Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:22])[N:4]=[C:3]1[N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C1COCC1.[H][H]>[Pd].CCOC(C)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:38])([CH3:1])[C:3]([N:23]([C:24]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[N:4][C@:5]3([CH3:22])[C:14]=2[CH:15]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To an argon flushed flask was added tert-butyl N-[(4aR,11bR)-3,3,11b-trimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.94 g, 3.50 mmol) and THF (35 ml), followed by a slurry of palladium on carbon (0.75 g, 0.70 mmol) in EtOAc (5 ml). The gas in flask was replaced with hydrogen balloon for three times. The mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The mixture was filtered through celite plug and concentrated to give tert-butyl N-[(4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.80 g, 98% yield) as an off-white solid. m/z (ESI) 524.2 (M+H)+.
Reaction SMILES: CN(C=O)C.[C:6]([NH:10][S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=2)=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:28]([C:32]1[NH:36][C:35]([CH:37]=[O:38])=[C:34]([Cl:39])[N:33]=1)[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[C:6]([NH:10][S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:36]3[C:35]([CH:37]=[O:38])=[C:34]([Cl:39])[N:33]=[C:32]3[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a DMF (75 mL) solution of 4′-bromomethylbiphenyl-2-sulfonic acid t-butylamide (4.7 g, 12.2 mmol), was added 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (2.3 g, 12.2 mmol) and potassium carbonate (1.7 g, 12.2 mmol). The mixture was stirred at room temperature overnight. EtOAc (400 mL) was added and the organic was washed 3 times with a sodium bicarbonate solution (200 mL) followed by saturated aqueous NaCl (200 mL). The solvent was removed and purification was achieved by silica gel chromatography (50/50 hexanes/EtOAc) using an isocratic gradient yielding intermediate (1a) as an off-white solid (5.0 g). Anal. HPLC: retention time=5.2 minutes. Gradient conditions: 10% solvent B/90% solvent A to 90% solvent B/10% solvent B over 6 minutes. MS m/z: [M+H]+ calcd for C25H30ClN3O3S, 488.18. found 488.6.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:16][O:17][CH3:18])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4].[CH2:19](O)[CH2:20]C.CS(O)(=O)=O>CCOCC>[Cl:1][CH2:2][C:3]([N:5]([CH2:16][O:17][CH2:18][CH2:19][CH3:20])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4]
Reactant: CCCO
Reactant: COCN(C(=O)CCl)c1c(OC)cccc1OC
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCCOCN(C(=O)CCl)c1c(OC)cccc1OC
Reaction time: 16 h
Yield: 68 %

Procedure:
A mixture containing alpha-chloro-N-[methoxymethyl]-N-[2,6-dimethoxyphenyl]acetamide (4.4 g; 0.0161 mole), 150 ml. of n-propanol and 0.2 ml. of methanesulfonic acid was heated at reflux temperature for 9 hours in a soxhlet extractor containing 22 g. of activated 3A molecular sieves. The reaction mixture was allowed to stand at 26° C. for 16 hours and was then concentrated in vacuo yielding a crude product. The crude product was taken up in ether and the ether solution was washed with a 5% sodium carbonate solution. The layers were separated and the organic ether layer was dried over magnesium sulfate, filtered and concentrated in vacuo to yield a white solid. The white solid was recrystallized from hexane to yield alpha-chloro-N-[propoxymethyl]-N-[2,6-dimethoxyphenyl]acetamide (3.3 g; 68% yield) as a white solid having a melting point of 83°-85° C. and the following analysis:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C@H:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25]>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C@H:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25])(=[O:5])=[O:4]
Reactant: O=C1OCC[C@@H]1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1OCC[C@@H]1OS(=O)(=O)C(F)(F)F
Reaction time: 0.08 h
Yield: 61.2 %

Procedure:
Trifluoromethanesulfonic anhydride (1.65 mL) was gently added to a solution of pyridine (0.83 mL) in dichloromethane mL) at 0° C., and the mixture was stirred for 5 minutes at the same temperature. Subsequently, (S)-2-hydroxybutyrolactone (1.0 g) was added dropwise thereto over 10 minutes at 0° C., followed by stirring for 12 hours at the same temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=2/1), to thereby yield a colorless oil (1.40 g, 61.2%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:9]
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(O)c1
Reaction time: 2 h

Procedure:
3′-Hydroxyacetophenone (500 mg) was dissolved in tetrahydrofuran (10 ml), and the solution was slowly added dropwise with a 3 M solution of methylmagnesium bromide in diethyl ether (3.7 ml) under ice cooling. The mixture was stirred at the same temperature for 2 hours, and then added with saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1 to 1:1) to obtain the title compound (224.3 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:20]=[CH:19][C:13]([O:14][CH:15]([CH3:18])[CH:16]=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[S:21](=[O:24])([OH:23])[O-:22].[Na+:25]>CO.O>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:20]=[CH:19][C:13]([O:14][CH:15]([CH3:18])[CH:16]([OH:17])[S:21]([O-:24])(=[O:23])=[O:22])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Na+:25]
Reactant: CC(C=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(O)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.7 %

Procedure:
A solution of 2-{p-[(3,5-dichloro-2-pyridyl)-oxy]phenoxy}propionaldehyde (25.38 g, 0.0813 mol) in methanol (300 mL) is added dropwise to a solution of sodium bisulfite (10.2 g, 0.0976 mol) in water (100 mL). The reaction mixture is stirred for 4 days at room temperature and filtered. The filter cake is dried in a vacuum oven overnight to obtain the title product as a white solid (24.6 g, mp 172°-173° C.).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10](=[CH2:14])[CH2:11][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[CH3:9][CH:10]([CH3:14])[CH:11]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8]
Reactant: O=Cc1ccccc1
Reactant: C=C(C)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a solution of benzaldehyde (3.05 mL, 30 mmol) in THF (30 mL) was added 2-methylallylmagnesium chloride (0.8 M in THF, 45 mL, 36 mmol, 1.2 equiv) under N2 at 0° C. (internal). The mixture was warmed to room temperature and was stirred for 1.5 h. The mixture was then poured into saturated aqueous NH4Cl solution (30 mL) and was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), then were dried (Na2SO4) and filtered. The solvent was removed by rotary evaporation and the residue was purified by Kugelrohr distillation to afford 4.33 g (89%) of 3-methyl-1-phenyl-1buten-1-ol as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:15]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=5)=[C:19]([Cl:32])[CH:18]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:33][C:6]=2[CH:5]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[NH:42]1[CH:46]=[CH:45][N:44]=[CH:43]1>CN(C=O)C>[Cl:32][C:19]1[CH:18]=[C:17]([NH:16][C:15]2[C:10]3[C:7]4[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:42]5[CH:46]=[CH:45][N:44]=[CH:43]5)=[CH:5][C:6]=4[S:33][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1
Reactant: c1c[nH]cn1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(CCBr)ccc5c34)cc2Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(CCn6ccnc6)ccc5c34)cc2Cl)c1
Temperature: 80 °C
Yield: 42.9 %

Procedure:
To a solution of 7-(2-bromoethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}[1]benzothieno[2,3-d]pyrimidin-4-amine (40 mg, 0.07 mmol, 1 equiv) in DMF were added sodium iodide (11 mg, 0.07 mmol, 1 equiv), sodium carbonate (16 mg, 0.15 mmol, 2 equiv), and imidazole (10 mg, 0.15 mmol, 2 equiv). The resulting mixture was heated at 80° C. for 14 h. The reaction was cooled to rt and then concentrated in vacuo. The resulting crude material was purified by prep-TLC (10% methanol/DCM) and afforded a yellow solid (17.9 mg, 0.03 mmol, 45%). 1H-NMR (CD3OD) δ 8.40 (s, 1H), 8.24 (d, J=8.3 Hz, 1H), 7.71 (m, 2H), 7.45-7.36 (m, 3H), 7.28 (d, J=8.1 Hz, 2H), 7.23 (d, J=9.6 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.09 (s, 1H), 7.04 (td, 1H), 6.92 (s, 1H), 5.12 (s, 2H), 4.35 (t, 2H), 3.23 (t, 2H); LCMS RT=3.22 min, [M+H]+=530
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH3:15])[CH2:12][O:11][C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:19]1([NH:25][C:16]([C@H:10]2[O:11][CH2:12][C@@H:13]([CH2:14][CH3:15])[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Reactant: NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC[C@@H]1CO[C@H](C(=O)NC2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To (2S,5R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-5-ethyl-2-morpholinecarboxylic acid (0.250 g, 0.964 mmol) in CH2Cl2 (10 mL) were added cyclohexylamine (0.096 g, 0.964 mmol), HOAt (0.131 g, 0.964 mmol) and EDC (0.222 g, 1.157 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was washed with H2O (2×) and the organics were dried over Na2SO4 and concentrated to afford the title compound (0.296 g) as a brown oil. LC-MS (ES) m/z=241 [M+H-Boc]+.
Reaction SMILES: BrC1C=C[C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4C(C)=NN(C)C=4)[C:5]=3[C:4]=2C=1.[Br:24]C1C=C([N+]([O-])=O)C(OC)=NC=1>>[Br:24][C:4]1[CH:5]=[C:6]2[N:12]([CH3:23])[C:13](=[O:22])[N:14]([CH3:15])[C:7]2=[N:8][CH:9]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Product: Cn1c(=O)n(C)c2ncc(Br)cc21

Procedure:
The title compound was synthesized in a similar manner as described for Intermediate A using 5-bromo-2-methoxy-3-nitro-pyridine (Stage 67.1.3) to give the title compound as a violet solid. (HPLC: tR 2.63 min (Method A); M+H=242, 244 MS-ES).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:14][C:13]2[CH:12]=[C:11]([C:10]#[C:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:18]=[CH:17][CH:16]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(C#CCCN2CCOCC2)c1
Product: C(#Cc1cccc(CN2CCOCC2)c1)CCN1CCOCC1

Procedure:
May be prepared analogously to Example 15 using the product of Example 10 and morpholine.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[CH2:12][OH:13].C(O)C.[H][H]>O1CCCC1.[C].[Pd]>[CH2:1]1[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[CH2:12][OH:13]
Reactant: OCC1CCC2(CCC=CCC2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: OCC1CCC2(CCCCCC2)C1
Yield: 96.6 %

Procedure:
A suspension of spiro[4.6]undec-8-ene-2-methanol (44 mg) obtained in Step 6 and 5% palladium carbon (4 mg) in tetrahydrofuran (1 mL)-ethanol (1 mL) was stirred in an atmosphere of hydrogen for 3 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography on silica gel to give spiro[4.6]undecane-2-methanol (43 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([SH:9])[N:6]2[N:10]=[C:11]([CH3:13])[N:12]=[C:5]2[N:4]=1.CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.O.N>C(#N)C>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:9][C:7]3[N:6]4[N:10]=[C:11]([CH3:13])[N:12]=[C:5]4[N:4]=[C:3]([CH2:2][OH:1])[CH:8]=3)[CH2:28][S:27][C@H:22]12
Reactant: Cc1nc2nc(CO)cc(S)n2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Solvent: O
Solvent: CC#N
Product: Cc1nc2nc(CO)cc(SCC3=C(C(=O)O)N4C(=O)C(N)[C@H]4SC3)n2n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
In 120 ml of acetonitrile were suspended 9.8 g of 5-hydr- oxymethyl-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine and 13.6 g of 7-aminocephalosporanic acid, and 22 ml of boron trifluoride-ethyl ether complex was added to the suspension and the mixture was stirred at 50° C. for 3 hours. After cooling the reaction mixture, 250 ml of water was added thereto and the mixture was adjusted to pH 2 with conc. aqueous ammonia. Precipitated crystal was collected by filtration, washed with water, washed with acetone and then dried to obtain 11.6 g of the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11](O)=[O:12])C1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:18][CH:19]([OH:21])[CH3:20]>C(Cl)Cl>[OH:12][CH2:11][CH2:10][C:9]([O:21][CH:19]([CH3:20])[CH3:18])=[O:8]
Reactant: O=C(O)CCOCc1ccccc1
Reactant: CC(C)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 3-benzyloxypropanoic acid (27.7 mmol) in propan-2-ol (40 mL) under nitrogen at 0° C. was added dropwise thionyl chloride (30.5 mmol). The reaction mixture was allowed to reach room temperature over 30 minutes and stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried on Na2SO4, filtered and concentrated under reduced pressure. The crude was diluted with isopropanol (80 mL) and Pd(OH)2 (20%, 1 g) in isopropanol was added. The system (reaction in a stainless steel reactor) was purged with nitrogen, vacuum and H2 and the reaction mixture was stirred under H2 atmosphere (3 bars) overnight at room temperature. The reaction mixture was filtered through autocup and the precipitate was washed with isopropanol. The filtrates were concentrated under reduced pressure and dried under vacuum pump to give the expected compound in 78% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.26 (d, J=6.31 Hz, 6H), 2.19 (brs, 1H), 2.54 (t, J=5.56 Hz, 2H), 3.86 (t, J=5.56 Hz, 2H), 5.06 (heptuplet, J=6.25 Hz, 1H).
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[O:20])[CH:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCCCCCCCCC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(C#N)C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 Moles of n-undecyl cyanide and 0.5 moles of diethyl oxalate are mixed in 1,000 ml of dimethylformamide. To this solution is added with ice cooling 0.52 moles of potassium t-butoxide. The mixture is allowed to stir overnight at room temperature. Following evaporation (rotary evaporator under vacuum) of most of the dimethylformamide the residue is mixed with 3 liters of diethyl ether followed by the addition of 1 liter water. The mixture is acidified with concentrated hydrochloric acid to a pH of 3 and then the ether phase is separated. After washing the ether with water and drying the ether over magnesium sulfate evaporation of the ether affords 3-cyano-2-oxotridecanoic acid ethyl ester. Recrystallization from petroleum ether at 30°-60° C. provides pure material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 89.1 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate (27 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 34 mg of the titled compound (yield, 88%). 1H NMR (300 MHz, CDCl3): δ 3.29 (s, 4H), 3.77 (s, 3H), 4.14 (s, 4H), 6.89-6.97 (m, 4H), 7.24-7.56 (m, 5H), 7.62-7.71 (m, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.O1CCCC1.[H-].[Na+].C1(C)C=CC(S(O[CH:28]([CH3:40])[CH2:29][CH:30]([CH3:39])[CH2:31][CH2:32][CH2:33][C:34]([O:37][CH3:38])([CH3:36])[CH3:35])(=O)=O)=CC=1>CN(C)P(=O)(N(C)C)N(C)C>[CH3:38][O:37][C:34]([CH3:35])([CH3:36])[CH2:33][CH2:32][CH2:31][CH:30]([CH3:39])[CH2:29][CH:28]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1)[CH3:40]
Reactant: COC(C)(C)CCCC(C)CC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc2c(c1)OCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(C)(C)CCCC(C)CC(C)Oc1ccc2c(c1)OCC2
Temperature: 25 °C

Procedure:
A solution of 2.7 g. of 6-hydroxy-2,3-dihydrobenzofuran in 10 ml. of absolute tetrahydrofuran is allowed to drop at 0° C. and while stirring into a suspension, cooled in ice, of 0.5 g. of sodium hydride in 5 ml. of absolute tetrahydrofuran. The mixture is stirred for 2 hours (during which time it is allowed to warm up to room temperature), again cooled to 0° C. and added dropwise to a solution of 7.13 g. of 7-methoxy-1,3,7-trimethyloctyl p-toluenesulfonate in 10 ml. of absolute tetrahydrofuran. The mixture is then diluted with 4 ml. of absolute hexamethylphosphoric acid triamide and stirred for 20 hours at room temperature. The mixture is then poured onto ice-water, extracted three times with diethyl ether, the ether extracts are washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (19:1 parts by volume) there is obtained pure 2,3-dihydro-6-[(7-methoxy-1,3,7-trimethyloctyl)-oxy]-benzofuran which is distilled in a bulb-tube at 145° C./0.03 mmHg; nD20 = 1.5046.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.ClC1N=C(N2CCOCC2)C2SC=CC=2N=1.C(OC(C1SC=C(C)C=1N)=O)C.[Li]CCCC.[I:51]I>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:5]2[S:10][C:9]([I:51])=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: II
Reactant: Cc1csc2c(N3CCOCC3)nc(Cl)nc12
Agent: CCOC(=O)c1scc(C)c1N
Agent: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: -40 °C
Reaction time: 0.83 h
Yield: 84 %

Procedure:
Also, to a solution of 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (3.0 g, 11.1 mmol; prepared according to the procedure for the synthesis of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine but commencing with 3-amino-4-methyl-thiophene-2-carboxylic acid ethyl ester) in THF (60 mL) at −78° C. was added n-BuLi (8.9 mL, 2.5 M in Et2O). The resulting slurry was warmed to −40° C. and stirred 50 min. The reaction mixture was then cooled to −78° C. and a solution of I2 (5.6 g, 22.2 mmol) in THF (30 mL) was added. The solution was warmed to room temperature and stirred 5 h. The reaction was quenched by the addition of water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous Na2S2O3, dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (3.8 g, 84% yield).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CCCO
Reactant: COc1ccc(Nc2ccc(C(=O)c3cc(N=[N+]=[N-])ccc3C)c(Cl)c2)cc1
Product: COc1ccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(Cl)c2)cc1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 448 (0.03 mmol) and but-3-yn-1-ol (0.06 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 30:70 to 100:0 as the eluent to afford the title compound. 13C NMR (CDCl3) δ 194.7, 157.3, 150.5, 146.2, 141.4, 138.1, 135.8, 134.6, 134.2, 132.5, 132.2, 126.5, 125.3, 122.1, 120.6, 120.1, 115.2, 115.0, 111.8, 61.5, 55.6, 28.6, 19.9
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[CH:21][CH:22]=[N:23][C:9]1=2)=[O:7].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(O)C>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[NH:11][C:10]3[CH:20]=[CH:21][CH:22]=[N:23][C:9]2=3)=[O:7])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCCCl)c2ccccc21
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CCCCN2CCCC2)c2ccccc21

Procedure:
4.5 gm of 11-(5-chlorovaleryl)-5,11-dihydro-6H-pyrido [2,3-b][1,4]-benzodiazepin-6-one and 10 ml of pyrrolidine were refluxed in 100 ml of ethanol for 12 hours. The alcohol was then distilled off, the residue was dissolved in chloroform/water, the organic phase was evaporated in vacuo to dryness, and the residue was recrystallized from ethyl acetate.