Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH:6]1[CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:15]([OH:17])=[O:16].CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.CO>[O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH:6]1[CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:15]([OH:17])=[O:16]
Reactant: CCCCCC(O)C=CC1CCC2(OCCO2)C1C(CCCCC)C(=O)O
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CCCCCC(=O)C=CC1CCC2(OCCO2)C1C(CCCCC)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.75 g. of 7-(3-hydroxy-1-octenyl)-1,4-dioxaspiro[4.4]non-6-ylheptanoic acid in 40 ml. of acetone was cooled to 0° C. and treated with 2.0 ml. of Jones Reagent. After stirring for 10 minutes, at 0° C., the reaction mixture was treated with 5 ml. of methanol, dilute sodium bicarbonate until basic and water. Following acidification with acetic acid, the mixture was extracted with ether and the extract washed with water, dried and evaporated. Silica chromatography of the resulting residue with 30% ethyl acetate-hexane gave 0.355 g. of the title product, λmaxfilm 3.1 (shoulder), 5.8, 6.1, 6.75, 8.6, 9.6, 10.1, 10.5 μ. NMR: δ 6.78 (dd, 1, J=8.3, 15.8, 13-H), 6.18 (d, 1, J-15.8, 14-H), 3.92 (S, 4, ketal) ppm. UV: λmaxEtOH 230 mμ (ε 10,000). Mass spectrum N+ at m/c 380.2523 (theory 380.2562).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:13][CH:12]3[N:14]([C:15]([N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:20][CH2:19][CH2:18]4)=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH:8]=2)[CH:2]=1>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:13][CH:12]3[N:14]([C:15]([N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:20][CH2:19][CH2:18]4)=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH:2]=1
Reactant: O=C(N1CCCc2ccccc21)N1C2C=C(c3cccnc3)CC1CC2
Agent: [Pd]
Solvent: CCO
Product: O=C(N1CCCc2ccccc21)N1C2CCC1CC(c1cccnc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
In a high-pressure reactor, under nitrogen, 0.148 g of 5% palladium-on-charcoal is added to 0.240 g of 1-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-1,2,3,4-tetrahydroquinoline solubilized in 9 ml of ethanol. The reaction mixture is placed under a hydrogen pressure of 3 atmospheres, at 25° C., and mechanically stirred for 15 hours. The palladium is filtered off on Whatman paper and washed with methanol. The solvent is evaporated off, and the residue then chromatographed on silica gel with an eluent gradient of heptane/ethyl acetate (3/7) to heptane/ethyl acetate (2/8). 0.146 g of 1-[(3-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinoline is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)COB([C:35]2[CH:36]=[CH:37][C:38]([N:41](C)[C:42](=O)OC(C)(C)C)=[N:39][CH:40]=2)OC1>>[CH3:42][NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:40][N:39]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OCC(C)(C)CO2)cn1
Product: CNc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-methanesulfonyl-piperazin-1-yl)methyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with tert-butyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-2-yl(methyl)carbamate (Kumar et al (2003) J. Label Compd. Radiopharm., 46:1055-1065) via General Procedure A. Purification on silica yielded 195 (note BOC group cleaved during Suzuki reaction). NMR (CDCl3): 2.66-2.68 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.00 (s, 3H, CH3), 3.28-3.30 (m, 4H, 2×CH2), 3.86-3.88 (m, 6H, 3×CH2), 4.00-4.02 (m, 4H, 2×CH2), 4.12 (s, H, NH), 6.57 (d, H, ArH, J=9.03 Hz), 7.26 (s, H, ArH), 8.62 (d, H, ArH, J=9.04 Hz), 9.00 (s, H, ArH). MS: (ESI+): MH+ 504.33
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:22])[CH3:21]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cccc(F)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
3-Fluorophenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([N:16]3[CH2:20][CH2:19][C@H:18]([F:21])[CH2:17]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][CH:38]=1)[C:26]([NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:27].CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[C:13]([C:12]1[CH:15]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:24]=[C:25]([CH:36]=[CH:37][CH:38]=3)[C:26]([NH:28][CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:27])[N:7]=2)[CH:9]=[N:10][C:11]=1[N:16]1[CH2:20][CH2:19][C@H:18]([F:21])[CH2:17]1)#[N:14]
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)cnc1N1CC[C@H](F)C1
Reactant: CN1CCC(NC(=O)c2cccc(N)c2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCC(NC(=O)c2cccc(Nc3nccc(-c4cnc(N5CC[C@H](F)C5)c(C#N)c4)n3)c2)CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
5-(2-Chloro-primidin-4-yl)-2-((S)-3-fluoro-pyrrolidin-1-yl)-nicotinonitrile (8) (100 mg, 0.329 mmol), 3-amino-N-(1-methyl-piperidin-4-yl)-benzamide (115 mg, 0.493 mmol), Pd2(dba)3 (30 mg, 0.0327 mmol), NaOtBu (48 mg, 0.499 mmol) and Dave-Phos (130 mg, 0.330 mmol) were dissolved in 1,4-dioxane (3 mL). Nitrogen was bubbled through the stirred mixture for 5 minutes. The reaction mixture was then stirred at 120° C. in the microwave (250 W, stirring) for 2 hours. The solvent was evaporated in vacuo and the residue dissolved in DMSO (3 mL). The crude product was purified by reversed phase preparative LC-MS. Fractions containing desired product were combined and the MeOH evaporated in vacuo. The aqueous solution was frozen (−78° C.) and the solvent evaporated in vacuo (freeze dried). The title compound was obtained as an off-white solid (68 mg, 38%); LCMS, Rt=4.94 min (Method A), m/z 501 (MH+).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13]C)(=[O:12])[CH:10]=[CH2:11].[OH-].[K+]>Cl>[CH2:1]([O:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CCOCc1ccccc1
Reaction time: 0.33 h

Procedure:
A mixture of benzyl alcohol (84 ml) and methyl acrylate (80.6 ml) is then added drop by drop to the stirred solution over a period of 20-30 minutes, and stirring is continued for additional 20 minutes. Once the reaction, which is monitored by gas chromatography, is completed, 4N KOH (500 ml) is added and the mixture is stirred at room temperature for 2 hours. Then, 8% HCl (420 ml) is added keeping the temperature at about 20°-25° C. and the mixture is extracted with methylene chloride (200 ml plus four 50-ml portions). The mother liquors are acidified with 37% HCl (102 ml) to reach a pH of about 2.5 and extracted again with toluene (200 ml plus three 100 ml portions) The toluene extracts are combined, dried over Na2SO4, and concentrated to dryness yielding an oily residue of 3-benzyloxypropionic acid (100 g) which is employed as such in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH2:4][N:3]2[C:7](=[O:10])[S:8][CH2:9][C:2]=12.[F:11][C:12]([F:33])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1.C([O-])(=O)C.[NH2+]1CCCCC1.O>CC(O)C>[F:33][C:12]([F:11])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19](/[CH:22]=[C:9]2\[S:8][C:7](=[O:10])[N:3]3[CH2:4][CH:5]=[CH:6][N:1]=[C:2]\23)[CH2:18][CH2:17]1
Reactant: O=C1SCC2=NC=CCN12
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(C)O
Product: O=c1s/c(=C\C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)c2n1CC=CN=2
Temperature: 60 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of 4,8-dihydro[1,3]thiazolo[3,4-a]pyrimidin-6-one (38 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (125 mg) in 2-propanol (2 mL) was added piperidinium acetate (54 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight. The reaction mixture was added to water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (38 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16](B(O)O)=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)C.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>[CH2:30]([O:29][C:27]([C:26]1[C:25]([C:16]2[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:35][CH:34]=[C:33]([Cl:36])[CH:32]=1)=[O:28])[CH3:31]
Reactant: OB(O)c1ccccc1-c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)c1cc(Cl)ccc1Br
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: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)ccc1-c1ccccc1-c1ccccc1OCc1ccccc1
Temperature: 90 °C
Yield: 71.1 %

Procedure:
A mixture of 2′-benzyloxy-biphenyl-2-boronic acid (61 mg, 0.2 mmol), ethyl 2-bromo-5-chlorobenzoate (53 mg, 0.2 mmol), potassium carbonate (207 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) in 1:1 toluene/ethanol (3 ml) was stirred and heated at 90° C. under nitrogen for 2 hours. After cooling the mixture was diluted with diethyl ether and water and the organic phase dried (MgSO4) and evaporated to dryness. The residue was purified using Biotage with ethyl acetate/iso-hexane (1:19) to yield the title compound as a colourless gum (63 mg, 71%).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[CH3:24][S:25]([O:4][C@@H:3]1[C@@H:5]([CH2:6][O:7][S:25]([CH3:24])(=[O:27])=[O:26])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
A 3 liter, 3 necked round-bottomed flask was equipped with an overhead stirrer and paddle, a 500 mL dropping funnel and a Claisen adapter containing a drying tube and a thermometer. Thymidine (200 g, 0.82M) and pyridine (750 mL) were added to the flask. The mixture was stirred and warmed with a water bath (20 mins) to give a clear solution. The solution was then cooled in an ice bath to 0°-3° C. and the dropping funnel was charged with methanesulfonyl chloride (206.5 g, 1.08M). The methanesulfonyl chloride was then added dropwise over 40 minutes with no noticeable exotherm. The solution was stirred at 0° C. for 1 hr and then stored at 5° C. for 18 hr. The light brown mixture was then poured onto rapidly stirred water (3 L) containing ice (approx. 500 g). The desired product crystallised immediately. After stirring for 0.5 hr, the product was collected by filtration and washed several times with water (3×100 mL). The white solid was then dried under vacuum overnight (crude weight, 322 g, 98% yield). The product was recrystallised from hot acetone to give 267 g of a white solid (81% yield), mp 169°-171° C. (lit. 170°-171° C.)
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10]C(=O)[O:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:18][NH2:19].O>C(OCC)(=O)C>[NH2:10][C:11]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:19][CH3:18])=[O:8]
Reactant: Cc1cccc2c(=O)oc(=O)[nH]c12
Reactant: CN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNC(=O)c1cccc(C)c1N
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
A mixture of 8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (PCT Patent Publication WO 00/27831) (18 g, 0.1 mol) and acetic acid (1.2 g, 0.02 mol) in ethyl acetate (200 mL) was warmed to 35° C., and aqueous methylamine (40%, 9.0 g, 0.12 mol) was added dropwise over 50 minutes at 35-37° C. Then more aqueous methylamine (40%, 0.9 g, 12 mmol) was added, and the mixture was stirred an additional 2.5 h at 36° C. Then water (20 mL) was added, the layers were separated, and the organic layer was washed with water, dried (MgSO4), and evaporated to afford the title compound, 15.45 g (92%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].Br[CH2:23][CH2:24][CH:25]=[CH2:26]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH:23]=[CH:24][CH2:25][CH3:26])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Reactant: C=CCCBr
Product: CCC=CN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a method analogous to that described in Example 4, with biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide and 4-bromobutene, reacted at 60° C. for 3 hours, the title compound was obtained as a white powder. δC (CDCl3, 62.9 MHz): 25.2, 29.6, 33.4, 47.8, 48.3, 62.4, 117.2, 127.3, 127.6, 127.7, 128.5, 129.1, 134.6, 138.4, 139.3 and 145.3. δH (CDCl3, 250 MHz): 1.58 (4H, m), 2.34 (3H, m), 3.21 (4H, m), 3.66 (2H, t, J 6.1), 5.04 (2H, m), 5.69 (1H, m), 7.46 (3H, m), 7.60 (2H, d, J 7.3), 7.70 (2H, d, J 8.2) and 7.86 (2H, d, J 8.2)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](=O)[C:11]([OH:13])=[O:12].B([O-])=O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)C(=O)c1sccc1Nc1c(Cl)cccc1Cl
Agent: O=B[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1sccc1Nc1c(Cl)cccc1Cl

Procedure:
3.16 g (10 mmoles) of 3-(2,6-dichloroanilino)-2-thiophenglyoxylic acid and 2 g of sodium boranate are warmed to 80° in 10 ml of dimethylformamide for 4 hours. The mixture is poured onto water and extracted with toluene, the aqueous phase is acidified and extracted with ethyl acetate, and the organic phase is dried and concentrated. Recrystallization of the residue from toluene yields 3-(2,6-dichloroanilino)-2-thiophenacetic acid (m. 164° to 168°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32])[CH2:6][O:7][C:8]1[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]=1.Cl.C([N:42]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:30][C:31]=1[CH3:32])[CH2:6][O:7][C:8]1[C:12]([C:13]([NH2:42])=[O:14])=[CH:11][N:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C(N)=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carboxylic acid (0.80 g), 1-hydroxy-1H-1,2,3-benzotriazole ammonia complex (0.27 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.34 g) and N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carboxamide (0.78 g, yield 98%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 190-191° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:23][O:24][C:25](=[O:27])[CH3:26])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:25]([O:24][CH2:23][C:6]([NH:28][C:29](=[O:31])[CH3:30])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:36]3[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=3)=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(=[O:27])[CH3:26]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(=O)NC(CCc1ccc(-c2ccc(O)cc2F)cc1)(COC(C)=O)COC(C)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC(CCc1ccc(-c2ccc(Oc3ccc(C)cc3)cc2F)cc1)(COC(C)=O)COC(C)=O
Yield: 77.4 %

Procedure:
A solution of N-[1,1-bis(acetoxymethyl)-3-(2′-fluoro-4′-hydroxybiphenyl-4-yl)propyl]acetamide (278 mg), 4-methylphenylboronic acid (175 mg), copper(II) acetate (117 mg), pyridine (255 mg) and molecular sieves 4A (500 mg) in methylene chloride (5 mL) was stirred at room temperature for 9 hr. 2% Aqueous citric acid solution (100 mL) was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.26 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=3[Cl:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1cc(Cl)ccc1Cl
Product: CCCNC(=O)c1nnc2c(-c3cc(Cl)ccc3Cl)cccc2c1N
Yield: 46.7 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2,5-dichloro-phenylboronic acid (190 mg, 1.00 mmol) were reacted to afford the title compound (85 mg, 47% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (br, 1H), 7.99-7.91 (m, 1H), 7.78-7.67 (m, 2H), 7.48-7.31 (m, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=375 (M+H). HPLC 2.24 min.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([Cl-]C([O-])=O)[CH:2]=1.[Cl:14][C:15]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[C:24](=O)([O-:26])[O-:25].[Na+].[Na+]>C(Cl)Cl>[Cl:14][C:15]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:24](=[O:25])[O:26][C:3]1[CH:2]=[CH:1][C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=1
Reactant: NCc1cccc(F)c1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 5 liter 3-neck RBF was charged with 4-nitrophenylchloroformate (126.3 g, 627 mmol), DCM (3000 mL), under N2 atm and chilled in a 0° C. ice bath. A solution of 2-chloro,3-fluorobenzylamine (100.0 g, 627 mmol) followed by solid Sodium Carbonate (155.0 g, 1460 mmol) was quickly added in one portion into the reaction solution. The reaction mixture was stirred at 0° C. for 1 h and an LC/MS was taken to confirm consumption of the starting material and presence of the nitrophenyl intermediate. The reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The mixture was filtered, and the filtrate was concentrated to give a white solid. The solid was redissolved with 600 ml of DCM and heated to 40° C. until all of the material went into solution. The solution was chilled in a 0° C. ice bath to form crystals. The crystals were collected and dried under vacuum to give 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate. (150 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[CH3:10].S(Cl)([Cl:13])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH2:8][Cl:13])=[CH:6][N:7]=1
Reactant: Cc1cc(CO)cnc1Cl
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(CCl)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (6-chloro-5-methylpyridin-3-yl)methanol 74-1 (1.57 g, 10 mmol) in dichloromethane (15 mL) was added dropwise thionyl chloride (3.6 mL, 50 mmol) at 0° C. slowly. The mixture was stirred for 2 hours at room temperature, diluted with dichloromethane (100 mL) and water (100 mL), neutralized with powder sodium carbonate to pH 8. The aqueous layer was further extracted with dichloromethane (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation to afford 2-chloro-5-(chloromethyl)-3-methylpyridine 74-2 as pale yellow solid, which was used for next step directly. MS m/z 176.1 (M+1)
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
A 500-mL round-bottomed flask was purged with nitrogen and charged with 200a (2.5 g, 8.2 mmol), 10% palladium on carbon (50% wet, 300 mg), and methanol (80 mL). The flask was evacuated, charged with hydrogen gas, and stirred at room temperature under hydrogen atmosphere for 12 h. The hydrogen was then evacuated and nitrogen was charged to the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 200b (1.8 g, 78%) as a white solid. MS-ESI: [M+H]+ 278.1