmol) to the stirring cold solution keeping the internal temperature below 3.5° C. Stir the solution cold for ˜2 hours, then pour into 4 L of saturated sodium bicarbonate and stir rapidly for ˜20 minutes. Filter and wash the solid with water, then air dry on the funnel. Separate the organic portion of the filtrate and wash with water then brine. Dry over sodium sulfate, filter and concentrate under vacuum. Suspend the resultant tan solid in dichloromethane, filter, wash the solid with dichloromethane and dry to yield 10.5 g of off-white solid. Combine all solids and dry over night in a vacuum oven at 45° C. to yield 78.6 g (95%) of a light-tan solid: MS: (m/z) 342 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: BrCCCBr
Product: Fc1ccc(OCCCBr)cc1F

Procedure:
Analogously to Example 91b, 2.00 g of 3,4-difluorophenol and 31.0 g of 1,3-dibromopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.66 (1:6 EtOAc-heptane); Rt=5.01.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:12]1[N:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[N:22]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([F:30])=[CH:25][CH:24]=3)=[O:20])=[CH:14][CH:13]=1.[NH:39]1[CH2:42][CH2:41][CH2:40]1>O1CCCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[N:39]1([C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[N:22]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)[C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([F:30])=[CH:25][CH:24]=4)=[O:20])=[CH:14][CH:13]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: O=C(Nc1ccc(Cl)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: C1CNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 100 °C

Procedure:
4.2 ml (4.2 mmol) of a 1M solution of lithium bistrimethylsilylamide in tetrahydrofuran are added to a mixture, stirred to 0° C. under an argon atmosphere, of 0.7 g (1.76 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide, prepared in step 3.1, of 0.123 g (2.11 mmol) of azetidine, of 8 mg (0.04 mmol) of palladium diacetate and of 19.5 mg (0.04 mmol) of (R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine in 1.8 ml of dry and degassed dimethoxyethane. The reactor is closed and then heated at 100° C. for 16 hours. The reaction mixture is then poured into 50 ml of water. 5 ml of a molar solution of hydrochloric acid and then 50 ml of a saturated sodium hydrogencarbonate solution are added slowly. The mixture is extracted twice with 50 ml of ethyl acetate. The organic phases are combined and then washed twice with 50 ml of a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and then concentrated under reduced pressure. The product obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and acetone. The resulting solid is then triturated in 20 ml of hot isopropanol, recovered by filtration, and then recrystallized from a mixture of ethanol and methanol. 0.31 g of a solid is recovered by filtration, and dried under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.[CH3:11]O>>[CH3:11][O:9][C:8](=[O:10])[CH2:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: CO
Reactant: Cc1cc(CC(=O)O)on1
Product: COC(=O)Cc1cc(C)no1

Procedure:
A solution of 3-methyl-5-isoxazole acetic acid (10.2 g, 72.6 mmol) in methanol (100 mL) was treated with p-toluene-4-sulfonic acid monohydrate (1.0 g, cat.) and the resulting mixture was then heated under reflux for 4 h. After cooling, the mixture was then evaporated and the brownish residue stirred with saturated sodium bicarbonate solution and diethylether. The organic phase was dried over sodium sulfate and concentrated to afford (3-methyl-isoxazol-5-yl)-acetic acid methyl ester (9.62 g) as a light yellow oil. This was then dissolved in butanol and reacted with hydrazine hydrate As described for example 112a. The resulting mixture was then heated under reflux for 16 h and after cooling and evaporation, the residue was crystallized from n-butanol/toluene to afford the title compound as a white solid (5.30 g). Concentration of the mother liquor provided another crop of solid material (2.95 g, overall yield: 73%). 1H-NMR (300 MHz, DMSO): δ=2.19 (s, 3H), 3.25 (s, 2H), 4.29 (s, 2H), 6.17 (s, 1H), 9.29 (s, 1H).
Reaction SMILES: [CH3:1][C:2]12[C:9]([C:11]#[CH:12])([OH:10])[C:6]([CH3:13])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[H][H]>[Ni]>[CH3:13][C:6]12[C:9]([CH2:11][CH3:12])([OH:10])[C:2]([CH3:1])([CH2:8][CH2:7]1)[CH2:3][CH2:4][CH2:5]2
Reactant: C#CC1(O)C2(C)CCCC1(C)CC2
Reactant: [H][H]
Agent: [Ni]
Product: CCC1(O)C2(C)CCCC1(C)CC2
Yield: 85 %

Procedure:
A solution of 178 g (1 mole) 5 in 1000 ml destilled methanole was mixed with 1 g Raney nickel and hydrogenated in an autoclave (20 bar/20° to 30° C.). After about 4 h the uptake of hydrogen was finished (2 equivalents H2). The reaction mixture was taken from the autoclave, filtered, evaporated and distilled. This resulted in 155 g (85%) of 7 in form of a colorless oil having a boiling point (1 mm) of 68° C. IR: 3500/3600 cm-1 (O--H).--NMR (CCl4): δ=0.88, s (1-, 5-CH2), 0.97, t, J=7 Hz (--CH2 --CH3), 1.45 ppm, br.s (6-, 7-CH2).--MS: m/e (%)=153 (100, M+ -29), 135 (56), 125 (20), 123 (20), 107 (71), 99 (20), 95 (45), 69 (46).C12H22O (M=182.30).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([Si](C)(C)[O:35][CH:36]1[CH2:39][N:38]([NH2:40])[CH2:37]1)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:40][N:38]3[CH2:39][CH:36]([OH:35])[CH2:37]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(N)C1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NN1CC(O)C1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 3-(t-butyl-dimethyl-silanyloxy)-azetidin-1-ylamine trifluoroacetate (1:1) as starting materials; the silyl protecting group was lost during reaction and work-up; MS (EI) 402.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[CH:7]=1.CC(C)([O-])C.[K+].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([OH:40])[CH:38]=3)[N:33]=[CH:32][N:31]=2)=[N:25]1.[Cl-].[NH4+]>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([O:40][C:37]2[CH:38]=[C:39]3[C:34](=[CH:35][CH:36]=2)[N:33]=[CH:32][N:31]=[C:30]3[NH:29][C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[CH:7]=1
Reactant: Fc1ncc(OCCC2OCCO2)cc1Cl
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(OCCC5OCCO5)cc4Cl)cc23)n1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
3-Chloro-5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine (4.6 g, 18.4 mmol) and potassium tert-butoxide (2.6 g, 23 mmol) were added to an N,N-dimethylacetamide suspension (5 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (2.2 g, 9.1 mmol), and reacted at 200° C. for 2 hours, using microwaves. The reaction solution was cooled to room temperature, aqueous saturated ammonium chloride solution was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25) to obtain 6-({3-chloro-5-[2-(1,3-dioxolan-2-yl)ethoxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (3.1 g, yield: 73%) as a yellow solid.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>CC(C)=O.O.O.[Ru](=O)=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C@@H:10]1[CH2:11][C@H:9]1[C:8]([OH:2])=[O:7])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(C[C@@H]1C[C@H]1CO)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C[C@@H]1C[C@H]1C(=O)O)OCc1ccccc1
Reaction time: 1 h
Yield: 98 %

Procedure:
Sodium metaperiodate (107 mg, 0.50 mmol) and ruthenium(IV) oxide hydrate (3.02 mg, 0.02 mmol) were added to a solution of benzyl trans-2-(2-(hydroxymethyl)cyclopropyl)acetate (44 mg, 0.20 mmol) in acetone (1 mL) and water (1 mL) at 0° C., and the mixture was stirred at 0° C. to room temperature for 1 hr. The reaction mixture was filtered through Celite (while washing with acetone), and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give trans-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (46.0 mg, 0.196 mmol, 98%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH3:17])[CH:5]=[CH:4][CH:3]=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH2:14]([C:12]1[C:11](=[O:16])[NH:10][C:9]([CH3:17])=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])[N:7]=2)[CH:13]=1)[CH3:15]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCc1cc(-c2cccc(N)n2)c(C)[nH]c1=O
Solvent: c1ccncc1
Product: CCc1cc(-c2cccc(NS(=O)(=O)c3ccccc3)n2)c(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
6-Amino-5′-ethyl-2′-methyl-1′H-[2,3′]bipyridinyl-6′-one (1 molar equivalent), prepared in accordance with the procedures of PREPARATION 12, is dissolved in pyridine (approx. 10 ml/mmol) and, at room temperature, 1.3 molar equivalent of benzene sulfonyl chloride is added, and the reaction mixture is stirred at room temperature for 36 hrs. The solution is completely concentrated and then purified directly by RP-HPLC. MS: m/e=370 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[CH:3]=[O:4].C1O[C:18]2C=CC=C[C:17]=2[O:16]1.O=CC(=C)C.C(OC(=O)C)(=O)C>>[C:17]([O:4][CH:3]=[C:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)(=[O:16])[CH3:18]
Reactant: c1ccc2c(c1)OCO2
Reactant: CC(C=O)Cc1ccc2c(c1)OCO2
Agent: C=C(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2

Procedure:
The production process (B) comprises the steps of (3) reacting 1,2-methylenedioxybenzene, methacrolein and acetic anhydride with each other to produce 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene; and (2) subjecting the obtained 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene to hydrolysis reaction or to transesterification reaction with an alcohol, followed by subjecting the resulting reaction mixture to distillative purification, to thereby adjust a content of 1-acetyl-3,4-methylenedioxybenzene as a by-product in the 2-methyl-3-(3,4-methylenedioxyphenyl)propanal to from 50 to 3000 ppm.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:20][CH:19]3[N:21]([CH3:22])[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:9][CH:8]=1)(=O)=O.Br[C:26]1[CH:27]=[N:28][CH:29]=[N:30][CH:31]=1.[Cl-].[Li+].C[Sn](C)C.C[Sn](C)C.[F-].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.O1CCOCC1>[CH3:22][N:21]1[CH:19]2[CH2:18][CH2:17][CH:16]1[CH2:15][CH:14]([S:13][C:10]1[CH:11]=[CH:12][C:7]([C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:8][CH:9]=1)[CH2:20]2
Reactant: CN1C2CCC1CC(Sc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C2
Reactant: Brc1cncnc1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN1C2CCC1CC(Sc1ccc(-c3cncnc3)cc1)C2
Reaction time: 2 h
Yield: 12.3 %

Procedure:
To a mixture of 4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl trifluoromethanesulfonate (450 mg), 5-bromopyrimidine (187 mg), lithium chloride (150 mg) and tetrakis(triphenylphosphine) palladium (0) (68 mg) under nitrogen were added hexamethylditin (386 mg) and dioxane (15 ml). The mixture was heated under reflux overnight and then poured into a mixture of aqueous potassium fluoride (1.9 g in 13 ml water) and ethyl acetate (13 ml). This mixture was stirred vigorously for 2 hours, passed through a sintered funnel and the layers separated. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated. The crude material was purified on an Isco CombiFlash device, followed by UV-guided LC to yield 8-methyl-3-{[4-(5-pyrimidinyl)phenyl]thio}-8-azabicyclo[3.2.1]octane (45 mg)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[S:28][C:29]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[S:28][C:29]([CH2:32][N:33]([CH3:34])[CH3:35])=[CH:30][CH:31]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)s1
Reactant: CN(C)Cc1ccc(CSCCN)s1
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccc(CN(C)C)s3)c(=O)[nH]2)s1

Procedure:
A solution of 2-(5-dimethylaminomethyl-2-thienylmethylthio)ethylamine (1.47 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone (2.0 g) in pyridine (10 ml) was refluxed overnight. The pyridine was removed under reduced pressure and the last traces of pyridine were removed by azeotroping with water yielding 2-(5-dimethylaminomethyl-2-thienylmethylthio)ethylamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone as an oil. The resultant oil was washed by decantation with water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[CH3:36]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:36])[CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1cc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Solvent: CI
Solvent: ClCCl
Product: Cn1cc(Cc2cn(C)c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4(1H)-pyrimidinone (71 mg, 0.109 mmol) in DCM (1.5 mL) was added DIPEA (0.038 mL, 0.217 mmol) and MeI (10.18 μL, 0.163 mmol). The mixture was stirred at room temp overnight. Purification via MDAP then afforded the title compound (34 mg, 60.3% yield). LCMS: rt=3.35 min, [M+H+]=519
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[S:30][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[S:30][C:29]([CH3:28])=[N:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)s1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1, 60 mg, 0.134 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (45.4 mg, 0.202 mmol), Pd2(dba)3 (2.463 mg, 2.69 μmol), 2-dichlohexylphosphino-2′-6′-dimethoxybiphenyl (4.42 mg, 10.76 μmol) and K3PO4 (86 mg, 0.403 mmol) were added to a MW vial, which was sealed and evacuated/purged with argon. Dioxane was added and the RM was stirred at 100° C. for 16 h. Additional 2-methylthiasole-5-boronic acid pinacol ester (15.14 mg, 0.067 mmol) and Pd2(dba)3 (2.463 mg, 2.69 μmol) were added and RM was stirred at 100° C. overnight. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 93 mg, 0.134 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 30% for 0.2 min then 30% to 60% in 12 min) to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=2.35 min, m/z=465.1-466.1 [M+H]+, m/z=463.1-464.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.80 (m, 1H) 1.81-1.92 (m, 1H) 2.70 (s, 3H) 3.03-3.09 (m, 1H) 3.25-3.40 (m, 2H) 3.45-3.55 (m, 1H) 4.20-4.27 (m, 1H) 4.88 (d, J=3.18 Hz, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.60 (s, 1H) 7.85 (d, J=9.05 Hz, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH2:6][CH2:7][C@@H:3]([F:2])[CH2:4]2)=[CH:11][CH:10]=1
Reactant: F[C@@H]1CCNC1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Product: F[C@@H]1CCN(Cc2ccc(Br)cc2)C1

Procedure:
The title compound was synthesized according to the method of Example A105B, except substituting (R)-3-fluoropyrrolidine hydrochloride (576 mg, 4.59 mmol) and 4-bromobenzaldehyde (849 mg, 4.59 mmol) which gave 1.09 g, 91% of a clear, colourless oil; MS ESI [M+H]+ 258.0, calcd for [C11H13BrFN+H]+ 258.03.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]([N+:30]([O-:32])=[O:31])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O1CCCC1.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[CH:24][C:25]=2[C:26]([O:28][CH3:29])=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(=O)OC)c1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(=O)OC)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (2.6 g), dimethyl 2-hydroxy-5-nitroisophthalate (1.6 g) and triphenylphosphine (4.4 g) in a mixture of dichloromethane (40 ml) and tetrahydrofuran (20 ml) was added diethyl azodicarboxylate (2.6 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/ethyl acetate=19/1 as an eluant to afford a yellow solid. To the solid was added hexane/ethyl acetate=4/1 and then the mixture was filtered to give the desired compound (2.2 g, yield 78%) as a white solid.