Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][N:3]=1.[C:11]([C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1)#[CH:12].C(OCC)(=O)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:12]#[C:11][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]2)=[CH:4][N:3]=1
Reactant: C#C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: COc1nc(Cl)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc(Cl)ncc1C#C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 2-chloro-5-iodo-4-methoxypyrimidine (Q1, 101 mg), tert-butyl ((1S,3R)-3-ethynylcyclohexyl)carbamate (P0, 100 mg), bis(triphenylphosphine)palladium(II) dichloride (26 mg) and copper(I) iodide (14 mg) in N,N-dimethylformamide (3 mL), triethylamine (258 μL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, ethyl acetate and saturated aqueous ammonium chloride were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 88 to 50% hexane in ethyl acetate) to obtain tert-butyl ((1S,3R)-3-((2-chloro-4-methoxypyrimidin-5-yl)ethynyl)cyclohexyl)carbamate (Q2, 118 mg).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[N:14][CH:13]=[C:12]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1)[CH:11]=2)(=O)=O.FC1C=C(C=CC=1F)COC1C=C2C(C=C(CO)C=N2)=[N:35][CH:34]=1.CS(Cl)(=O)=O>C(Cl)Cl>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:12]2[CH:11]=[C:10]3[C:15]([CH:16]=[C:7]([CH2:6][C:34]#[N:35])[CH:8]=[N:9]3)=[N:14][CH:13]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: OCc1cnc2cc(OCc3ccc(F)c(F)c3)cnc2c1
Reactant: CS(=O)(=O)OCc1cnc2cc(OCc3ccc(F)c(F)c3)cnc2c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: N#CCc1cnc2cc(OCc3ccc(F)c(F)c3)cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
(7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methyl methanesulfonate. To a solution of (7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methanol (Example 73, 90 mg, 0.3 mmol) in DCM (4 mL) was added methanesulfonyl chloride (0.05 mL, 0.61 mmol) followed by TEA (0.06 mL, 0.43 mmol). The reaction mixture was stirred at RT for 1 h and quenched with saturated NaHCO3 solution. The mixture was extracted with DCM (2×) and the combined organic layers were dried, filtered and concentrated under reduced pressure. Purification (FCC, SiO2, 0-80%, EtOAc/hexanes) afforded the title compound as a white solid (73 mg, 64%). [M+H]=381.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22]CO)[N:18]=[C:17]([O:25][CH3:26])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(NC2N=C(Cl)N=C(OC)N=2)CC1)=O)(C)(C)C.CN.C(N(C(C)C)C(C)C)C.COC1N=C(NC2CCNCC2)N=C(NCCO)N=1>C(#N)C>[CH3:26][O:25][C:17]1[N:18]=[C:19]([NH:21][CH3:22])[N:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:16]=1
Reactant: COc1nc(NCCO)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: CN
Agent: COc1nc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: COc1nc(NCCO)nc(NC2CCNCC2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(NC2CCNCC2)nc(OC)n1

Procedure:
The compound was prepared in analogy to the synthesis of 4-[4-(2-hydroxy-ethylamino)-6-methoxy-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (intermediate C26/step 2) from 4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (intermediate C26/step 1) and methylamine (12 M solution in water) and N-ethyl diisopropylamine in acetonitrile at rt, followed by BOC cleavage in analogy to the procedure described for 2-[4-methoxy-6-(piperidin-4-ylamino)-[1,3,5]triazin-2-ylamino]-ethanol (intermediate C26/step 3). MS (ISP): 239.1 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1.[CH3:16][C:17]([CH3:24])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][NH2:19].Cl>>[ClH:1].[CH3:14][CH:13]([S:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:19][CH2:18][C:17]([CH3:24])([CH3:16])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:8]=1)[CH3:15]
Reactant: CC(C)Sc1ccc(OCCCCl)cc1
Reactant: CCCCC(C)(C)CN
Agent: Cl
Product: CCCCC(C)(C)CNCCCOc1ccc(SC(C)C)cc1

Procedure:
Reaction of 1-chloro-3-[4-(1-methylethylthio)phenoxy]propane with 2,2-dimethylhex-1-ylamine according to the procedure of Example 2(b) and conversion of the base to the hydrochloride provides N-[3-[4-[(1-methylethyl)thio]phenoxy]propyl]-2,2-dimethylhex-1-ylamine hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.CCOC(C(C#N)=NOC([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.N1CCOCC1>CN(C=O)C>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[C:24]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)=[O:25])=[O:23]
Reactant: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)cnn1C
Reactant: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)N2CCOCC2)cnn1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 1-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylic acid (40 mg, 113 μmol) in DMF (1 mL) were added COMU (58.0 mg, 135 μmol) and N,N-diisopropylethylamine (14.6 mg, 19.7 μL, 113 μmol) at 0-5° C. After 10 min the suspension became a clear solution and subsequently morpholine (11.8 mg, 135 μmol) and N,N-diisopropylethylamine (14.6 mg, 19.7 μL, 113 μmol) were added. The ice bath was removed after 10 min and the mixture was stirred at RT for 3 h. The product was obtained after purification by preparative HPLC using an acetonitrile/water (containing 0.1% formic acid) gradient as off-white waxy solid (31 mg, 73.2 μmol, 64.9%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7](C)[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:27]([C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[CH3:38])#[N:28]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:32]4[CH:31]=[C:30]([CH3:38])[C:29]([C:27]#[N:28])=[N:34][CH:33]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: Cc1cc(B(O)O)cnc1C#N
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: Cc1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)cnc1C#N

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and (6-cyano-5-methylpyridin-3-yl)boronic acid (Combi-Blocks, Cat. No. PN-5814). LCMS (M+H)+: m/z=441.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:23]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N:11][C:12]([OH:23])=[CH:13][CH:14]=2)[S:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])[CH3:2]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc[n+]2[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C(=O)OC)sc2nc(O)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 3-(2-ethoxy-2-oxoethoxy)thieno[2,3-b]pyridine-2-carboxylate 7-oxide (500 mg) and DMF (8 mL) was added TFAA (2.233 mL) at 0° C. The mixture was stirred at room temperature for 4 h. After evaporation of TFAA, the residue was added to water at 0° C., and the resulting precipitate was collected by filtration, washed with hexane to give the title compound (418.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22].CO>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:22][C:14]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=2[F:12])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: CO
Solvent: Clc1ccccc1
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Temperature: 120 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
4-Chloropyridine-2-carboxylic acid methyl ester (30 g) and 2-fluoro-4-nitrophenol (41.2 g) were dissolved in chlorobenzene (24 ml), followed by stirring under a nitrogen atmosphere at 120° C. for 4 hr. The reaction mixture was allowed to cool down to room temperature, methanol (100 ml) was added, and stirred for 30 min. The solvent was removed under reduced pressure, then the resultant residue was partitioned between ethyl acetate (300 ml) and a 1N aqueous solution of sodium hydroxide (150 ml). The separated organic layer was washed with a 1N aqueous solution of sodium hydroxide (100 ml) and brine (150 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, ethanol (200 ml) was added to the resultant residue, followed by stirring for 30 min. The solid was collected by filtration and the filtrate was purified by silica gel column chromatography (YMC, SIL-60-400/230W, eluent; heptane:ethyl acetate=1:1). Fractions containing the target compound were concentrated under reduced pressure, the resultant solid was combined to the solid above to provide 4-(2-fluoro-4-nitrophenoxy)pyridine-2-carboxylic acid methyl ester as a pale brown solid (20.0 g, 40.0%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>C(O)C.O.C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NC(C)=O)cc1OCCOc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCCCc1ccc(N)cc1OCCOc1ccccc1
Temperature: 25 °C
Yield: 80 %

Procedure:
N-(4-Butyl-3-(2-phenoxyethoxy)phenyl)acetamide (132 g, 0.41 mol) was dissolved in ethanol (897 mL) and water (104 mL). KOH (312 g, 5.57 mol) was added at 0° C. and the solution was allowed to reflux for 18 hrs. Upon completion the reaction was cooled to room temperature and diluted with 2 L of water and 2 L of DCM. The organic layer was washed with water (×2) and dried over sodium sulfate. The crude compound was purified further via flash chromatography with hexane:ethyl acetate (1:1) to obtain the title compound in 80% yield (92 g) as a pink solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[C:20]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:21][C:22]([CH3:24])=O>C1C=CC=CC=1>[CH2:27]([O:26][C:20](=[O:25])[CH:21]=[C:22]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([CH3:12])=[CH:14][CH:15]=1)[CH3:24])[CH3:28]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)Nc1ccc(C)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
p-Toluenesulfonic acid (catalytic amount) was added to a solution of p-methylaniline (10.7 g, 100 mmol) and ethyl acetoacetate (13.0 g, 110 mmol) in benzene (250 mL) at room temperature. The reaction mixture was refluxed with a Dean-Stark apparatus over night. After cooling down to room temperature, the reaction mixture was concentrated and purified by column chromatography (5% ethyl acetate in n-hexane) to give 3-p-tolylamino-but-2-enoic acid ethyl ester (18.6 g, 85% yield).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.Cl.[NH2:16][C@H:17]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[OH:23].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:16][C@H:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[OH:23])=[O:14])[CH:3]=1
Reactant: O=C(O)c1cc(Br)c2ccccc2n1
Reactant: N[C@H]1CCOC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Br)c2ccccc2n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 4-bromoquinoline-2-carboxylic acid (A3) (0.5 g, 2.0 mmol) in 10 mL CH2Cl2 was added (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrogen chloride (0.37 g, 2.4 mmol), BOP reagent (1.1 g, 2.6 mmol), and triethylamine (0.83 mL, 6.0 mmol). The reaction was stirred at room temperature for 4.5 h, diluted with CH2Cl2, washed twice with water, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 30-100% ethyl acetate in hexanes to afford 4-bromo-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide (O1) that gave a mass ion (ES+) of 353.2 (81Br) for M+H+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=O)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCCCc1nc(=O)c2cc(C=CC(=O)OCC)ccc2[nH]1
Yield: 46.4 %

Procedure:
A mixture of 3.202 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde and 5.093 g of (carbethoxymethylene)triphenylphosphorane in 50 ml of acetonitrile is heated at reflux for 18 hours. The reaction mixture is cooled and the resulting solid washed with ether and dried to give 1.94 g of the desired product. CI mass spec 301 (MH+)
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]1[CH:15]=[CH:14][C:9]([S:10][CH2:11][C:12]#[CH:13])=[CH:8][CH:7]=1.Br[CH2:17][C:18]#[C:19][CH2:20][C:21]#[CH:22].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[CH3:5][C:6]1[CH:15]=[CH:14][C:9]([S:10][CH2:11][C:12]#[C:13][CH2:17][C:18]#[C:19][CH2:20][C:21]#[CH:22])=[CH:8][CH:7]=1
Reactant: C#CCC#CCBr
Reactant: C#CCSc1ccc(C)cc1
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCC#CCC#CCSc1ccc(C)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
27.15 ml (13.75 g, 0.103 mol) of a 3.8N solution of ethylmagnesium bromide in ether was added dropwise under argon to a cold solution of 15.3g (0.085 mol) of 3-(p-methylthiophenoxy)-1-propyne in 80 ml of anhydrous tetrahydrofuran, at such a rate to maintain the temperature at -10°C. The resulting mixture was stirred for 1 hour and then treated with 677.2mg of cuprous cyanide. After stirring 20 minutes more, a solution of 10.8 g(0.0687 mol) of 1-bromo-2,5-hexadiyne in 25 ml of anhydrous tetrahydrofuranwas added dropwise, maintaining the temperature between 0°-5°C. The reaction mixture was stirred at room temperature for 3 additional hours, and then poured into 150 ml of 1N sulfuric acid and ice. After extraction with ether (3×150 ml) the combined organic extracts were concentrated in vacuo to a small volume, and washed several times with EDTA and then with water, dried over sodium sulfate and evaporated. The crude material was purified by column chromatography on 200 g of silica gel, using hexane:ethyl acetate (95:5) as eluant, and the product crystallized from methylene-chloride-hexane, to yield 9-(p-methylthiophenoxy)-1,4,7-nonatriyne, as an oil. The product was stored in dry ice.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:30])=[N:25][CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:21][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)cc2)n1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(OC3CCCCC3)cc2)=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 5.29 g) in THF (dry) (100 mL) was added 2-chloroethanesulfonyl chloride (5.57 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(cyclohexyloxy)phenyl)-5-methylpyrazin-2-amine (7.5 g) in THF (dry) (75 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 2 days. The mixture was quenched with water/THF at 0° C. carefully and water was added to form precipitates which were washed with EtOAc and water and dried in vacuo to give crude title compound (4.7 g). The part of this material (ca. 4.3 g) was crystallized from DMSO (200 mL)-EtOH (40 mL)/water (400 mL) to give 9-[4-(cyclohexyloxy)phenyl]-7-methyl-3,4-dihydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide as light-yellow crystals (3.6 g), which was recrystallized from DMSO (100 mL)-EtOH (15 mL)/water (100 mL) at 80° C. to room temperature to give the title compound (3.09 g) as light-yellow crystals.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N+:6]1([O-])[CH:11]=[CH:10][CH:9]=[C:8]2[CH2:12][CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[C:7]=12.O>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:3][C:11]1[N:6]=[C:7]2[CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:12][C:8]2=[CH:9][CH:10]=1
Reactant: COC(=O)C1CCc2ccc[n+]([O-])c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 62.2 %

Procedure:
To a cooled (0° C.) solution of 0.21 mL (2.28 mmol) of phosphorous oxychloride in 0.2 mL of anhydrous DMF was added a solution of 1.1 g (5.69 mmol) of methyl 6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate 1-oxide from Step B above in 15 mL chloroform dropwise over 10 min. The resulting solution was allowed to warm to ambient temperature and then refluxed for 4 h. The mixture was cooled and poured into 30 mL of cold water. The aqueous solution was extracted with diethyl ether (3×30 mL) followed by a single extraction with 30 mL of dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting brown residue was purified by silica gel chromatography eluting with 50% ethyl acetate in hexane to afford the title compound as a light brown solid (0.30 g, 25%). LC-MS: m/z (E/S) 212.0 (MH)+.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:15][CH2:16][CH2:17]CCC>>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[CH2:17][CH:16]=[CH2:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CCCCCC
Product: C=CC[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
In an argon atmosphere, 8.39 g (36.0 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 17 mL of hexane and after adding a (prop-2-en-1-yl)magnesium bromide diethyl ether solution (0.99 mol/L, 38.0 mL, 37.6 mmol), the resulting solution was stirred at room temperature for 18 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 88° C./4.4×102 Pa) to obtain 1,3-di-tert-butyl-2-(prop-2-en-1-yl)-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)CH2CHCH2) as a yellow liquid (yielded amount: 7.33 g, yield: 85%).
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.CCCCCC.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc2c(oc3ccccc32)c1O
Solvent: CCCCCC
Product: N#Cc1cnc2c(oc3ccccc32)c1Cl
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2.10 g (11.0 mmol) of 4-hydroxybenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile in 15 mL of phosphorous oxychloride is heated at reflux temperature for 1.5 hours, then cooled to room temperature. Hexane is added and the solid is collected by filtration, dissolved in ethyl acetate and washed with cold 1 N NaOH. The organic layer is dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo to give 1.55 g (65%) of a red solid, mp 229-231° C.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH3:27])[N:14]([CH2:15][CH2:16][O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:28].CO>>[CH3:27][C:13]1[N:14]([CH2:15][CH2:16][O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:28])[C:11]=2[N:12]=1
Reactant: Cc1nc2c(Cl)nc3ccccc3c2n1CCOC/C=C/c1ccccc1
Reactant: N
Solvent: CO
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOC/C=C/c1ccccc1
Temperature: 150 °C

Procedure:
4-Chloro-2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinoline (2.12 g, 5.61 mmol), was combined with an ammonia/methanol solution (7%, 70 mL) in a bomb and heated to 150° C. for 16.5 hours and cooled to ambient temperature. Analysis indicated that the reaction was incomplete. The solution was concentrated under reduced pressure to 10 mL, diluted with ammonia/methanol (7%, 50 mL) and reacted in a bomb at 150° C. for 8.5 hours to complete the reaction. The solution was partitioned between dichloromethane and saturated aqueous sodium bicarbonate and the organic layer removed. The aqueous layer was saturated with sodium chloride and extracted with dichloromethane (3×). The organic fractions were combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting brown solid was recrystalized from methanol to provide 0.963 g of 2-methyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 111.8-112.5° C.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: BrP(Br)Br
Reactant: C=CCCCCCCCCCO
Solvent: Cc1ccccc1
Product: C=CCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A five liter reaction flask was fitted with a mechanical stirring apparatus, a condenser, an addition funnel, and a thermocouple. The reaction flask was flame dried, and then cooled under a nitrogen atmosphere to room temperature. Under a static nitrogen blanket the reaction flask was charged with 10-undecen-1-ol (468 g, 3 mol) and toluene (1 L) while stirring. The contents were cooled to −10° C. and phosphorus tribromide (270 g, 1 mol) was added dropwise. The temperature was maintained at −10° C. with the aid of a Jack-o-matic, and the reaction mixture was aged for one hour. The reaction mixture was subsequently quenched and washed with brine (1 L). The organic layer was removed, and the product was distilled to provide 11-bromo-undec-1-ene (boiling point 95° C. at a pressure of 10 mm Hg).