Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][S:10][C:11]([CH2:14][O:15][Si](C(C)(C)C)(C)C)=[CH:12][CH:13]=1)=[O:5].F>C(#N)C>[OH:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][S:10][C:11]([CH2:14][OH:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CNC(=O)c2ccccc2O)SS1
Agent: F
Solvent: CC#N
Product: O=C(NCC1=CC=C(CO)SS1)c1ccccc1O
Temperature: 0 °C
Yield: 65 %

Procedure:
To a stirred solution of the above (silyloxy)amide 22 (52 mg; 0.127 mmol) in 2.0 mL of acetonitrile was added 2.0 mL of a 1:3 solution of 30% aqueous hydrofluoric acid solution in acetonitrile. The resulting orange solution was stirred for 40 minutes in the ice bath then the excess acid was destroyed by the addition of about 10 mL of a 10% aqueous potassium carbonate solution. The reaction mixture was partitioned between 50 mL of ethyl acetate and 20 mL of saturated aqueous sodium chloride. The layers were separated and the aqueous phase was extracted with 50 mL of ethyl acetate. The combined organic phases were washed with 50 mL of saturated aqueous sodium chloride, dried (Na2SO4) and concentrated in vacuo. The residue (35 mg) was chromatographed over 20 g of silica gel (ethyl acetate-hexane, 1:1) to give 24.4 mg (65%) of the benzamide as an orange oil. 1H NMR (CD3OD; spectrum shows amide bond isomers) δ7.773 (dd, J=8.0, 1.6 Hz, 1H, ArH), 7.383 (dt, J=8.4, 1.6 Hz, 1H, ArH), 6.925-6.860 (m, 2H, ArH), 6.371 (br s, 2H, C=CH), 4.691 (s, 2H, CH2 ; minor isomer), 4.669 (s, 2H, CH2 ; minor isomer), 4.198 (s, 2H, CH2 ; major isomer), 4.173 (s, 2H, CH2 ; major isomer); 13C NMR (CD3OD; spectrum shows amide bond isomers) δ170.987, 161.079, 136.252, 134.962, 133.294, 129.055, 127.061, 125.984, 120.175, 118.424, 116.816, 64.778 (major isomer), 60.079 (minor isomer), 44.033 (major isomer), 39.112 (minor isomer); MS (LSIMS) m/z=55.0 (100%), 295.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[N:4][C:3]=1[OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1nncc(Cl)c1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
4,5-Dichloro-3-hydroxypyridazine (3000 g, 18.18 moles), dihydropyran (1943 g, 23.08 mole), p-toluenesulfonic acid monohydrate (283 g, 1.49 moles) and 16 L of tetrahydrofuran were added to a 50 L round bottomed flask equipped with a heating mantle, reflux condenser and a mechanical stirrer. The mixture was stirred at reflux for 29 h. Additional dihydropyran was added at 6 h (1328 g, 15.79 mol) and at 21 h (780 g, 9.25 moles). The reaction mixture was allowed to cool to room temperature overnight. The mixture was concentrated in vacuo to an oily residue. The residue was taken up in 16 L of ethyl acetate and washed with 2N NaOH (2×6 L). The organic solution was dried (MgSO4) and concentrated in vacuo to give 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone which was a black oily solid which was used without further purification in the next step. The product was purified by filtration through silica gel with ethyl acetate followed by evaporation and recrystallization from ethyl acetate/cyclohexane to give a white solid, mp=74°-76° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:31][C:32]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])[CH3:33]>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([O:15][Si:35]([C:32]([CH3:34])([CH3:33])[CH3:31])([CH3:37])[CH3:36])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)CCC1O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (3S,SR)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate (1.0 equiv.) in dichloromethane (0.1 M solution) was added imidazole (1.1 equiv.), DMAP (0.1 equiv.), and TBDMSCl (1.1 equiv.) sequentially The reaction mixture was stirred at room temperature for 20 h. After worked up with dichloromethane, the crude material was purified by silica column chromatography (10% to 20% EtOAc in hexanes) yielding (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate. LCMS (m/z): 365.2 [(M-Boc)H+]; LC Rt=6.05 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[B-](F)(F)(F)[F:12].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CC(O)=O>C(C#N)(C)=O>[Cl:1][C:2]1[C:3]2[C:10]([F:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: F[B-](F)(F)F
Reactant: Clc1nc[nH]c2nccc1-2
Agent: CC(=O)C#N
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Product: Fc1c[nH]c2ncnc(Cl)c12
Temperature: 70 °C
Reaction time: 26 h
Yield: 36 %

Procedure:
To a stirred solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (3.00 g, 19.5 mmol) in AcCN (148 mL) was added Selectfluor™ (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), 10.4 g, 29.4 mmol) and AcOH (29.8 mL, 524 mmol), and then the mixture was allowed to stir for 26 hrs at 70° C. under an atmosphere of nitrogen. After cooling to rt, the mixture was concentrated in vacuo and the mixture was co-evaporated with dry toluene (2×30 mL). The residue was dissolved in a solution of 50% DCM in EtOAc and filtered through a pad of silica gel which was thoroughly washed. The filtrate was concentrated in vacuo, the residue was purified by silica gel chromatography eluting with a gradient of 0 to 30% EtOAc in DCM to afford the title compound as a light brown solid (1.22 g, 36%). LC/MS: Rt=1.51 min, ES+ 243 (AA standard).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl[C:19]1[C:20]([C:25]2([C:31]#[N:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19]2[C:20]([C:25]3([C:31]#[N:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: N#CC1(c2nccnc2Cl)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#CC1(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCOCC1
Temperature: 60 °C

Procedure:
To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (0.097 g, 0.402 mmol) and 4-(3-chloropyrazin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (0.09 g, 0.402 mmol) in DMSO (1 mL) was added cesium carbonate (0.262 g, 0.805 mmol). The resulting mixture was heated to 60° C. overnight. Purification by Biotage (0-100% EtOAc/hexane) provided product. MS (ESI, pos. ion) m/z: 430.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: N1(O[C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:48]1[CH:52]=[CH:51][N:50]=[CH:49]1>COCCOC>[N:48]1([C:11]2[N:41]=[CH:40][N:39]=[C:38]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21])[CH2:17]2)[CH:52]=[CH:51][N:50]=[CH:49]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(-n4ccnc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 85 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
In a clean, dry reaction vial equipped with a stirring bar were placed O6-(benzotriazol-1-yl)-2′,3′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and imidazole (13.6 mg, 0.200 mmol). Dry DME (1.0 mL) was added and the reaction mixture was flushed with N2 and the mixture was allowed to stir at 85° C. for 4 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The mixture was washed with water, dried over Na2SO4, and evaporated to dryness. Chromatographic purification (SiO2, elution with 50% EtOAc in hexanes) afforded 32.0 mg (60% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.07. 1H NMR (500 MHz, CDCl3): δ 9.19 (s, 1H, Ar—H), 8.77 (s, 1H, Ar—H), 8.48 (s, 1H, Ar—H), 8.40 (s, 1H, Ar—H), 7.25 (s, 1H, Ar—H), 6.56 (t, 1H, H-1′, J=6.3), 4.64 (app q, 1H, H-3′, Japp˜4.2), 4.06 (m, 1H, H-4′), 3.90 (dd, 1H, J=11.2, 3.9), 3.80 (dd, 1H, H-5′, J=11.2, 2.9), 2.65 (app quint, 1H, H-2′, Japp˜6.3), 2.51 (m, 1H, H-2′), 0.92, 0.915 (2 s, 18H, tert-Bu), 0.11, 0.10 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 153.0, 152.1, 145.6, 143.0, 137.7, 130.6, 122.9, 117.3, 88.1, 84.7, 71.7, 62.6, 41.5, 25.9, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4]P(=O)(OC)OC.[H-].[Na+].[CH:17](=O)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[O:22]1[CH:21]=[CH:20][CH:19]=[C:18]1/[CH:17]=[CH:4]/[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[Br:1]
Reactant: COP(=O)(Cc1ccccc1Br)OC
Reactant: O=Cc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1/C=C/c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
A solution of dimethyl 2-bromobenzylphosphonate (10.35 g) in dry DMF (50 ml) was added dropwise at room temperature to a stirred suspension of sodium hydride (0.979 g) in dry DMF (100 ml) (effervescence). After 20 minutes, a solution of furfural (3.56 g) in dry DMF (50 ml) was added (exotherm) and the resulting mixture was stirred at room temperature for 4 hours, then diluted with water and extracted with ether. The extracts were washed with water, treated with magnesium sulphate and charcoal, filtered, concentrated under reduced pressure, and chromatographed using 40°-60° C. petrol as eluant to give E-1-(2-furyl)-2-(2-bromophenyl)-ethylene (3.755 g), a pale yellow liquid (containing about 6% of the corresponding Z-isomer by GC).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.O.[NH2:26][NH2:27]>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:27][N:26]=1
Reactant: N#Cc1ccc(-c2cc(NCC3CCCCC3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1nc(NCC2CCCCC2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a solution of 4-{2-amino-6-[(cyclohexylmethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (300 mg, 0.92 mmol) in EtOH (2 mL) was added hydrazine monohydrate (3.0 mL, 61.2 mmol), and the resulting suspension was stirred at 120° C. for 1 hour under microwave conditions. The clear reaction mixture was concentrated, and the resulting residue was purified by RPHPLC (CH3CN/H2O w/0.1% THF) to afford the title compound (160 mg, 48%) as a light yellow solid. LC-MS (ES) m/z=338 [M+H]+. 1HNMR (400 MHz, DMSO-d6): δ 0.92 (m, 2H), 1.19 (m, 3H), 1.51 (m, 1H), 1.68 (m, 5H), 3.14 (s, 2H), 5.37 (s, 2H), 5.95 (s, 2H), 6.29 (s, 1H), 6.85 (bs, 1H), 7.40 (bs, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 11.5 (s, 1H).
Reaction SMILES: [CH:1]1([Si:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)([CH3:8])[CH3:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.Br[CH2:19][CH2:20][O:21][Si:22]([CH3:25])([CH3:24])[CH3:23].C[Si](C)(C)OCCC1C([Si](C2C=CC=C2)(C)C)C2C(C=1)=CC=CC=2>C1COCC1>[CH3:23][Si:22]([CH3:25])([CH3:24])[O:21][CH2:20][CH2:19][C:1]1([Si:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)([CH3:8])[CH3:7])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: C[Si](C)(C)OCCBr
Reactant: C[Si](C)(C1C=CC=C1)C1C=Cc2ccccc21
Agent: C[Si](C)(C)OCCC1=Cc2ccccc2C1[Si](C)(C)C1C=CC=C1
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCC1([Si](C)(C)C2C=Cc3ccccc32)C=CC=C1
Reaction time: 12 h
Yield: 42 %

Procedure:
To a suspension of 0.63 g (26.3 mmol) of HNa in THF at −78° C., a solution of 6.3 g (26.3 mmol) of cyclopentadienylindenyldimethylsilane in THF was added. Immediately a purple solution was formed. Then, the volatiles were removed and the residue was washed with hexane to give a pink solid. The solid was solved again in THF and a solution of 5.2 g (26.3 mmol) of 2-bromo-1-trimethylsiloxyethane in THF was added at room temperature. A white suspension was formed immediately. The mixture was stirred for 12 h, and then the solvents were removed and the residue was treated with hexane and the supernatant solution was filtered. The removal of the hexane led to a brown oil. This oil was distilled in order to obtain a yellow-orange oil, which was characterized as a mixture of position isomers of (2-trimethylsiloxyethylindenyl) cyclopentadienyl dimethyl silane. (Tb: 170–175° C.; 1 mm Hg), (3.9 g, 11 mmol, yield: 42%). 1H-RMN(CDCl3): 7.54–7.42 (m, 2H); 7.31–7.12 (m, 2H); 6.95 (m, 1H); 6.91 (m, 1H); 6.72 (m, 1H); 6.61 (m, 1H); 6.60–6.42 (m, 3H); 3.78 (m, 2H); 3.62 (m, 1H); 3.42 (m, 2H); 2.62 (m, 2H); 0.17 (m, 15 H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH:28]=[C:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nc(N)nc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Reaction time: 48 h
Yield: 82.1 %

Procedure:
A mixture of 500 mg (1.9 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine, 1.2 g (3.9 mmol) 4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, 135 mg (1.9 mmol) Pd(PPh3)2Cl2, 40 mL 1 M aqueous Na2CO3 solution and 244 mg LiCl (5.78 mmol) in 100 mL toluene/ethanol (4:1 v/v) is kept over 2 days at reflux. After cooling the solvent is evaporated, water is added and the aqueous suspension is extracted 4 times with ethyl acetate (200 mL each). The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified using flash column chromatography yielding 635 mg (1.56 mmol) of the desired product which is used without further purification in the next step.
Reaction SMILES: CON(C)[C:4](=[O:14])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[Li]C.[CH3:18]COCC.Cl>C1COCC1>[CH3:6][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4](=[O:14])[CH3:18]
Reactant: CCOCC
Reactant: CON(C)C(=O)C(C)(C)c1ccccc1
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)c1ccccc1

Procedure:
To a solution of N-methoxy-N-methyl-2-phenyl-isobutyramide (example 207E) (16 g, 77.2 mmoles) in THF (300 mL) cooled at −50° C. is added dropwise a 1.6M solution of MeLi in Et2O (80 mL, 131.2 mmoles). The reaction mixture is allowed to reach 0° C. and 1N HCl (130 mL, 130 mmoles) is added. The aqueous phase is extracted with Et2O. The organic phase is washed with brine, dried over MgSO4, filtered and the solvent is removed under reduced pressure to give 3-methyl-3-phenyl-butan-2-one.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[BH4-].[Na+]>C1COCC1.C(O)C.O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To water (40 ml) was added glycine (246 mmol, 18.5 g) and aqueous sodium hydroxide (10M; 100 mmol, 10 ml). 4-Bromobenzaldehyde (130 mmol, 24 g) was added to afford a suspension. Ethanol (40 ml) and THF (90 ml) were added, followed by sodium borohydride (174 mmol, 6.6 g) and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and washed with ether (×3) and the aqueous layer acidified to pH ˜6.5 at which point precipitation occurred. The solid was filtered and washed with water and diethyl ether before co-evaporation with toluene to give 2-(4-bromobenzylamino)acetic acid (7H2) 11.3 g; 1H NMR (400 MHz, DMSOd6) δ 7.56 (d, 2H) 7.38 (d, 2H) 3.85 (s, 2H) 3.10 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH:13](Br)[C:12]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH:13]([O:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=1)[C:12]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCC1Br
Product: COC(=O)c1cccc(OC2COc3ccc(OCc4ccccc4)cc3C2=O)c1

Procedure:
By the method of Example 72, 6-benzyloxy-3-bromo-4-chromanone (49.9 g, 0.15 mol) and methyl 3-hydroxy-benzoate (22.8 g, 0.15 mol) were converted to present title product purified by chromatography on silica gel using CH2Cl2 as eluant, 2.19 g; tlc Rf 0.22 (CH2Cl2).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:27])[O:8][C@@H:7]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH2:6][O:5]1.CC1C=CC(S(O[CH2:39][C@@H:40]2[O:42][CH2:41]2)(=O)=O)=CC=1>CN(C)C=O>[CH3:3][C:4]1([CH3:27])[O:8][C@@H:7]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:39][C@H:40]4[CH2:41][O:42]4)=[CH:24][CH:25]=3)([CH3:18])[CH3:19])=[CH:15][CH:16]=2)[CH2:6][O:5]1
Reactant: CC1(C)OC[C@H](COc2ccc(C(C)(C)c3ccc(O)cc3)cc2)O1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(C(C)(C)c3ccc(OC[C@H]4CO4)cc3)cc2)O1
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 391 mg, 9.78 mmol, 1.5 equiv) was added slowly to a stirred solution of (S)-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol (2230 mg, 6.52 mmol, 1 equiv) in anhydrous dimethyl formamide (15 mL), at room temperature, and the contents were stirred under an atmosphere of argon for 30 min. A solution of (2R)-(−)-glycidyl tosylate 98% (2230 mg, 9.78 mmol, 1.5 equiv) in anhydrous dimethyl formamide (5 mL) was added via syringe and the mixture was allowed to react at room temperature for 16 h. Then, the reaction was quenched by the addition of a saturated solution of ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The organic layer was washed with deionized water (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 20% to 40% ethyl acetate in hexane) to provide the title compound (2.53 g, 94%) as a clear foam.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1C(=O)CCC1.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[C:19]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:18]=[N:17][CH:16]=1
Reactant: Brc1cncc(Br)c1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: Brc1cncc(N2CCOCC2)c1
Temperature: 180 °C
Yield: 19.5 %

Procedure:
To a solution of morpholine (3.67 g, 4.23 mmol), NMP (2 mL) and toluene (4 mL) was added 3,5-dibromopyridine (1.00 g, 4.20 mmol) and the mixture was heated under microwave conditions at 180° C. for 1 h. The solution was partitioned between DCM and water, the organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography eluting with (EtOAc: PE=1:5). (200 mg, yield 19.5%) MS (ESI+) e/z: 243.0 [M+1]+ LCMS.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[NH2:11][C:12]([NH2:14])=[S:13].II>>[NH2:14][C:12]1[S:13][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[N:11]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NC(N)=S
Agent: II
Product: Nc1nc(-c2ccc(O)cc2)cs1

Procedure:
According to Group 4-scheme 2, 4'-hydroxyacetophenone (Aldrich Chemical Co., Milwaukee, Wis., USA) was reacted with thiourea and iodine according to the method of R. M. Dodson and L. C. King, J. Amer. Chem. Soc. 1945, 67, 2242 to give 4-(2-amino-4-thiazolyl)phenol (5). Reaction of the latter compound with 1,1-dimethylethyl 2-bromoacetate in the presence of potassium carbonate gave 1,1-dimethylethyl 2-{4-(2-amino-4-thiazolyl)phenoxy}acetate (6). Subsequent hydrolysis of the later compound gave the thiazolylphenoxyacetic acid derivative of formula 2 wherein R1C is amino.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH2:10])[C:8]#[N:9].[OH-:11].[K+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH2:10])[C:8]([NH2:9])=[O:11]
Reactant: [OH-]
Reactant: C=C(C#N)c1ccccn1
Agent: [K+]
Product: C=C(C(N)=O)c1ccccn1

Procedure:
The Scheme 18 shows a proposed process for synthesizing pyridinyl acrylamide (76). Diketone (72) is reacted with compound (35) to yield pyridinyl ketone compound (73), which is transformed to the pyridinyl acrylonitrile compound (74) by reacting with cyanomethylphosphonic acid diethyl ester and NaH. 3-(2-Alkyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (75) obtained by hydrolyzing the pyridinyl acrylonitrile compound (74) with KOH is reacted with the amine compound (1) to yield pyridinyl acrylamide (76).