Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([C:13]([O-])=[O:14])[NH:7][C:6]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:5][CH:4]=[CH:3]1.[BH4-].[Na+].Cl>CO.C(Cl)Cl>[OH:14][CH2:13][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=CC=CC(C)(C(=O)[O-])N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 108.8 %

Procedure:
To a solution of 2-ethyl 6-methylpyridine-2,6-dicarboxylate (3.0 g, 14.3 mmol) in MeOH (20 mL) and CH2Cl2 (10 mL) was added slowly NaBH4 (1.95 g, 51.6 mmol) in several portions at −40° C. After 10 min, the reaction mixture was stirred at rt for 1 h. To the reaction mixture was added 5 mL of 1 N HCl and the mixture was stirred for 20 min. The solvents were removed in vacuo and the residue was diluted with CHCl3 and saturated aqueous NaHCO3 solution (20 mL). The organic layer was separated, dried over MgSO4, filtered and the filtrate solution was concentrated in vacuo to give the desired compound (2.6 g, 54%) as a white solid. 1H NMR (DMSO-d6) δ 8.02 (t, J=8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 4.62 (d, J=8.0 Hz, 2H), 3.88 (s, 3H). MS (ESI): 168.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2([C:42](O)=[O:43])[CH2:41][CH2:40]2)=[O:38])=[CH:32][CH:31]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:42]([C:39]4([C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=5)=[O:38])[CH2:41][CH2:40]4)=[O:43])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 29.6 %

Procedure:
4-(Dimethylaminomethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (88 mg) was dissolved in N,N-dimethylformamide (2.5 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (101 mg), triethylamine (0.0633 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (201 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of heptane to the resultant residue. The solid was collected by filtration, and dried under aeration to provide the titled compound as white powder (39.8 mg, 30%).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].Cl.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:29]3[CH2:30][CH2:31][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH3:19])[CH2:27][CH2:28]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc2ccc(OCC3CO3)cc2o1
Reactant: Cc1ccccc1N1CCNCC1
Agent: Cl
Product: Cc1ccccc1N1CCN(CC(O)COc2ccc3cc(C(N)=O)oc3c2)CC1

Procedure:
The procedures of Example 10 were repeated except that 1.2 g (0.005 mole) of 2-carbamoyl-6-(2,3-epoxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methylphenyl)piperazine hydrochloride were employed. The obtained residue was crystallized from ethyl acetate and ether.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1.[C:11]([Zn]C#N)#[N:12].CN(C=O)C>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.O>[CH3:10][O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[N:12])=[N:3][CH:4]=1
Reactant: COCc1ccc(Cl)nc1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(C#N)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
A mixture of 2-chloro-5-(methoxymethyl)pyridine (0.831 g, 5.27 mmol), tetrakis (1.219 g, 1.055 mmol), dicyanozinc (0.929 g, 7.91 mmol) and DMF (17.58 ml) was stirred at 100° C. for 3 hrs. The reaction was treated with water and extracted with EtOAc. The organic portion was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography, eluting with 10-40% EtOAc/Heptanes to give the title compound (550 mg, 3.71 mmol, 70.4%). MS m/z=149.1 (M+H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:23]COC(C)=O.O>CO>[C:1]1([N:7]2[C:11]([C:12]([O:14][CH3:23])=[O:13])=[CH:10][C:9]([C:15]([F:17])([F:18])[F:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 0 °C

Procedure:
Intermediate 7 (1.55 g, 6.0 mmol) was dissolved in MeOH (15 ml), cooled to 0° C. and thionyl chloride (1.3 ml, 18.2 mmol) was added. Reaction mixture was heated to 60° C. for overnight. Work up (AcOEt:H2O) followed by evaporation on high vacuum obtained the title compound as an yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.51-7.47 (m, 3H), 7.46-7.41 (m, 2H), 7.50 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1/[CH:29]=[CH:30]/[C:31](Cl)=[O:32]>C(Cl)Cl>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=[CH:30][C:31]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=1)=[O:32]
Reactant: O=C(Cl)/C=C/c1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Anhydrous pyridine (0.331 g, 4.2 mmol, 1.2 eq) and ethyl 4-aminobenzoate (0.577 g, 3.50 mmol) were added to a solution of (E)-3-(2-naphthyl)propenoyl chloride (prepared from its corresponding acid) (0.757 g, 3.50 mmo) in anhydrous DCM (15 ml) under Ar. After stirring overnight at room temperature, the white precipitate was filtered, washed with DCM (10 ml) and dried under vacuum to give the amide 42 (0.960 g, 2.78 mmol, 80%) as a white solid, mp 173-175° C. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (3H, t, J 7.2 Hz), 4.28 (2H, t, J 7.2 Hz), 6.97 (1H, d, J 15.4 Hz), 7.54-7.57 (2H, m), 7.7 (1H, d, J 15.4 Hz), 7.77 (1H, dd, J 1.6, 9.2 Hz), 7.84 (2H, d, J 8.8 Hz), 7.93-7.97 (5H, m), 8.15 (1H, s), 10.58 (1H, bs). 13C NMR (100 MHz, DMSO-d6) δ 14.88, 61.09, 119.30, 122.91, 124.18, 124.99, 127.47, 127.83, 128.38, 129.09, 129.36, 130.05, 130.98, 132.82, 133.68, 134.26, 141.64, 144.33, 164.69, 166.01. νmax (solid)/(cm−1) 3357, 1702, 1660, 1619, 1607, 1591, 1521, 1403, 1282. MS (API-ES): m/z 346 [M+H]+ (100%), HRMS (API-ES) m/z found 346.1443 [M+H]+.
Reaction SMILES: [N:1]1[C:2]([CH2:10][N:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[I:18]N1C(=O)CCC1=O.O>C(#N)C>[I:18][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[CH2:10][N:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CN(C)Cc1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: COC(=O)CN(C)Cc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
0.107 g (0.459 mmol) of methyl 2-((imidazo[1,2-a]pyridin-2-ylmethyl)(methyl)amino)acetate were dissolved in 4 ml of acetonitrile with magnetic stirring, to this solution were added 0.112 g (0.482 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 16 h. The reaction mixture was treated with 10 ml of water and then extracted with 3×10 ml of ethyl acetate. The combined organic phases were washed with 20 ml of a saturated NaCl aqueous solution, and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: ethyl acetate 100%). 0.093 g (yield=46%) of methyl 2-(((3-iodoimidazo[1,2-a]pyridin-2-yl)methyl)(methyl)amino)acetate were obtained as a yellow oil. LC-MS: m/z=360 (MH+); UV purity at 254 nm=82%. 1H NMR (300 MHz, DMSO) δ 8.30 (d, J=6.8 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.41-7.23 (m, 1H), 7.03 (t, J=6.7 Hz, 1H), 3.79 (s, 2H), 3.62 (s, 3H), 3.37 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28]O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:36])CC)C>C(Cl)Cl>[F:36][CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][N:9]1[CH:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:11][CH2:12][CH2:13][CH:8]1[C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1CO
Solvent: ClCCl
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1CF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
To a cold (0° C.) solution of [2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-phenyl]-methanol (0.107 g,0.28 mmol) in CH2Cl2 (3 mL) was added (diethylamino)sulfur trifluoride (80 μL, 0.61 mmol). After 15 minutes, the cooling bath was removed and the reaction mixture was warmed to room temperature. After an additional 3 hours, the reaction mixture was treated with saturated aqueous NaHCO3 (5 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.032 g (29%) of COMPOUND 62 as a white solid. 1H NMR (CDCl3) δ 1.60-1.74 (m, 3H), 2.02-2.10 (m, 1H), 2.26-2.41 (m, 8H), 3.56 (s, 2H), 4.13 (d, 2H, J=11.1 Hz), 5.06 (d, 2H, JC-F=48 Hz), 6.81-6.88 (m, 5H), 7.14-7.16 (m, 3H), 8.31 (d, 2H, J=3.6 Hz). 13C NMR (CDCl3) δ 19.24, 25.64, 28.65, 50.09, 67.20, 82.93 (d, JC-F=648 Hz), 122.29, 125.94, 127.47, 127.62, 129.79, 132.36, 133.66 (d, JC-F=62 Hz), 138.14, 139.34, 146.63, 159.99; ES-MS m/z 390 (M+H). Anal. Calcd. For C25H28N3F.0.1H2O: C, 76.73; H, 7.26; N, 10.74. Found: C, 76.66; H, 7.23; N, 10.70.
Reaction SMILES: [CH2:1]([C:7]1[CH2:11][CH:10]=[CH:9][CH:8]=1)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[K].[Cl-:13].[Cl-].[Cl-].[Cl-].[Zr+4:17].[OH2:18]>C1COCC1>[Cl-:13].[Cl-:13].[CH2:1]([C:7]1[CH:11]([Zr+2:17][CH:11]2[CH:10]=[CH:9][CH:8]=[C:7]2[CH2:1][CH:2]2[O:18][CH2:5][CH2:4][CH2:3]2)[CH:10]=[CH:9][CH:8]=1)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: [Zr+4]
Reactant: C1=CCC(CC2CCCO2)=C1
Reactant: O
Agent: [Cl-]
Agent: [K]
Solvent: C1CCOC1
Product: C1=CC([Zr+2]C2C=CC=C2CC2CCCO2)C(CC2CCCO2)=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of 7.0 g (46.7 mmol) tetrahydrofurfurylcyclopentadiene prepared according to step (b) above in 50 ml THF was added to 1.82 g (46.5 mmol) clean, dry potassium metal under nitrogen. This was stirred for two hours at room temperature and was then warmed to 40° C. for a further two hours. After cooling, the solution was filtered and the remaining potassium washed, dried and weighed. The yield of potassium tetrahydrofurfuryl-cyclopentadienylide (KCp') was calculated to be 6.26 g (33.3 mmol). The KCp ' solution was added to 3.73 g (16.0 mmol) zirconium tetrachloride in 20 ml THF and stirred for two hours. Approximately 0.5 ml water was added to the reaction vessel and the volatiles removed under reduced pressure. The residue was extracted with diethyl ether and filtered. The volume of ether was reduced under vacuum until precipitation began. Cooling to -50° C. in a low temperature freezer yielded 4.50 g (9.78 mmol, 61.1%) of product as colourless needles shown to be spectroscopically pure by 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:23]2[N:24]=[CH:25]C=CC=2N=N1.C(N(CC)CC)C.CNC>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([N:24]([CH3:25])[CH3:23])=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc(I)ccc1N
Reaction time: 0.08 h
Yield: 98 %

Procedure:
2-Amino-5-iodobenzoic acid (5.0 g, 19 mmol) was dissolved in dichloromethane (100 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.9 g, 21 mmol) and triethyl amine (2.1 g, 21 mmol) were added with magnetic stirring. After 5 min., dimethyl amine (2 N in THF, 19 mL, 38 mmol) was added and the resulting solution was stirred overnight. The reaction solution was washed with aqueous saturated sodium chloride and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford 2-amino-5-iodo-N,N-dimethyl-benzamide (5.4 g, 98% yield) as yellow solids. MS: m/z 291 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][NH2:25]>CCO>[CH3:24][NH:25][C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: CN
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: CNc1cc(C)nc2c(S(=O)(=O)c3ccc(C)cc3)c(SC)nn12

Procedure:
In an analogous manner to that described in Example 3, from 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl) -pyrazolo[1,5-a]pyrimidine and methylamine in EtOH there was obtained methyl-[5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine as colorless crystals, m.p. >230°.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.Cl[C:13]1([CH3:33])[CH2:17][CH2:16][N:15](S(C2C=CC(C)=CC=2)(=O)=O)[C@@H:14]1[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(OCC)C>C1COCC1>[CH3:33][C:13]1[CH:17]=[CH:16][NH:15][C:14]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)[C@H]1N(S(=O)(=O)c2ccc(C)cc2)CCC1(C)Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CCOC(=O)c1[nH]ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
DBU (15.0 mL, 100 mmol) was added dropwise to a solution of ethyl 3-chloro-3-methyl-1-[(4-methylphenyl)sulfonyl]prolinate (15 g, 43 mmol) in THF (100 mL). The mixture was stirred overnight at RT. Diethyl ether (100 mL) and ice cold 5% HCl (100 mL) were added, the layers separated. The organic layer was washed again with washed with ice cold 5% HCl (100 mL) and water (50 mL) followed by saturated sodium bicarbonate (100 mL) and saturated NaCl (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford ethyl 3-methyl-1H-pyrrole-2-carboxylate (5.6 g, 84%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (br. s., 1H) 6.84 (t, 1H) 6.00 (t, 1H) 4.21 (q, 2H) 2.25 (s, 3H) 1.28 (t, 3 H). MS: m/z 153.9 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][O:4]1.[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[O-:29][C:30]#[N:31].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(Cl)Cl>[OH:1][CH2:2][C:3]1([CH2:8][O:9][C:30]([NH:31][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:29])[CH2:7][CH2:6][CH2:5][O:4]1
Reactant: N#C[O-]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: OCC1(CO)CCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CO)CCCO1
Temperature: 100 °C
Reaction time: 23 h

Procedure:
A suspension of 2.64 g (20 mmol) of 2,2-bis(hydroxymethyl)tetrahydrofuran, 7.99 g (24 mmol) of octadecyl bromide, 2.43 g (30 mmol) of potassium cyanate and 0.644 g (2 mmol) of tetrabutyl ammonium bromide in 300 ml of dry acetonitrile was refluxed, with stirring, at 100° C. for 23 hours. The resultant mixture was then diluted with hot methylene chloride, filtered and the filtrate concentrated in vacuo. The crude product was then purified by flash silica gel chromatography employing a mixture of petroleum ether and ethyl acetate in a 4:1 ratio as the eluent to yield the title compound as a solid, m.p. 57°-58° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][NH2:6])[CH2:3][NH2:4].Cl[C:9]([CH3:15])([CH3:14])[CH:10]([N:12]=[O:13])[CH3:11].O.[CH3:17]O>>[NH2:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][NH:6][C:9]([CH3:15])([CH3:14])[C:10](=[N:12][OH:13])[CH2:11][CH3:17]
Reactant: CC(N=O)C(C)(C)Cl
Reactant: CO
Reactant: CC(C)(CN)CN
Solvent: O
Product: CCC(=NO)C(C)(C)NCC(C)(C)CN
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2,2-dimethyl-1,3-propane diamine (69 g, 0.75 mole) in dry methanol (100 mL), 3-chloro-3-methyl-2-nitrosobutane (20.55 g, 0.15 mole, Example 1) was added in portions at 0° C. over a period of 2 hours. The reaction mixture was then stirred at room temperature for 20 hours. The solvent was removed under reduced pressure to give a paste. Water (50 mL) was added, and the solution was cooled in an ice bath. The solution was filtered and the filtrate was adjusted to pH 10-11 by the addition of sodium hydroxide. The solution was cooled again and filtered. The filtrate was concentrated under reduced pressure to a paste and then extracted with ether repeatedly (10×50 mL). The combined ether solution was concentrated to give an oil which was recrystallized twice from petroleum ether to yield the title A compound as a colorless crystalline solid (20.0 g), m.p. 58-60° C. 1H NMR [CDCl3]: δ 0.85 (s, 6H, C-Me2), 1.28 (s, 6H, N—CMe2), 1.9 (s, 3H, N═CMe), 2.2 (s, 2H, NCH2) and 2.6 (s, 2H, N—CH2).
Reaction SMILES: C([Li])CCC.C[C:7]1(C)[CH2:12][CH2:11]C[C:9](C)(C)[NH:8]1.[N:16]1C=CC=CN=1.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>O.O1CCCC1.CCCCCC>[N:8]1[CH:7]=[CH:12][C:11]([Sn:26]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:16][CH:9]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: c1ccnnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
58.0 ml of a hexane solution containing 2.52 mol of n-butyllithium was slowly added dropwise into a solution of 200 ml of tetrahydrofuran containing 25.0 mol of 2,2,6,6-tetramethylpiperidine at −30° C. After stirring at 0° C. for 30 minutes, a mixture of 9.1 ml of pyridazine, 46.0 ml of tri-n-butyltin chloride and 100 ml of tetrahydrofuran was slowly added dropwise thereinto at −78° C. After stirring at −78° C. for 4 hours, water was added to the reaction solution and then extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. Then, the residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (10:1). Then, it was subjected to silica gel chromatography and eluted with hexane/ethyl acetate (10:1) and then with hexane/ethyl acetate (1:1), to give 6.6 g of the target compound.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[N:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=3)[CH:10]=2)[CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:30]([O:18][C:15]1[CH:14]=[N:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6]([CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=[C:2]3[F:1])=[CH:7][CH:8]=2)=[N:17][CH:16]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCOc1cc2ccc(-c3ncc(O)cn3)cc2c(F)n1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(-c2ccc3cc(OCCCCCCCC)nc(F)c3c2)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxyisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1-fluoro-3-octyloxyisoquinoline. 1-Fluoro-7-(5-hydroxypyrimidin-2-yl)-3-alkyloxyisoquinolines can for example be reacted analogously to Example 3 with 2-fluoroalkyl sulfonates, 2,3-difluoroalkyl sulfonates, 3-alkyloxirane-2-methyl sulfonates, (ω-bromoalkyl)cyclopropanes or 1-bromodimethylsilanylalkanes.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C([N-]C(C)C)(C)C.[Li+].[Br:22][C:23]([CH2:25]Br)=[CH2:24]>C1COCC1>[Br:22][C:23](=[CH2:24])[CH2:25][CH:6]1[CH2:5][CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2]1=[O:1]
Reactant: C=C(Br)CBr
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Br)CC1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
In a 250 mL round-bottom flask, tert-butyl 2-oxopyrrolidine-1-carboxylate (4.12 g, 22.2 mmol) was combined with 25 mL of THF and cooled to −78° C. Lithium diisopropylamide (1.5M in THF) (14.8 mL, 22.2 mmol) was added slowly and the mixture was agitated for 30 minutes. 2,3-Dibromopropene (2.72 mL, 22.2 mmol) was added and the mixture was agitated overnight and allowed to warm to ambient temperature. The reaction was then quenched with sodium bicarbonate solution and extracted twice with ether. The extracts were washed with brine and evaporated. The crude product was purified by column chromatography, eluting with 20% ethyl acetate/hexane, to provide the title compound (0.560 g, 8.3% yield).