Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:22])[C:16]=1[CH3:32].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[Cl:62][C:63]1[CH:68]=[CH:67][C:66]([NH2:69])=[C:65]([NH2:70])[CH:64]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:69][C:66]2[CH:67]=[CH:68][C:63]([Cl:62])=[CH:64][C:65]=2[NH2:70])=[O:30])=[O:22])[C:16]=1[CH3:32]
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Reactant: Nc1ccc(Cl)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)Nc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
6-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (441 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-chloro-o-phenylenediamine (171 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (402 mg, 71% yield) as a red solid. LC-MS (m/z) 566 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][OH:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[O-][CH2:18]C.[Na+].CI>C1COCC1.CO>[C:6]([O:5][C:3]([NH:10][C@@H:11]([CH2:12][O:13][CH3:18])[C:14]([OH:16])=[O:15])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CI
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.4 h

Procedure:
Under nitrogen a mixture of 74 ml abs. THF and 6 ml abs. methanol is cooled to −70° C. and 2 g sodium hydride (55-65% dispersion) are added. The suspension is stirred for 0.4 hour at ambient temperature. Under nitrogen, 2.05 g N-Boc-L-serine are suspended in 100 ml abs. THF and 40 ml of the prepared sodium ethoxide solution are added. The suspension is stirred for 1 hour at ambient temperature and 1 ml methyliodide are added. After 1 hour the remainder of the sodium ethoxide solution and another 2 ml of methyliodide are added. After 18 hours the reaction mixture is evaporated to dryness. The residue is washed with water and ether and extracted. The water phase is acidified and extracted with ethyl acetate and dichloromethane. 0.52 g of the product are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.B1([C:31]2[CH:36]=[N:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:33][CH:32]=2)OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:31]3[CH:32]=[N:33][C:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[N:35][CH:36]=3)=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2cnc(N3CCOCC3)nc2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4cnc(N5CCOCC5)nc4)cc32)c1Cl
Yield: 27 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester as in General Procedure 4A to give the title compound as an off-white solid (27% yield). M.p. 250-251° C., LCMS: m/z=459.17 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.29-3.35 (m, 2H), 3.52-3.56 (m, 2H), 3.78-3.84 (m, 8H), 4.51 (s, 2H), 4.86 (bs, 1H), 6.96 (s, 1H), 7.00-7.08 (m, 1H), 7.10-7.17 (m, 1H), 7.59 (d, J=1.8 Hz, 1H), 8.46 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=O)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>C(O)C>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[N:19][OH:20])[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(=O)CO2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2c1C(=NO)CO2
Temperature: 25 °C
Yield: 174.2 %

Procedure:
A mixture of 4-methoxy-benzofuran-3-one (CAS 7169-35-9) (4.9 g, 19 mmol), sodium acetate (3.06 g, 38 mmol) and hydroxylamine hydrochloride (2.58 g, 38 mmol) in ethanol (40 ml) was refluxed for 6 h. Cooled to room temperature, filtered the precipitate off, washed with ethanol and dried in high vacuum to give 4-methoxy-benzofuran-3-one oxime as a white solid (5.93 g, 100%); MS: m/e=180.2 (M+H+).
Reaction SMILES: [NH3:1].[Na].[Cl:3][C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[O:11][CH3:12]>CCCCCC.O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:1])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: N
Reactant: COc1cc(Cl)ccc1Cl
Agent: [Fe+3]
Agent: O=[N+]([O-])[O-]
Agent: [Na]
Solvent: CCCCCC
Solvent: O
Product: COc1cc(N)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
900 mL of ammonia was condensed at −78° C. 1 g of thinly shaven strips of sodium was added followed by 1.0 g of iron (III) nitrate nonahydrate. Upon disappearance of the deep blue color 25 g of thinly shaven strips of sodium was added. After 30 mins of stirring at −78° C., 50 g of 2,5-dichloroanisole was added as a solution in hexane (70 mL) dropwise and the reaction warmed to −45° C. for 2 hrs. Upon completion the ammonia was allowed to evaporate. The crude pot was then diluted in chloroform and 100 g of NH4Cl was added slowly. The combines were taken up in a separatory funnel and washed with water (3×) followed by brine (1×). The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting solid can be used without further purification. Yield: 99%.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[CH3:65])[CH2:54][CH2:53]1>CN(C=O)C.O>[O:18]=[C:16]([N:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[CH3:65])[CH2:54][CH2:53]1)[CH2:15][NH:14][C:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][N:10]=1)=[O:13]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Cc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1NC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.102 g, 0.00042 mol) in DMF (1 mL) was added DIPEA (0.245 g, 0.00190 mol), HOBt (0.056 g, 0.000418 mol) and EDCI.HCl (0.145 g, 0.00076 mol) at ambient temperature. After 2 minutes piperidin-4-yl-o-tolyl-amine dihydrochloride (0.1 g, 0.00038 mol) was added and the resulting mixture was stirred for 16 hours. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.15 g (94% of 5-phenyl-1H-pyrazole-3-carboxylic acid [2-oxo-2-(4-o-tolylamino-piperidin-1-yl)-ethyl]-amide.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].S(=O)(=O)(O)O.NS(O)(=O)=O.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29]>O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[Cl:16][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:29]=[CH:28][C:27]([O:31][CH3:32])=[O:30])[CH:15]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: NS(=O)(=O)O
Solvent: O
Product: COC(=O)C=Cc1cc(Cl)ccc1C(=O)OC
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
At 2° C., a solution of 79.5 g of sodium nitrite in 150 ml of water is added to a mixture of 185.5 g of methyl 2-amino-4-chlorobenzoate, 785 ml of water and 190.5 ml of concentrated sulfuric acid. Subsequently, the mixture is stirred for 30 minutes, and 5.3 g of amidosulfonic acid are then added. The resulting reaction mixture is added dropwise to 108.2 g of methyl acrylate. 766 mg of palladium acetylacetonate are then added to the reaction mixture, which is then heated to 40° C. After a further 3.5 hours at 40° C., the resulting precipitate is filtered off, giving, after drying, 248.3 g of methyl 4-chloro-2-(3-methoxy-3-oxo-1-propenyl)-benzoate of melting point 87-89° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[CH:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])[CH3:33]>>[F:19][C:18]([F:21])([F:20])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[O:30])=[CH:13][CH:12]=1)[O:22][C:23]1[CH:24]=[CH:25][C:26]([C:38]2[CH:39]=[CH:40][C:35]([CH:32]([CH3:34])[CH3:33])=[CH:36][CH:37]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: CC(C)c1ccc(-c2ccc(OC(CCCC(F)(F)F)c3ccc(C(=O)NCCC(=O)O)cc3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. The isomers are resolved by methods described herein or known to one skilled in the art. Isomer 1 MS: 526.2 [M−H]−; Isomer 2 MS: 526.2 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C1C=NC2C3N=CC=CC=3C=CC=2C=1.[CH:23]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:28][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: OC1CCCC1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Brc1ccc(OC2CCCC2)cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of 1-bromo-4-iodo-benzene, (1.00 g, 3.53 mmol), o-phenanthroline (255 mg, 1.41 mmol) and cyclopentanol (1.50 g, 17.44 mmol) in toluene (1.500 mL) was added copper(I) iodide (135.00 mg, 0.70 mmol) and Cs2CO3 (2.87 g, 8.83 mmol). The resulting mixture was then stirred at 120° C. in a sealed tube for 15 hours. The solvent was then removed under reduced pressure and the product was purified by flash chromatography (eluted by hexane).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16](O)=[O:17])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:19]=[CH:20][CH:21]=[N:22][C:5]1=2.ClP(=O)(OCC)OCC.[NH3:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]([NH2:32])=[O:17])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:19]=[CH:20][CH:21]=[N:22][C:5]1=2
Reactant: N
Reactant: COCN1c2cc(/C=C/C(=O)O)ccc2Sc2nccnc21
Agent: CCOP(=O)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCN1c2cc(C=CC(N)=O)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
950 mg of (E)-3-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)propenoic acid was dissolved in a solvent mixture of tetrahydrofuran (10 ml) with N,N-dimethylformamide (10 ml) in a nitrogen atmosphere. Under ice-cooling, 0.48 ml of diethyl chlorophosphonate was dropped into the reaction mixture. After stirring at room temperature for 30 minutes, ammonia gas was blown into the system. Then the reaction mixture was distributed into an aqueous solution of sodium carbonate and ethyl acetate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were recrystallized from diisopropyl ether/ethyl acetate to thereby give 400 mg of the title compound as yellow crystals.
Reaction SMILES: C1(C)C(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=CC=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[O:16].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[O:16]1[C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]=[CH:12]1
Reactant: CCOC(=O)C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cnco1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Toluenesulfonylmethyl isocyanide (TosMIc) (12.31 g, 1 wt, 1 eq) is dissolved in DCM (61.6 ml, 5 vols) at 0° C. under N2. In a separate vessel, ethyl glyoxalate (50 wt % solution in toluene, 20.6 g, 20.0 ml, 1.67 wt) is diluted with DCM (61.6 ml, 5 vols) under N2 and DBU (12.48 g, 12.35 ml, 1.3 eq, 1.01 wt) is added resulting in a purple solution. The second solution is added to the TosMIc solution over 1 hr, maintaining temperature at 0° C., then checked by HPLC for completion after a further 20 mins. The reaction is quenched by slow addition of 2M HCl (10 vols, 123 ml) and the DCM layer separated. The aqueous layer is re-extracted with DCM (5 vols, 61.6 ml), and the combined organics dried over Na2SO4, then evaporated on Buchi, 25° C., 100 mbar to remove DCM and toluene. Distilled at 12 mbar, jacket temperature 105° C., vapour temperature 60-80° C. to afford ethyl oxazole-5-carboxylate as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[C:16]([CH:21]=[O:22])[CH2:17][O:18]3)=[CH:13][CH:12]=2)[S:5][C:6]=1[CH2:7][CH3:8].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1OB(O)O.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH4+].[Cl-]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:7]([C:6]1[S:5][C:4]([CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[C:16]([CH:21]=[O:22])[CH2:17][O:18]3)=[CH:13][CH:12]=2)=[CH:3][C:2]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([F:36])([F:35])[F:23])[CH3:8]
Reactant: OB(O)Oc1ccccc1C(F)(F)F
Reactant: CCc1sc(COc2ccc3c(c2)OCC(C=O)=C3)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCc1sc(COc2ccc3c(c2)OCC(C=O)=C3)cc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 7-[(4-bromo-5-ethyl-2-thienyl)methoxy]-2H-chromene-3-carbaldehyde (150 mg) in dioxane (4.5 mL) were added [2-(trifluoromethyl)phenyl]boric acid and a 2 M aqueous Na2CO3 solution at 25° C. Then, to the reaction mixture were added palladium acetate (4.44 mg) and PPh3 (20.75 mg), followed by warming to 100° C. and stirring for 5 hours. To the reaction liquid was added a saturated aqueous NH4Cl solution (30 mL), followed by extraction with EtOAc (30 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=95:5 to 80:20) to obtain 7-({5-ethyl-4-[2-(trifluoromethyl)phenyl]-2-thienyl}methoxy)-2H-chromene-3-carbaldehyde (134.8 mg) as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.C([O:23][CH2:24][CH3:25])(=O)C>O1CCOCC1.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:4][C:25]=1[CH2:24][OH:23]
Reactant: CCOC(C)=O
Reactant: OB(O)c1cccnc1F
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cc(-c2cccnc2F)ccc1F
Temperature: 90 °C
Yield: 47 %

Procedure:
The crude oil was dissolved in dioxane (100 mL) and treated with 2-fluoropyridin-3-ylboronic acid (3.47 g, 24.63 mmol), potassium phosphate (5.23 g, 24.63 mmol), and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.25 g, 0.35 mmol). Water (10 mL) was added and the reaction heated to 90° C. for 10 min. Water (300 mL) and ethyl acetate (200 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification of the crude material using silica chromatography (hexane to ethyl acetate gradient) gave (2-fluoro-5-(2-fluoropyridin-3-yl)phenyl)methanol (2.54 g, 47%). MS m/z=222.1 [M+H]+. Calculated for C12H9F2NO: 221.05.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:9].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH3:7][C:4]1[S:3][C:2]([C:13]2[CH:14]=[CH:15][C:10]([CH:8]=[O:9])=[CH:11][CH:12]=2)=[N:6][N:5]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1nnc(Br)s1
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
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc(C=O)cc2)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
To a solution of 2-bromo-5-methyl-1,3,4-thiadiazole (2.0 g, 11.17 mmol) in dioxane (40 ml) was added 4-formylbenzeneboronic acid (3.35 g, 22.34 mmol) and 2M Na2CO3 (23 ml). This mixture was degassed with a stream of argon for 2 min. Tetrakis(triphenylphosphine)palladium (0.636 g, 0.55 mmol) was added and this mixture was heated at reflux overnight under argon. After cooling to room temperature, H2O (30 ml) and EtOAc (50 ml) were added and stirred for 5 min. The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (10 to 20% EtOAc/hexanes) gave 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde as a pale yellow liquid (1.16 g, 51% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N(CC)(CC)CC.Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].O>C(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[CH2:16][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: COC(=O)CBr
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)CN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
Treat a 0° C. solution of 4-hydroxy-piperidine (20.0 g, 0.19 mol) and (CH3CH2)3N (24.0 g, 0.24 mol) in CH2Cl2 (200 mL) with methyl bromoacetate (30.21 g, 0.197 mol), warm to room temperature, and stir 2 hours at room temperature under N2. Dilute the reaction with water and extract with 3:1 chloroform:isopropanol. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 5% methanol in CH2Cl2 to afford 20.13 g (59%) of the titled product. Rf=0.13 (9/1 CH2Cl2/methanol). ES MS (m/z): 174 (M+).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C(OCC)(OCC)OCC.C1(C)C=CC=CC=1.[C:29]([C@@H:34]([C@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[OH:37])O)([O:31][CH2:32][CH3:33])=[O:30]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]3[O:37][C@@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[C@H:34]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:8]3)=[CH:5][C:4]=2[O:9]1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)[C@@H]1OC(c2ccc3c(c2)OCO3)O[C@H]1C(=O)OCC
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of piperonal (60 g, 0.4 mol), triethyl orthoformate (59.2 g, 0.4 mol), toluene (250 mL) and p-toluenesulfonic acid (2 g, 0.01 mol) was heated at 100°-110° C. for 0.5 h. Diethyl L-tartrate (103 g, 0.5 mol) was added to the hot solution over a 10 min. period. The mixture was then heated at reflux for 2 h. Subsequently over a 3 hour period, distillate (150 mL) was collected (pot temperature 84° C. to 110° C.). The mixture was cooled (25° C.) and washed with sodium bicarbonate solution (2×50 mL) and brine (1×50 mL). Evaporation of solvents under reduced pressure provided 130.7 g of crude product. Recrystallization from methanol provided 90 g (67% yield) of (4R,5R)-2-(3,4-methylenedioxyphenyl)-4,5-dicarboethoxy-1,3-dioxolane, mp 39°-40° C., [α]D -34.8° (c, 1.0 methanol). 1H-NMR (CDCl3) δ7.12 (1H, d, J=1.5 Hz), 7.03 (1 H, dd, J=1.5 Hz and 7.9 Hz), 6.80 (1H, d, J=7.9 Hz), 6.06 (1H, s), 5.97 (2H, s), 4.91 (1H, d, J=4.0 Hz), 4.80 (1H, d, J=4.0 Hz), 4.36-4.26 (4H, 2 q, overlapping, J=7.0 Hz), 1.38-1.30 (6H, 2 t, overlapping, J=7.0 Hz). IR (KBr) 2980, 2900, 1735, 1490, 1445, 1415 cm-1. MS m/e (% abundance) 338 (3), 265 (16), 166 (100), 149 (96), 135 (54), 121 (35), 93 (10), 65 (12), 43 (8).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])(C)(C)C.[NH:18]1[CH2:23][CH2:22][O:21][CH:20]([CH2:24][OH:25])[CH2:19]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:7][CH:8]([C:10]1[CH:11]=[C:12]([N:18]2[CH2:23][CH2:22][O:21][C@H:20]([CH2:24][OH:25])[CH2:19]2)[CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: OCC1CNCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(N)c1cccc(N2CCO[C@H](CO)C2)c1
Yield: 48.1 %

Procedure:
The solution of (S)-[1-(3-bromo-phenyl)ethyl]carbamic acid tert-butyl ester (2.6 g, 8.8 mmol), morpholin-2-yl-methanol (1.1 mg, 9.7 mmol), palladium acetate (10 mol %, 197 mg), 2-(di-t-butylphosphino) biphenyl (20 mol %, 523 mg), and sodium tert-butoxide (1.1 g, 1.3eq) in toluene (28 ml) was stirred in sealed tube at 80° C. for 4 days. The reaction mixture was filtered through Celite pad and washed with 10% methanol/dichloromethane. The filtrate was concentrated under vacuum and purified by flash chromatography with 40% acetone/hexane. Yellow solid was obtained as the title compound (1.0 g, 39% yield).
Reaction SMILES: C(O[CH:5]=[C:6]([Cl:9])[CH:7]=[CH2:8])(=O)C.[C:10]1([S:16]([C:19]#[N:20])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:10]1([S:16]([C:19]2[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:20]=2)(=[O:17])=[O:18])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C=CC(Cl)=COC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc(Cl)cn1
Temperature: 100 °C
Reaction time: 7 h
Yield: 70.1 %

Procedure:
Toluene (60 ml) was heated to 100° C. Thereto was added dropwise a solution of 39.6 g of 2-chloro-1,3-butadienyl acetate and 30.0 g of benzenesulfonyl cyanide (purity:82%) in 60 ml of toluene over 30 minutes. The reaction mixture was stirred at 100° C. for 7 hours and then concentrated under reduced pressure. The crystals obtained were washed with 150 ml of toluene which was cooled to 0° C. and dried under reduced pressure using a vacuum pump to give 31.9 g of 2-benzenesulfonyl-5-chloropyridine (yield 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:21]#[N:22])([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].C(O)C.N>[Ni].CO.ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:22][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(C)c(C)c1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC1(c2ccc(C)c(C)c2)CNC(=O)C1
Reaction time: 48 h

Procedure:
Combine 3-cyano-3-(3,4-dimethylphenyl)pentanedioic acid diethyl ester (56 g, 177 mmol) and ethanol (500 mL) in a Parr bottle. Add Raney nickel (50 g) and an aqueous concentrated ammonia solution (85 mL). Hydrogenate at 50° C. and 100 psi for 48 h. Filter through a celite pad and rinse the solids with ethanol. Evaporate the filtrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 6% methanol/dichloromethane to give the title compound.