Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1)[C:5]([O:7]C)=[O:6].[N:16]1([C:20]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][N:23]=2)=[O:21])[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br>[N:16]1([C:20]([C:22]2[N:23]=[CH:24][C:25]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:11]=3)[C:5]([OH:7])=[O:6])=[CH:26][CH:27]=2)=[O:21])[CH2:19][CH2:18][CH2:17]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)O)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 74.4 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(1-methylethyl)oxy]benzoate (0.84 g, 4 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (1.16 g, 4.8 mmol), cesium carbonate (3.92 g, 1.2 mmol) and bromotris(triphenylphosphine)copper(I) (744 mg, 0.8 mmol) in DMA (20 mL) was stirred in a microwave reactor at 160° C. for 6 hours. The mixture was diluted with water (100 mL), washed with ethyl acetate (2×20 mL) and the aqueous layer filtered then acidified with 2N hydrochloric acid. The acidic layer was extracted with ethyl acetate (3×50 mL), the combined organics washed with water (2×20 mL), brine (20 mL), dried (MgSO4), and the solvent removed in vacuo. The residue was triturated with ether to give the desired compound as a white solid (1.06 g). 1H NMR δ (d6-DMSO): 1.28 (d, 6H), 2.28 (quin, 2H), 4.08 (t, 2H), 4.59 (t, 2H), 4.69 (quin, 1H), 6.98 (t, 1H), 7.10 (s, 1H), 7.28 (s, 1H), 7.56 (d, 1H), 7.99 (d, 1H), 8.41 (s, 1H); m/z 357 (M+H)+
Reaction SMILES: [CH3:1][C@@H:2]([N:9]=[C:10]=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O:13][C:14](=[O:64])[C@@H:15]([NH:31][C:32]([C@@H:34]1[CH2:43][C:42]2[CH:41]=[C:40]3[O:44][CH2:45][C@H:46]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH2:55][C:56]5[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=5)[CH:49]=4)[O:47][C:39]3=[CH:38][C:37]=2[CH2:36][NH:35]1)=[O:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[C:24]=2[CH3:30])=[CH:19][CH:18]=1.CO>C(Cl)Cl>[Cl:63][C:58]1[CH:57]=[C:56]([CH:61]=[CH:60][C:59]=1[Cl:62])[CH2:55][O:54][C:50]1[CH:49]=[C:48]([C@H:46]2[CH2:45][O:44][C:40]3=[CH:41][C:42]4[CH2:43][C@@H:34]([C:32]([NH:31][C@@H:15]([CH2:16][C:17]5[CH:22]=[CH:21][C:20]([C:23]6[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[C:24]=6[CH3:30])=[CH:19][CH:18]=5)[C:14]([OH:64])=[O:13])=[O:33])[N:35]([C:10](=[O:11])[NH:9][C@@H:2]([C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)[CH3:1])[CH2:36][C:37]=4[CH:38]=[C:39]3[O:47]2)[CH:53]=[CH:52][CH:51]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Reactant: C[C@@H](N=C=O)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N[C@H](C)c3ccccc3)O[C@@H](c3cccc(OCc4ccc(Cl)c(Cl)c4)c3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
(R)-(+)-α-Methylbenzyl isocyanate (5 mg) was added to a solution of (S)-2-({(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (20 mg) in 0.5 mL DCM and stirred for 1 h at room temperature. The reaction mixture was directly loaded onto a silica gel column (1:1 EtOAc/hexanes to 6% MeOH in 1:1 EtOAc/hexanes) to isolate the desired product (16 mg).
Reaction SMILES: [Cl:1][CH:2]([Cl:35])[C:3]([N:5]([CH2:25][CH2:26][P:27](=[O:34])([O:31]CC)[O:28]CC)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:13]=2)[CH:7]=1)=[O:4].Br[Si](C)(C)C>C(Cl)Cl>[Cl:35][CH:2]([Cl:1])[C:3]([N:5]([CH2:25][CH2:26][P:27](=[O:28])([OH:34])[OH:31])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=3[Cl:23])[CH:13]=2)[CH:7]=1)=[O:4]
Reactant: CCOP(=O)(CCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(C(Cl)Cl)N(CCP(=O)(O)O)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Reaction time: 4 h

Procedure:
Diethyl 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylphosphonate (Cpd. No. 1, 50 mg, 0.09 mmol) was dissolved in anhydrous methylene chloride (1 mL). Bromotrimethylsilane (750 μL, 5.7 mmol) was added and the mixture was stirred for 4 h whereupon the LC-MS confirmed the starting material was consumed. The solvent was removed under reduced pressure. The resulting residue was dissolved in methanol:water (1:1, 3 mL) and shaken for 30 min. The mixture was filtered over a pad of Celite. The Celite was washed with ethyl acetate. The combined filtrates were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylphosphonic acid (Cpd. No. 2) as a white solid. 1H NMR (DMSO-d6): 8.02 (m, 2H), 7.69-7.56 (m, 5H), 7.38 (s, 1H), 6.33 (s, 1H), 3.86 (m, 2H), 1.83 ppm (m, 1H). MW=524 confirmed by LC-MS, tr=11.24 min (Method Y) MH+=522-526.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:14]1=2)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>[Pd].CCO>[NH2:23][C:20]1[CH:21]=[CH:22][C:14]2[N:13]([CH2:12][CH2:11][N:2]([CH3:1])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])[CH2:18][CH2:17][S:16][C:15]=2[CH:19]=1
Reactant: CN(CCN1CCSc2cc([N+](=O)[O-])ccc21)CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CN(CCN1CCSc2cc(N)ccc21)CC(=O)OC(C)(C)C
Yield: 99.9 %

Procedure:
A round bottom flask containing tert-butyl 2-(methyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)amino)acetate (925 mg, 2.52 mmol) was purged with argon and then charged with palladium on carbon (10% wt; 268 mg, 0.252 mmol). To this mixture was added EtOH (40 mL). The resulting suspension was evacuated using a pump, and hydrogen was let into the system via a balloon. The mixture was stirred under a balloon filled with hydrogen for 3 hours. The balloon was removed, and argon was bubbled through the suspension for 10 minutes. The mixture was filtered through a pad of Celite, and the Celite pad was rinsed with methanol (20 mL). The filtrate was concentrated, and the residue was dried under reduced pressure to give the title compound (850 mg, quantitative). 1H-NMR (CDCl3) δ 6.59 (d, J=8.7 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.40 (dd, J=2.7, 8.4 Hz, 1H), 3.54-3.45 (m, 2H), 3.33 (t, J=7.2 Hz, 2H), 3.27 (brs, 2H), 3.20 (s, 2H), 3.04-2.98 (m, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.42 (s, 3H), 1.46 (s, 9H); ESI-MS (m/z, %): 338 (MH+, 95), 282 (100).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2].[BH4-].[Na+].[OH2:28]>O1CCCC1.[OH-].[Na+]>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][C:19]([OH:28])([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: O
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)OCC)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCC(C)(O)CCCC(CCCCCCC(=O)OCC)C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Mercuric acetate (3.8 g., 0.012 mole) is dissolved in water (12 ml.) and tetrahydrofuran (20 ml.) is added to give a suspension of a yellow solid. Then, ethyl 8-acetyl-12-methyl-11-heptadecenoate (4.2 g., 0.012 mole) in tetrahydrofuran (20 ml.) is added, and the mixture stirred at room temperature for 24 hours. After 6 hours, the yellow suspended solid has disappeared and a cloudy solution results. To the solution is added 3M sodium hydroxide solution (12 ml.), followed by 0.5M sodium borohydride solution in 3M sodium hydroxide (12 ml.). Liquids are decanted from the precipitated mercury. The organic layer is taken up in ether, washed with three portions of water and dried over sodium sulfate. Evaporation of the ether leaves 4.4 g. of ethyl 8-acetyl-12-hydroxy-12-methylheptadecanoate as a yellowish oil used in the next step without further purification; pmr (CDCl3)δ 0.88 (3H,t), 1.13 (3H,s, CH3COH), 1.25 (3H,t, CH3CH2OCO--), 2.12 (3H,s, CH3CO), 4.12 (2H,q).
Reaction SMILES: O.[N-:2]=[N+:3]=[N-:4].[Na+].CS(O[CH2:11][C:12]1[O:13][CH2:14][CH2:15][CH2:16][CH:17]=1)(=O)=O>CN(C)C=O>[N:2]([CH2:11][C:12]1[O:13][CH2:14][CH2:15][CH2:16][CH:17]=1)=[N+:3]=[N-:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1=CCCCO1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1=CCCCO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Water (35 mL) and sodium azide (15.1 g, 232 mmol) were added to a solution of the crude (5,6-dihydro-4H-pyran-2-yl)methyl methanesulfonate (about 193 mmol) in N,N-dimethylformamide (350 mL), and the mixture was stirred at room temperature for 20 hours. Water (300 mL) was added to the reaction solution, followed by extraction with ethyl acetate (1.5 L). The resulting organic layer was washed with water (3×200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to about 300 mL. The resulting crude title compound solution was used for the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([F:25])[C:5]([OH:26])=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]([F:25])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:13]=[CH:12][C:11]=1[F:23]
Reactant: O=C(Nc1c(Cl)ccc(O)c1F)c1cc(-c2cccc(F)c2)ccc1F
Solvent: C1CCOC1
Product: Oc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 60 °C
Yield: 67.4 %

Procedure:
To a solution of N-(6-chloro-2-fluoro-3-hydroxy-phenyl)-2-fluoro-5-(3-fluorophenyl)benzamide (200 mg, 0.53 mmol, 1.0 eq) in THF under N2 was added dropwise a solution of BH3 (1M in THF, 2.65 mL, 2.65 mmol, 5.0 eq) at room temperature. The reaction mixture was heated at 60° C. for 3 h. After cooling, the resulting mixture was quenched by addition of 1M HCl and the mixture extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as an oil (130 mg, 68%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:18]([Mg]Br)#[CH:19].[Cl-].[NH4+]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:18]#[CH:19])[CH:10]=[CH:11][C:12]=1[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)c1ccc(C=O)cc1C(C)(C)C
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(N(CC)CC)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
1.5 g (6.7 mmol) of 3-tert-butyl-4-diethylamino-benzaldehyde are dissolved in 20 ml of dry THF, under a light nitrogen flow, at 0° C. 17 ml (8.7 mmol) of a 0.5M solution of ethynylmagnesium bromide are added dropwise and the medium is then brought back to ambient temperature and stirred for 30 minutes. The mixture is then poured into a saturated solution of ammonium chloride, extracted with ethyl acetate, dried over sodium sulphate and then concentrated to dryness. The residue is purified by flash chromatography (90/10 heptane/ethyl acetate). 780 mg of 1-(3-tert-butyl-4-diethylaminophenyl)prop-2-yn-1-ol are obtained in the form of a colourless oil (yield=47%).
Reaction SMILES: [CH3:1][CH:2]([N:18]([CH3:20])[CH3:19])[CH2:3][N:4]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2.C([C@H]([C@@H](C([O-])=O)O)O)([O-])=O.CC(N(C)C)CN1C2C=CC=CC=2SC2C=CC=CC1=2.[C:51]([C@:59]([C:74]([OH:76])=[O:75])([OH:73])[C@:60]([C:65](=[O:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([OH:64])[C:61]([OH:63])=[O:62])(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CC(C)=O>[CH3:1][CH:2]([N:18]([CH3:19])[CH3:20])[CH2:3][N:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.[C:65]([C@:60]([C:61]([O-:63])=[O:62])([OH:64])[C@:59]([C:51](=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([OH:73])[C:74]([O-:76])=[O:75])(=[O:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Agent: CC(CN1c2ccccc2Sc2ccccc21)N(C)C
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Solvent: CC(C)=O
Product: O=C([O-])[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)[O-])C(=O)c1ccccc1
Reaction time: 72 h

Procedure:
To prepare promethazine-D-tartrate, promethazine (10 g, 0.035 mol) dissolved in 80 ml acetone was heated in a 60° C. bath while dibenzoyl-D-tartaric acid (12.789 g, 0.036 mol) was added. The resulting clear yellow solution was left at ambient temperature for 3 days (step 2). A heavy precipitate formed, which was filtered off and recrystalized from ethanol four times to give 4.0 g promethazine dibenzoyl-D-tartrate white crystals (step 3).
Reaction SMILES: [C:1]([C:3]1[CH2:4][N:5](C)[CH2:6][CH2:7][CH:8]=1)#[N:2].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)(Cl)C>[C:1]([C:3]1[CH2:4][NH:5][CH2:6][CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=1)#[N:2]
Reactant: CN1CCC=C(C#N)C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)(Cl)Cl
Product: CCOC(=O)C1C=C(C#N)CNC1

Procedure:
A mixture of 3 (23.9 g, 0.2 mol), ethyl chloroformate (25 g, 0.23 mol) and potassium carbonate (30 g, 0.22 mol) in 1,1,1-trichloroethane (200 ml) was refluxed overnight.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2.[CH2:14](N(CC)CC)[CH3:15].C([B-](F)(F)F)=C.[K+]>CCO.C(Cl)(Cl)Cl.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].C(Cl)Cl>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2)=[CH2:15]
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=C[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc2c(c1)C[C@@H](C)OC2=O
Temperature: 100 °C

Procedure:
A solution of (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 9.96 mmol) and triethylamine (2.78 mL, 19.91 mmol) in EtOH (39.8 mL) was added to a microwave vial containing PdCl2(dppf)-CH2Cl2, (0.406 g, 0.498 mmol) and potassium vinyltrifluoroborate (2.000 g, 14.93 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH2:7][O:6][C:4](=[O:5])[CH2:3]1.[BrH:9]>ClCCl>[Br:9][CH2:7][CH2:8][CH:2]([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC1CCOC(=O)C1
Reactant: Br
Solvent: ClCCl
Product: CC(CCBr)CC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of β-methyl-δ-valerolactone (3.0 g) in anhydrous dichloromethane (30 ml), cooled to 0-5° C., was saturated with hydrogen bromide gas and the mixture was stirred for three days at room temperature. The mixture was diluted with dichloromethane (100 ml) and the resulting solution was washed with 10-% NaCl (3×30 ml). Next the solution was dried with anhydrous MgSO4 and the solvent was distilled under reduced pressure, Yield 4.6 g. NMR ˜100% pure product.
Reaction SMILES: O1CCOCC1.[CH3:7][N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[N:10]=[CH:9]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:31]1[CH:32]=[CH:33][C:34]([NH2:38])=[N:35][C:36]=1[CH3:37]>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].C(Cl)Cl.O>[CH3:37][C:36]1[N:35]=[C:34]([NH2:38])[CH:33]=[CH:32][C:31]=1[C:11]1[N:10]=[CH:9][N:8]([CH3:7])[CH:12]=1
Reactant: Cn1cnc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nc(N)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1nc(N)ccc1-c1cn(C)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Dioxane (3.61 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (200 mg, 0.962 mmol), water (0.40 mL) and tribasic potassium phosphate, (511 mg, 2.41 mmol) were added to 5-bromo-6-methylpyridin-2-amine (150 mg, 0.802 mmol) in a scintillation vial. The vial was purged and flushed with argon 3 times before adding PdCl2(dppf)-CH2Cl2 adduct (66 mg, 0.080 mmol). The vial was then purged with argon, sealed, and heated to 100° C. After 16 hours, the reaction mixture was cooled to room temperature, filtered through CELITE (washed with chloroform), and diluted with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-100% (10% methanol in chloroform)/hexanes, linear gradient) to afford 6-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine. MS ESI calc'd. for C10H13N4 [M+H]+ 189. found 189. 1H NMR (500 MHz, CDCl3) δ 7.52 (s, 1H), 7.37 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 6.38 (d, J=8.3 Hz, 1H), 3.94 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]([CH3:10])=O>[OH-].[OH-].[Pd+2]>[CH:8]([NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:10])[CH3:7]
Reactant: NC1CCCC1
Reactant: CC(C)=O
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)NC1CCCC1

Procedure:
Pearlman's catalyst (20% w/w palladium hydroxide-on-carbon) (1.5 g) was added to a solution of cyclopentylamine (15 ml, 0.21 mol) in acetone (200 ml). The reaction mixture was stirred under an atmosphere of hydrogen gas at 414 kPa (60 psi). After stirring for 16 hours the reaction mixture was filtered through Arbocel (Trade Mark) and the solvent was removed under reduced pressure to give the title compound (15 ml) as a thin oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[O:2]1.[BrH:12]>C(O)(=O)C>[Br:12][CH2:1][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][C:3]([OH:2])=[O:11]
Reactant: O=C1Cc2ccccc2CO1
Reactant: Br
Solvent: CC(=O)O
Product: O=C(O)Cc1ccccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of isochroman-3-one (1.5 g, 10 mmol) in 30% HBr in acetic acid (13 mL) was stirred at room temperature for 2 h, and 70° C. for 1 h. The reaction mixture was cooled to room temperature, and poured into ice-water. The precipitate was collected to afford (2-bromomethylphenyl)acetic acid as an off-white solid (2.15 g, 93%): 1H NMR (300 MHz, DMSO-d6) δ 7.45-7.23 (m, 4H), 4.73 (s, 2H), 3.73 (s, 2H).
Reaction SMILES: Br[C:2]1[C:3]([C:29]#[N:30])=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][CH2:13][C:14]2[C:15]([OH:22])=[N:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])=[CH:8][C:7]=1[Cl:25].C(OC([N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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:25][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:6]=1[O:5][C:4]1[CH:26]=[CH:27][CH:28]=[C:2]([C:41]2[CH:42]=[N:38][NH:39][CH:40]=2)[C:3]=1[C:29]#[N:30])[C:10]([NH:12][CH2:13][C:14]1[C:15]([OH:22])=[N:16][C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])=[O:11]
Reactant: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(Br)c3C#N)c(Cl)c2)c(O)n1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
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
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(-c4cn[nH]c4)c3C#N)c(Cl)c2)c(O)n1
Temperature: 90 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
To a solution of 4-(3-bromo-2-cyanophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (500 mg, 1.03 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (323 mg, 1.1 mmol), sodium carbonate (425 mg, 3.07 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.1 mmol). The reaction mixture was stirred at 90° C. under nitrogen atmosphere for 12 hours. After the reaction, it was allowed to cool to room temperature, and concentrated in vacuo, then diluted with ethyl acetate, washed with water. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the pure product 3-chloro-4-(2-cyano-3-(1H-pyrazol-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (331 mg, 68%). LRMS (M+H+) m/z: calcd 473.13. found 473. 1H NMR (300 MHz, d6-DMSO): δ 13.33 (s, 1H), 11.48 (s, 1H), 8.53 (t, J=4.8 Hz, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.90 (d, J=6.9 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 5.86 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NCCCCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:87])[C:53]([C:55]1[CH:56]=[C:57]([S:61]([C:64]2[CH:65]=[C:66]3[C:71](=[C:72]([CH3:74])[CH:73]=2)[N:70]=[CH:69][C:68]([C:75]([NH2:77])=[O:76])=[C:67]3[NH:78][C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][CH3:86])[CH:80]=2)(=[O:63])=[O:62])[CH:58]=[CH:59][CH:60]=1)=[O:54]>>[CH3:86][O:85][C:81]1[CH:80]=[C:79]([NH:78][C:67]2[C:66]3[C:71](=[C:72]([CH3:74])[CH:73]=[C:64]([S:61]([C:57]4[CH:58]=[CH:59][CH:60]=[C:55]([C:53](=[O:54])[N:52]([CH3:87])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]=[O:45])[CH:56]=4)(=[O:63])=[O:62])[CH:65]=3)[N:70]=[CH:69][C:68]=2[C:75]([NH2:77])=[O:76])[CH:84]=[CH:83][CH:82]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCCO)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCC=O)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 112, using Intermediate 80 as a substrate. ES/MS calcd. for C32H35N4O6S+ 603.2. Found m/z=603 (M+H)+.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:19]O>>[C:1]([CH2:9][CH2:10][C:11]([O:13][CH3:19])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccccc1
Yield: 100 %

Procedure:
To a 1.0 L round bottom flask was added 49.25 g (0.276 mol) of 3-benzoylpropionic acid. To this was added 700 mL of ACS methanol and the solution stirred until all of the acid had dissolved. To this solution was added approximately 2.0 mL of conc. H2SO4 and the reaction refluxed for 2.5 hours. The reaction can be monitored by HPLC. After the reaction was determined to be complete, the methanol was removed on the rotoevaporator and to the residual oil was added ethyl acetate (~500 mL). To the ethyl acetate layer was then added 150 mL of a saturated sodium carbonate solution. The layers were extracted and allowed to separate. The organic layer was then dried (MgSO4), filtered and concentrated to yield methyl 3-benzoylpropionate (1) as a light yellow oil. Yield 53.30 g; yield 100%; >97% cp.