Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25].C([CH2:29][C:30]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=[O:36])=[O:31])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:29]/[C:30]([NH:32][C:33]2[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=2[C:35]([OH:37])=[O:36])=[O:31])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCCCC#CCCOc1cc(C=O)ccc1OC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCCCC#CCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 83.7 %

Procedure:
Piperidine (190 μL, 1.9 mmol) was added to a suspension of 4-methoxy-3-(oct-3-ynyloxy)benzaldehyde (0.50 g, 1.9 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.39 g, 1.7 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(4-methoxy-3-(oct-3-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.60 g, 82%) as a colourless crystalline solid; mp 157-158° C.; δH (400 MHz, DMSO-d6) 0.85 (t, J=7.2 Hz, 3H, CH3), 1.32-1.42 (m, 4H, CH3CH2CH2), 2.14 (t, J=7.2 Hz, 2H, CH2), 2.62 (t, J=7.2 Hz, 2H, CH2CH2O), 3.80 (s, 3H, OCH3), 4.10 (t, J=7.2 Hz, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 7.00 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5,6′=8.0 Hz, 1H, H6′), 7.40 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 13.4, 17.8, 19.3, 21.3, 30.5, 55.6, 67.1, 76.9, 81.5, 111.9, 112.1, 116.6, 120.0, 120.3, 122.6, 122.9, 127.3, 131.1, 134.0, 141.0, 141.5, 147.9, 150.8, 164.2, 169.4; HRMS (ESI) calculated for C25H27NO5 [M+H]+ 421.1962. found 421.1962; vmax 757, 1131, 1259, 1515, 1582, 1671, 2954, 3335 cm−1.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[CH3:11][CH:2]([S:12][C:13]#[N:14])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#C[S-]
Reactant: CC(Br)C(=O)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(SC#N)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of 2-bromopropiophenone (7.14 ml, 46.9 mmol) and potassium thiocyanate (4.56 g, 46.9 mmol) in ethanol (80 ml) was stirred at 80° C. for 3 hours. After cooling to room temperature, water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 7.27 g (81.0%) of the desired product as an oil.
Reaction SMILES: C([O-])(O)=O.[Na+].C1(C)C=CC=CC=1.C(O)C.[C:16]([C:20]1[N:25]=[C:24](Cl)[C:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][N:21]=1)([CH3:19])([CH3:18])[CH3:17].[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>CCOC(C)=O.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>[C:16]([C:20]1[N:25]=[C:24]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=2)[C:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][N:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1Cl
Reactant: OB(O)c1cccc(F)c1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1-c1cccc(F)c1
Temperature: 75 °C
Yield: 72 %

Procedure:
In a mix of sat'd NaHCO3:toluene:ethanol (1:2:1) (8 mL) was dissolved ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate from Example B40 (300 mg, 1.24 mmol), 3-fluorophenylboronic acid (350 mg, 2.47 mmol) and to this was added tetrakis(triphenylphosphine)palladium(0) (29 mg). The mixture was heated overnight at 75° C. under Ar. The mixture was diluted with EtOAc (25 mL) and water (25 mL). The mixture was filtered to remove insolubles and the organic phase separated, washed with 5% citric acid (25 mL), then saturated sodium bicarbonate (25 mL) and brine (25 mL). The solvents evaporated at reduced pressure and the residue purified by silica gel column chromatography (Biotage: 25M, 5-50% EtOAc/Hex—550 mL) to give ethyl 2-tert-butyl-4-(3-fluorophenyl)pyrimidine-5-carboxylate (0.27 g, 72% yield).
Reaction SMILES: CO.[C:3](Cl)(=O)C.[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:18][C:19]([OH:21])=[O:20]>CCCCCC.CCOCC>[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:18][C:19]([O:21][CH3:3])=[O:20]
Reactant: CC(=O)Cl
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Solvent: CO
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOc1cc(C(CC(=O)OC)N2Cc3ccccc3C2=O)ccc1OC
Reaction time: 4 h
Yield: 87.3 %

Procedure:
To an ice bath cooled solution of 50 mL of methanol was added acetyl chloride (7.2 mL, 100 mmol). After stirring for 10 minutes 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy4-methoxyphenyl)propionic acid (6.00 g, 16.9 mmol) was added to the mixture. After 30 minutes the ice bath was removed and the reaction was monitored by HPLC ( Waters radial pak phenyl 8×100 mm column, 240 nm, 1.5 mL/min, 35/65 acetonitrile/0.1% phosphoric acid). After 4 hours the reaction had reached completion. The methanol was removed in vacuo and the resulting residue was diluted with 50 mL of methylene chloride. The mixture was extracted with aqueous sodium bicarbonate (50 mL) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a thick oil. Hexane (50 mL) and ether (5 mL) were added to the oil and the mixture stirred overnight in an open flask. An additional 25 mL of hexane were added to facilitate stirring. After 6 hours the slurry was filtered and the solid air dried and then dried in vacuo (60° C., <1 mm) to afford 5.45 g (87%) of methyl 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate as a white solid: mp 78-80° C.; 1H NMR (DMSO-d6) δ7.75-7.40 (m, 4H), 7.10-6.80 (m, 3H), 5.72 (t, J=7.8 Hz, 1H), 4.51 (d, J=17.7 Hz, 1H), 4.09 (d, J=17.7 Hz, 1H), 3.97 (m, 2H), 3.73 (s, 3H), 3.55 (s, 3H), 3.24 (m, 2H), 1.30 (m, 3H); 13C NMR (DMSO-d6) δ170.8, 166.8, 148.5, 147.9, 141.6, 132.0, 131.3, 131.2, 127.8, 123.4, 122.8, 119.3, 112.2, 111.8, 63.7, 55.4, 51.5, 51.0, 46.3, 36.2, 14.6; Anal. Calcd. for C21H23NO5. Theoretical: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.13; H, 6.27; N, 3.70.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(#N)C.C(N(CC)CC)C>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1c(Cl)ccnc1Cl
Reactant: NCCCc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1c(NCCCc2ccccc2)ccnc1Cl
Temperature: 80 °C

Procedure:
To a mixture of 2,4-dichloro-3-(trifluoromethyl)pyridine (197 mg, 0.912 mmol) and 3-aminopropylbenzene (0.136 mL, 0.925 mmol) was added acetonitrile (8.0 mL) and triethylamine (0.153 mL, 1.095 mmol). The mixture was heated to 80° C. After five hours the mixture was removed from heat and concentrated. This material was purified on silica gel (25 g) equilibrated in hexane, loaded in dichloromethane and eluted using hexane (96 mL) 0 to 30% EtOAc/hexane (600 mL, linear gradient). Early eluting fractions gave 51 mg of a pale yellow film as a 1:1 mixture of the minor 2-isomer and pyridine starting material by 1H NMR. Later eluting fractions gave 172 mg of a pale yellow film. This was consistent with the desired product by 1H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (d, J=6.0 Hz, 1H), 7.37-7.29 (m, 2H), 7.27-7.17 (m, 3H), 6.45 (d, J=6.0 Hz, 1H), 5.52-5.31 (m, 1H), 3.27-3.16 (m, 2H), 2.75 (t, J=7.4 Hz, 2H), 2.02 (quin, J=7.3 Hz, 2H).
Reaction SMILES: [C:1](=[S:3])=[S:2].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([NH:22][NH2:23])=N>CO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[S:2][C:1](=[S:3])[NH:23][N:22]=1
Reactant: S=C=S
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=N)NN)c1Cl
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2n[nH]c(=S)s2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
Carbon disulfide (100 μl, 1.58 mmol) is added dropwise to a room temperature solution of 2-[(2,6-dichloro-3-methylphenyl)amino]benzene carboximidic acid hydrazide (183.4 mg, 0.595 mmol) in 5 ml of methanol. The solution is stirred under a nitrogen atmosphere at room temperature for two hours and then concentrated. The residue is purified by chromatography eluting with ethyl acetate:hexane (1:4) to give 107.0 mg (49%) of a yellow solid, mp 250°-252° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[C:7]1=[N:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[Cl:85][C:86]1[CH:91]=[CH:90][C:89]([C:92]2[CH2:97][CH2:96][C:95]([CH3:99])([CH3:98])[CH2:94][C:93]=2[CH2:100][N:101]2[CH2:106][CH2:105][NH:104][CH2:103][CH2:102]2)=[CH:88][CH:87]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:32]([O:31][C:29]([N:28]=[C:7]1[N:8]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]1[CH2:5][C:4]1[CH:36]=[CH:37][CH:38]=[C:2]([N:104]2[CH2:103][CH2:102][N:101]([CH2:100][C:93]3[CH2:94][C:95]([CH3:99])([CH3:98])[CH2:96][CH2:97][C:92]=3[C:89]3[CH:90]=[CH:91][C:86]([Cl:85])=[CH:87][CH:88]=3)[CH2:106][CH2:105]2)[CH:3]=1)=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N=c1n(CCCOc2cccc(C(=O)O)c2)c2ccccc2n1Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3cccc(Cn4c(=NC(=O)OC(C)(C)C)n(CCCOc5cccc(C(=O)O)c5)c5ccccc54)c3)CC2)C1
Temperature: 95 °C

Procedure:
To a degassed solution of 3-(3-{3-(3-bromo-benzyl)-2-[tert-butoxycarbonylimino]-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid (0.15 g, 0.25 mmol) in toluene (2 ml) at rt under nitrogen was added Pd(OAc)2 (5 mg, 0.12 mmol) and BINAP (30 mg, 0.048 mmol). Nitrogen was bubbled through the mixture for 10 min before a degassed solution of 1-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazine (90 mg, 0.28 mmol) in toluene (1 ml) was introduced. After 5 min Cs2CO3 (0.84 g, 2.58 mmol) was added. During all additions nitrogen was continuously bubbled through the reaction. Once the additions were completed the reaction vessel was sealed and then heated to 95° C. where it was maintained for 3 h. After this time, the reaction was cooled to rt and additional Pd(OAc)2 (5 mg, 0.12 mmol) and BINAP (30 mg, 0.048 mmol) were introduced. The reaction was then heated to 95° C. where it was maintained for a further 2 h. After this time, the reaction was cooled to rt and filtered through Celite®. The collected solids were washed with dichloromethane and the combined filtrate and washings were concentrated under reduced pressure. The crude product 3-{3-[2-[tert-butoxycarbonylimino]-3-(3-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid (290 mg) was used in the next step without further purification. HPLC-MS 818, 820 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:24])[C:17](=[O:23])[N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:25])=[C:10]([CH2:26][CH2:27][CH3:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:32])=[N-]>C(Cl)(Cl)Cl>[CH3:24][N:16]1[C:15]2[N:14]=[C:13]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9](=[O:29])[C:10]([CH2:26][CH2:27][CH3:28])=[C:11]([O:25][CH3:32])[N:12]3[C:20]=2[C:19](=[O:21])[N:18]([CH3:22])[C:17]1=[O:23]
Reactant: CCCc1c(O)n2c3c(=O)n(C)c(=O)n(C)c3nc2n(Cc2ccccc2)c1=O
Reactant: C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Product: CCCc1c(OC)n2c3c(=O)n(C)c(=O)n(C)c3nc2n(Cc2ccccc2)c1=O
Reaction time: 1.5 h

Procedure:
Dissolve 9-benzyl-1,3-dimethyl-6-hydroxy-7-(n-propyl)-pyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione (3 g) in 200 ml chloroform at 0° C. and treate with an ethereal solution of diazomethane. Stir the solution at 0° for 1.5 hours and destroy the excess diazomethane by the addition of acetic acid. Wash the chloroform solution with a solution of sodium bicarbonate and remove the chloroform under reduced pressure. Chromatograph the solid obtained on silica gel using 1% methanol in chloroform to give the title compound, mp 199°-201° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[N:12]([C:16]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[N:17][CH:18]=2)[CH:13]=[CH:14][N:15]=1.O.C(OCC)(=O)C>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:18]1[N:17]=[C:16]([C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[N:12]2[CH:13]=[CH:14][N:15]=[C:10]([Cl:9])[C:11]=12
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1ncc2c(Cl)nccn12
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1nc(Br)c2c(Cl)nccn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
N-Bromosuccinimide (24.69 mmol, 4.4 g) was added to a stirred solution of (S)-benzyl 2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (24.94 mmol, 8.9 g) in DMF (145 mL). The reaction was stirred 3 h at rt. The mixture was poured (slowly) in a stirred mixture of water (145 mL), ethyl acetate (145 mL) and brine (145 mL). The mixture was then transferred into a separating funnel and extracted. The water layer was extracted with 2×145 mL ethyl acetate. The combined organic layers were washed with 3×300 mL water, 300 mL brine, dried over sodium sulfate, filtered and evaporated. The product was purified using silica gel chromatography (ethyl acetate/heptane=3/1 v/v %) to give 8.95 g of (S)-benzyl 2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (82.3%).
Reaction SMILES: C1(CC([C@@H:10]2[C:21](=[O:22])[N:12]3[C:13]([C:18]([OH:20])=[O:19])=[CH:14][CH:15](N)[S:16][C@H:11]23)=O)C=CC=CC=1.C[Si](C)(C)Cl.[N:28]1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.C(N(CC)CC)C.O.CO>[NH2:28][C@@H:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[CH:14][CH2:15][S:16][C@H:11]12
Reactant: c1ccncc1
Reactant: NC1C=C(C(=O)O)N2C(=O)[C@@H](C(=O)Cc3ccccc3)[C@H]2S1
Agent: C[Si](C)(C)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.955 g of 7β-phenylacetyl-amino-ceph-3-em-4-carboxylic acid in 60 ml of absolute methylene chloride is treated with 0.720 g of trimethylchlorosilane and 0.474 g of absolute pyridine. The mixture is stirred for 60 minutes at room temperature and cooled to -20° C., and a solution of 3.20 g of absolute pyridine in 30 ml of absolute methylene chloride and 23.4 ml of an 8% strength solution of phosphorus pentachloride in absolute methylene chloride are then added successively. The whole is stirred for 60 minutes at -10° C. to -12° C. and again cooled to about -20° C., and 15 ml of absolute methanol are then run in. The mixture is stirred for 25 minutes at -10° C. and then for 35 minutes at room temperature, 15 ml of water are added, the pH-value of the reaction mixture is raised from 1.8 to 2.2 by dropwise addition of triethylamine and the mixture is stirred for 20 minutes at room temperature. The pH-value is raised to 3.8 by renewed addition of triethylamine and the two-phase mixture is stirred for 90 minutes whilst cooling in an ice bath and is then filtered. The filter residue is washed with methanol, methylene chloride and diethyl ether and is dried in a vacuum desiccator. 7β-Amino-ceph-3-em-4-carboxylic acid is thus obtained in the amorphous form; the product is used further without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]([O:12]C)=[O:11])=[N:7][C:8]=1[CH3:9].O.[Li+].[OH-].C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[N:7][C:8]=1[CH3:9]
Reactant: COC(=O)c1ccc(OC)c(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)O)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To methyl 5-methoxy-6-methyl-pyridine-2-carboxylate (1.00 g, 5.52 mmol) was dissolved in tetrahydrofuran (5.4 mL) was added water (2.7 mL) and LiOH (132.2 mg, 5.52 mmol). The mixture was stirred at room temperature overnight, then at 60° C. for 1.5 hours. Additional LiOH in water (2.76 mL of 2 M, 5.519 mmol) was added and the reaction was heated at 60° C. for 0.5 hours. The mixture was poured into water (5 mL) and ethyl acetate (15 mL) and the layers were separated. The aqueous layer was acidified to pH 4 with 2 N HCl and was extracted with ethyl acetate (7×25 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 5-methoxy-6-methylpicolinic acid (0.71 g, 77%) as a white solid. 1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 3.89 (s, 3H), 2.40 (s, 3H). ESI-MS m/z calc. 167.1, found 168.3 (M+1)+; Retention time: 0.19 minutes (3 min run).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.[H-].[Na+].[O:25]1[CH2:29][CH2:28]OS1(=O)=O.O>CN(C)C=O>[OH:25][CH2:29][CH2:28][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: O=S1(=O)OCCO1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.01 g of tert-butyl 3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate in 40 ml of N,N-dimethylformamide is added at 0° C. to the suspension of 0.26 g of sodium hydride dispersion (60%) in 40 ml of N,N-dimethylformamide. After 30 minutes, the reaction mixture is admixed with 0.83 g of [1,3,2]dioxathiolane 2,2-dioxide and stirred at room temperature over 18 hours. The reaction mixture is cooled to 0° C., admixed with water and concentrated by evaporation. The residue is stirred in a 1:10 mixture of 0.1 M H2SO4/dioxane at 50° C. over 60 hours, neutralized with saturated aqueous sodium hydrogencarbonate solution and concentrated by evaporation. The residue is dissolved in ethyl acetate, washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:1 EtOAc-heptane); Rt=4.24.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])(C)(C)C.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:17]([OH:20])[OH:18])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1cnc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
3-Bromoquinoline (0.4 mL, 3 mmol) was dissolved in THF, and the solution was cooled to −78° C. To this solution was added t-butyllithium (4.1 mL, 7 mmol), and the reaction mixture was stirred for 20 minutes. Trimethyl borate (0.81 mL, 7.1 mmol) was added at −78° C., and the mixture was stirred and allowed to warm to room temperature. The reaction was quenched with water, and the solvents were removed under vacuum. The residue 180 mg was taken directly to the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1>CN(C=O)C.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]>[CH3:20][O:19][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[NH:17][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=3)=[CH:3][CH:4]=1)=[N:9]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(Br)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2c1
Yield: 2 %

Procedure:
A solution of 2-(4-bromophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (1.1 g, 3.23 mmol), K2CO3 (1.3 g, 9.69 mmol), PdCl2(dppf) (0.261 g, 0.32 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 3.23 mmol) in DMF (50 mL) was heated to 110° C. overnight. The resulting solution was concentrated in vacuo and the material was purified twice by flash chromatography on silica gel, eluting with 0% to 5% of MeOH/CH2Cl2. The residue was further purified by flash chromatography on silica gel, eluting with 10% to 50% of EtOAc/CH2Cl2, to afford tert-butyl 4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.030 g, 49%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][CH:6]=1.[Li]C(CC)C.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[CH3:14][O:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][C:7]=1[B:20]([OH:25])[OH:21]
Reactant: COCOc1ccc(OCOC)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COCOc1ccc(OCOC)c(B(O)O)c1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Cool a solution of 1,4-bis-methoxymethoxy-benzene 5 (12.0 g, 60.6 mmol) in dry THF (250 mL) to −78° C. Add s-BuLi (1.3 M in hexane, 51 mL, 66.6 mmol) dropwise. Stir the reaction for 15 minutes and then add triisopropyl borate (14.2 mL, 60.6 mmol) slowly. Stir the reaction at −78° C. for 1 hour and warm to room temperature. Quench the reaction with 10% HCl and stir for 10 minutes. Extract with EtOAc (2×). Dry combined organic extracts (Na2SO4), filter, and concentrate in vacuo. Purify by flash chromatography (250 g SiO2, 20-50% EtOAc/hexanes and then 50% EtOAc/hexanes) to give 2,5-Bis-methoxymethoxy phenylboronic acid 7 (9.73 g, 40.2 mmol, 66%) as a yellow solid. 1H NMR (δ, 400 MHz, CDCl3): 7.50 (d, J=2.0 Hz, 1H), 7.09-7.07 (m, 2H), 5.93 (s, 2H), 5.24 (s, 2H), 5.14 (s, 2H), 3.49 (s, 3H), 3.48 (s, 3H). LRMS calcd. for C10H14BO6: 241.0; found (electrospray, M−1) 241.0.