Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([CH:38]([F:40])[F:39])=[N:11][CH:12]=[C:13]([C:15]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:30]=[CH:31][N:17]3[N:16]=2)[CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:40][CH:38]([F:39])[C:10]1[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][C:13]([C:15]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3=[C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:30]=[CH:31][N:17]3[N:16]=2)=[CH:12][N:11]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cnc1C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)cnc1C(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
N-(tert-Butyl)-2-(difluoromethyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino) pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.520 g, 0.923 mmol) was dissolved in CH2Cl2 (4 mL). Then TFA (1.0 0 mL, 13.0 mmol) was added and stirred at RT for 16 h. The volatile components were removed under reduced pressure and the resulting residue was diluted with 10% NaHCO3 (25 mL). The reaction mixture was extracted with EtOAc (2×25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition B-96 as described in general methods) to afford 2-(difluoromethyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.140 g, 29.9%) as a pale yellow solid. LCMS Condition B-78: retention time 2.29 min, [M+1]=508.2. HPLC Condition B-31: retention time 8.65 min, purity 98.6%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.95 (d, J=4.8 Hz, 2H), 6.87 (d, J=2.8 Hz, 1H), 7.28-7.62 (m, 9H), 7.75-7.82 (m, 1H), 7.99 (d, J=2.4 Hz, 1H), 8.17 (s, 2H), 8.38-8.40 (m, 1H), 9.09 (d, J=1.6 Hz, 1H), 9.67 (d, J=2.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3COCC[Si](C)(C)C)[CH3:21])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:42][CH2:43][N:44]([CH3:46])[CH3:45].Cl.OC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1>CO>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Reactant: CN(C)CCCl
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Agent: Cl
Solvent: CO
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(OCCN(C)C)c3)c(=O)c12

Procedure:
Compound 126 (300 mg, 0.54 mmol) was treated with 2-chloro ethyl dimethylamine hydrochloride salt, at 90° C. for 17 hrs, using the procedure described above for compound 127. The resulting compound was then treated with 4N HCl, in MeOH, using the procedure described for compound 121 (step D). Compound 129 was obtained. m/z=485 (M+H). The structure of compound 129 is shown below.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[I-].[CH3:15][S+](C)(C)=O.O>CS(C)=O>[O:1]1[C:5]2[C:6]([CH:10]3[CH2:15][O:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2ccoc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1cc(C2CO2)c2occc2c1

Procedure:
A solution of benzofuran-7-carboxaldehyde (4.4 g) in dry dimethylsulphoxide was added dropwise to a stirred solution of sodium hydride (60% dispersion in oil, 2.5 g) and trimethylsulphoxonium iodide (7.6 g) in dimethylsulphoxide (50 ml) at room temperature. After 1 hour iced water was added and extracted with diethylether. The extracts were washed with water, dried, filtered and evaporated to a yellow oil. Chromatography on silica eluting with 10:1:90 ether:triethylamine:hexane gave 7-benzofuranyl oxirane as an oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C(OC([O-])=O)([O-])=O.[K+].[K+].[I-].[K+].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([O:33][C:34]1[C:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47]Cl)=[CH:43][C:42]=2[O:49][CH3:50])=[C:38]([CH3:51])[N:37]=[C:36]([NH2:52])[N:35]=1)(=[O:32])=[O:31]>C(#N)C>[NH2:52][C:36]1[N:35]=[C:34]([O:33][S:30]([C:23]2[C:22]([CH3:21])=[CH:27][C:26]([CH3:28])=[CH:25][C:24]=2[CH3:29])(=[O:31])=[O:32])[C:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][N:3]([CH2:1][CH3:2])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:43][C:42]=2[O:49][CH3:50])=[C:38]([CH3:51])[N:37]=1
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CCNCC(=O)OCC
Agent: O=C([O-])OC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(CC)Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The product from step (vi) (390 mg) was added to the mixture of potassium dicarbonate (410 mg), potassium iodide (49 mg) and the crude product from step (v) in acetonitrile (5 mL). After the mixture was stirred at 70° C. for 4 h, the reaction mixture was cooled to RT, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford the sub-title compound (490 mg) as a colourless amorphous solid; 1H NMR (300 MHz, CDCl3); 6.91 (2H, s), 6.87 (1H, s), 6.72 (2H, s), 4.65 (2H, br s), 4.14 (2H, q), 3.82-3.79 (5H, m), 3.70 (2H, s), 3.28 (2H, s), 2.67 (2H, q), 2.56 (6H, s), 2.28 (3H, s), 2.23 (3H, s), 1.25 (3H, t), 1.07 (3H, t).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][CH2:34][NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:38]([O:37][C:36](=[O:45])[NH:35][CH2:34][CH2:33][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Oc1ccc(-n2cccn2)cc1
Reactant: O=C(NCCO)OCc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCOc1ccc(-n2cccn2)cc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
A round-bottomed flask was charged with 4-pyrazole-1-yl-phenol (175 mg, 1.09 mmol), and 3.6 ml of toluene, triphenylphosphine (430 mg, 1.64 mmol), and benzyl N-(2-hydroxyethyl)carbamate (320 mg, 1.64 mmol) were then added. The solution was cooled to 0° C. and 1,1′-(azodicarbonyl)-dipiperidine (414 mg, 1.64 mmol) was added. The mixture was allowed to stir for about ten minutes at about 0° C. and was then allowed to warm to room temperature. An additional 3.6 ml of toluene and 3.6 ml of tetrahydrofuran were added to the viscous solution. The reaction mixture was stirred for about forty-eight hours, and the precipitated solids were filtered off and washed with a minimum volume of 1:1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuo to afford the intermediate [2-(4-pyrazole-1-yl-phenoxy)-ethyl]-carbamic acid benzyl ester as an oil which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12](OS(C)(=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:20]=[N+:21]=[N-:22])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Temperature: 65 °C

Procedure:
A solution of methanesulfonic acid trans-4-tert-butoxycarbonylamino-cyclohexyl ester (21 g, 72 mmol) in DMSO (350 mL) was charged with sodium azide (14 g, 216 mmol) and heated at 65° C. for 14 h. After cooling to RT, the solution was diluted with EtOAc and washed successively with water, 5% aq. NaHCO3, water, and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo, and the resulting residue was purified via flash chromatography to afford (cis-4-azido-cyclohexyl)-carbamic acid tert-butyl ester (16 g, 92% yield). MS found: (M+H)+=241.7.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH:15]([NH:20]S(C(C)(C)C)=O)[C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C:8]3(OCC[O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>C(O)(=O)C.C(O)C>[NH2:20][CH:15]([C:5]1([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH2:6][CH2:7][CH:8]([OH:9])[CH2:13][CH2:14]1)[C:16]([F:17])([F:18])[F:19]
Reactant: CC(C)(C)S(=O)NC(C(F)(F)F)C1(CC2CC2)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(C(F)(F)F)C1(CC2CC2)CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-methyl-propane-2-sulfinic acid [1-(8-cyclopropylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-2,2,2-trifluoro-ethyl]-amide (20, 1.00 g, 2.52 mmol) in 80% acetic acid (10 mL) was heated in a microwave oven for 10 min at 130° C. Then, the reaction mixture was slowly dropped into cold saturated sodium bicarbonate solution (150 mL), stirred for 30 min at room temperature and extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo to give the crude ketone, which was taken up in ethanol (20 mL), cooled to 0° C. and treated with sodium borohydride (190 mg, 5.03 mmol, 2.0 eq.). After the reaction went to completion, the mixture was poured onto water (20 mL) and extracted three times with dichloromethane. The organic layers were concentrated in vacuo and the residue was dissolved in a mixture of 2-propanol (15 mL) and 6N aqueous hydrochloric acid (5 mL). After stirring overnight at room temperature, another 5 mL of 6N aqueous hydrochloric acid were added and the mixture was warmed to 50° C. for 1 h. The reaction mixture was concentrated in vacuo and lyophilized twice from water to give the title compound (21) as racemic mixture of diastereoisomers as its hydrochloride. Rt=0.73 min, 0.82 min (Method B). Detected mass: 252.3 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.Br[CH:17]([CH2:19][CH3:20])[CH3:18].O>CN(C=O)C>[CH3:18][CH:17]([S:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)[CH2:19][CH3:20]
Reactant: CCC(C)Br
Reactant: COc1ccc(S)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Sc1ccc(OC)cc1
Reaction time: 8 h

Procedure:
Potassium t-butoxide (30.6 g, 275.0 mmol) is added to a solution of 4-methoxybenzenethiol (30.0 ml, 250.0 mmol) in 250 ml of DMF. The mixture is heated at 80° until homogeneous, after which 2-bromobutane (30.0 ml, 275.0 mmol) in 30 ml of DMF is added dropwise over approx. 30 min. The mixture is stirred at 60° overnight after which it is cooled and is then poured into water and the aqueous phase is extracted with ether (3×). The combined ether extracts are washed with water, with 5% sodium hydroxide, with water and with brine, dried, and the solvent removed to give 4-(1-methylpropylthio)anisole.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18](F)[C:19]=2[F:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]1)[CH3:10]>N1C=CC=CC=1>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18]([N:7]3[CH2:6][CH2:5][NH:4][CH:3]([CH2:2][F:1])[CH2:8]3)[C:19]=2[F:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]1)[CH3:10]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: FCC1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CF)C3)c(F)c21
Reaction time: 2.5 h
Yield: 55.2 %

Procedure:
A mixture of 650 mg of 2-(fluoromethyl)piperazine, 500 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid and 5 ml of pyridine was stirred under nitrogen in a capped bottle at for 2.5 hours. The solvent was removed and the residue triturated with methanol. The solid was collected, washed twice with methanol and dried, giving 376 mg of racemic 1-ethyl-6,8-difluoro-7-[3-(fluoromethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18]([OH:20])=O)=[N:10]1.[NH2:21][CH:22]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[CH2:23][OH:24]>>[OH:24][CH2:23][CH:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)=[O:20])[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: NC(CO)C1CCOCC1
Product: O=C(NC(CO)C1CCOCC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using Intermediate 1 (see Example 1.1) and 2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol. LCMS m/z=404.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46-0.50 (m, 1H), 1.15 (td, J=7.8 and 4.8 Hz, 1H), 1.40-1.53 (m, 2H), 1.70 (d, J=12.6 Hz, 2H), 1.93-2.03 (m, 1H), 2.08-2.15 (m, 1H), 2.24-2.32 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.06 (dd, J=16.8 and 6.2 Hz, 1H), 3.33-3.43 (m, 2H), 3.77-3.85 (m, 3H), 3.95-4.02 (m, 2H), 6.99-7.05 (m, 3H), 7.59-7.66 (m, 1H).
Reaction SMILES: BrC1N=C(C#C[Si](C)(C)C)C(N)=NC=1.[CH3:15][C:16]1[CH:17]=CC(S(O)(=O)=O)=C[CH:21]=1.[Br:26][C:27]1[N:28]=[C:29]([C:44]#[C:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:30]([N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:34](=[O:36])[O-:35])=[N:31][CH:32]=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C>CCOC(C)=O.CN(C1C=CN=CC=1)C>[C:40]([O:39][C:37]([N:33]([C:30]1[C:29]([C:44]#[C:45][Si:46]([CH3:47])([CH3:49])[CH3:48])=[N:28][C:27]([Br:26])=[CH:32][N:31]=1)[C:34](=[O:35])[O:36][C:16]([CH3:17])([CH3:21])[CH3:15])=[O:38])([CH3:42])([CH3:43])[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)[O-])c1ncc(Br)nc1C#C[Si](C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1C#C[Si](C)(C)C

Procedure:
A solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (Compound C-2) PTSA salt 3 (2350 g, 5.31 mol) in EtOAc (11.5 L) is stirred with a 20% w/w aq. solution of KHCO3 (4.5 kg, 1.5 eq.) for at least 30 min. The layers are separated and the organic layer is concentrated then dissolved in EtOAc (7 L) and added to a reactor. DMAP (19.5 g, 0.16 mol) is added followed a solution of Boc2O (2436 g, 11.16 mol) in EtOAc (3 L) is added lowly. The reaction is stirred for at least 30 min to ensure complete reaction then activated charcoal (Darco G-60, 720 g) and Celite (720 g) are added and stirred for at least 2 h. The mixture is filtered washing the solid pad with EtOAc (2×1.8 L). The filtrate is concentrated to afford tert-butyl N-tert-butoxycarbonyl-N-[5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-yl]carbamate (Compound C-3) that is used directly in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].CCN(CC)CC.[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N(C)OC
Reaction time: 2 h

Procedure:
To a CH2Cl2 solution (200 mL) containing N-methoxy-N-methylamine hydrochloride (8.09 g, 82.9 mmol) and Et3N (12.6 g, 124 mmol) was added valeryl chloride (10 g, 82.9 mmol) dropwise at room temperature. The resulting solution bubbled vigorously and stirred for 2 hours after which time it was carefully quenched with H2O. The organic layer was separated and washed with 2.0 N NaOH. The organics were extracted with CH2Cl2, dried (MgSO4) and the solvent removed in vacuo. The resulting colorless oil was taken on without further purification.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:42]([O:45]CC)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([OH:45])(=[O:44])/[CH:43]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C=O
Reactant: CCOC(C)=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To trans-2-decenal (5.0 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenylphosphorane (11.99 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-dodecadienoic acid (6.1 g). Potassium hydroxide (8.1 g) was dissolved in a mixed solvent of ethanol-water (1:1) (100 ml). The methyl ester of trans,trans-2,4-dodecadienoic acid (6.1 g) was added to the mixture, and the resulting mixture was stirred at 60° C. for 40 minutes. After the reaction mixture was cooled, it was adjusted to the weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-dodecadienoic acid (5.4 g). To trans,trans-2,4-dodecadienoic acid dissolved in N,N-dimethylformamide (DMF, 50 ml) were added para-nitrophenol (3.8 g) and N,N'-dicyclohexylcarbodiimide (5.8 g), and the mixture was stirred for 12 hours. After precipitates obtained were removed by filtration and the solvent (DMF) was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-dodecadienoic acid (3.4 g). To the active ester (800 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (800 mg) and triethylamine (2.0 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK282 in the yield of 310 mg.
Reaction SMILES: COS(OC)(=O)=O.[Br:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1.[C:20]1(C)C=CC=CC=1.[OH-].[Na+]>O>[Br:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1
Reactant: Brc1cccc(-c2c[nH]cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: Cn1cnc(-c2cccc(Br)c2)c1
Temperature: 100 °C
Yield: 33 %

Procedure:
Using the method of Hazeldine et al., J. Chem. Soc., 125, 1431-41 (1924) a mixture of dimethylsulphate (145 μl, 1.53 mmol) and 4-m-bromophenyl imidazole (341 mg; 1.54 mmol) was stirred under N2 until the reaction mixture became extremely viscous. Toluene (150 μl) was added, and the mixture was heated at 100° C. for 1 hour. After cooling to ambient temperature, H2O (5 ml) was added, and the reaction mixture was brought to pH 9 with NaOH solution. It was then extracted with CH2Cl2 (2×10 ml). The organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give 262 mg crude product mixed with starting material. Purification using preparative TLC on 2-1000μ Si Gel GF plates (eluting with 5% MeOH in CH2Cl2 and extracting with 10% MeOH in CH2Cl2) provided the product, 4-m-bromophenyl-1-methylimidazole (121 mg, 33% yield) as the least polar band.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[Na+].[N+:17](CC)([O-])=O>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:17]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C#N)c(O)c1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2-hydroxy-4-methoxybenzaldehyde (25.0 g, 164 mmol), sodium acetate (26.4 g, 322 mmol), nitroethane (23 g, 307 mmol) in acetic acid (45 mL) was heated at reflux for 6 h. The mixture was then cooled to room temperature and poured onto ice water. The solids were filtered off, washed with water and dried. Recrystallization of the crude solid in ethyl acetate gave 2-hydroxy-4-methoxy-benzonitrile as a brown solid (15.9 g, 65%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.CCCCCC.C([Li])CCC.CN(C)[CH:23]=[O:24]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:23]=[O:24]
Reactant: c1ccc2occc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc2ccccc2o1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 63 %

Procedure:
2.18 g of benzofuran was dissolved in 40 ml of anhydrous tetrahydrofuran. Thereto was dropwise added 12.3 ml of 1.5 M n-butyllithium hexane solution, in 5 minutes with stirring at -50° C. The mixture was stirred at 0° C. for 30 minutes and then cooled to -60° C. Thereto was added 1.61 g of N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure. The residue was mixed with 50 ml of ethyl acetate and 20 ml of water to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: n-hexane/ethyl acetate =20/1 to 10/1) to obtain 1.70 g (yield: 63%) of 2-benzofurancarbaldehyde as a colorless oily material.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1.O>ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][C:19]=1[N+:24]([O-:26])=[O:25]
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)cc3[N+](=O)[O-])c2cc1OC
Temperature: 180 °C
Reaction time: 23 h
Yield: 27.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.15 g) and 4-methyl-2-nitrophenol (1.52 g) were suspended in o-dichlorobenzene (7 ml), and the suspension was stirred at 180° C. for 23 hr. The reaction solution was cooled to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (480 mg, yield 27%).