Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([S:24][CH3:25])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:10](=[O:12])[CH:11]=1.O1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH-].[Na+].O>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([S:24][CH3:25])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:10](=[O:12])[CH:11]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(SC)nc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(OCc2ccc(F)cc2F)cc(=O)n1-c1cc(C(=O)O)ccc1C
Yield: 100.9 %

Procedure:
A mixture of the ester (0.4 g, 0.0009 mol) obtained from step 3, in 2N NaOH (0.9 mL) and dioxane (0.5 mL) was stirred at room temperature for 1.5 h. The resulting clear solution was diluted with water (5.0 mL), acidified with 5% citric acid and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (2×15 mL), dried (Na2SO4), and concentrated to afford the title compound (0.38 g) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.06 (d, 1H, J=8.0 Hz), 7.81 (s, 1H ), 7.51 (m, 2H), 6.99 (m 2H), 5.64 (s, 1H), 5.48 (s, 2H), 2.50 (s, 3H), and 2.15 (s, 3H); ES-HRMS m/z 419.0892 (M+H calcd for C20H17N2O4SF2 requires 419.0872).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)=[O:3]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCc2ccccc2C1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A solution of methyl chloroformate (15.45 mL, 200 mmol) in CH2Cl2 (50 mL) was added to a solution of 1,2,3,4-tetrahydroisoquinoline (13.3 g, 100 mmol) and triethylamine (57 mL, 400 mmol) in CH2Cl2 (200 mL) at 0° C. The reaction mixture was stirred for 3 hours then was quenched with water. The organic layer was separated and washed with water (2×50 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and the resultant filtrate was concentrated in vacuo to provide the title compound (19.1 g). The crude material thus obtained was used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[C:17]2([CH2:22][CH2:21][CH2:20][CH:19]=[C:18]2[C:23](=[O:25])[CH3:24])[CH2:16][CH2:15][CH2:14]1.[CH:26](=[O:28])[CH3:27].[NH4+].[Cl-]>O1CCCC1>[OH:28][CH:26]([CH3:27])[CH2:24][C:23]([C:18]1[C:17]2([CH2:22][CH2:21][CH2:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:25]
Reactant: CC=O
Reactant: CC(=O)C1=CCCCC12CCCC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)CC(=O)C1=CCCCC12CCCC2
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 125.7 %

Procedure:
At −70° C., a solution of diisopropylamine (40.9 g, 0.4 mol) in tetrahydrofuran (200 ml) was treated within 10 min. with n-butyl lithium (271 ml, 1.6M in hexane, 0.437 mol). The resulting solution was stirred at −40° C. for 20 min., cooled to −78° C., and treated within 20 min. with a solution of 1-(spiro[4.5]dec-6-en-6-yl)ethanone (62 g, 0.35 mol). The resulting solution was stirred 20 min. at −70° C. and treated with a solution of acetaldehyde (76.6 g, 1.75 mol) in tetrahydrofuran (100 ml). After 90 min. stirring, the reaction mixture was poured into a cold saturated aqueous solution of NH4Cl (400 ml) and extracted twice with MTBE (400 and 200 ml). The combined organic phases were washed with a water (200 ml), and twice with a saturated solution of NaCl, dried (MgSO4), and concentrated to give the desired intermediate 3-hydroxy-1-(spiro[4.5]dec-6-en-6-yl)butan-1-one (97.8 g) which was dissolved in acetic anhydride (70 ml, 0.73 mol). The resulting solution was treated with sodium acetate (31.4 g, 0.383 mol), heated at 80° C. for 8 h, treated with sodium acetate (10 g, 0.122 mol), heated at 80° C. for 15 h, treated with sodium acetate (10 g, 0.122 mol), heated at 80° C. for 2 h. The reaction mixture was cooled to 0° C., poured into ice/water and extracted three times with MTBE (200 ml). The combined organic phases were washed with 2N aqueous NaOH (300 ml), with a saturated aqueous NaCl solution (250 ml), dried (30 g MgSO4) and concentrated. Short-path Vigreux distillation (0.08 mbar, bath temperature 140-180° C., head temperature: 80-146° C.) of the crude product (89.6 g) followed by distillation (0.08 mbar, bath temperature 150-180° C., head temperature: 98° C.) using a microdistillation column (20×1.5 cm, filled with 3×3 mm rolled wire netting) gave (E)-1-(spiro[4.5]dec-6-en-6-yl)but-2-en-1-one (55.6 g, 58%).
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[N:12][C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][CH2:8][CH3:9].CCCCCC.C[CH2:30][O:31]C(C)=O>CO.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:6]([C:10]1[C:15]([CH2:30][OH:31])=[C:14]([Cl:16])[N:13]=[N:12][C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCOC(C)=O
Reactant: CCCCc1cc(Cl)nnc1-c1ccccc1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: CCCCc1c(-c2ccccc2)nnc(Cl)c1CO
Temperature: 75 °C

Procedure:
Concentrated H2SO4 (0.17 ml, 3.2 mmol), (NH4)2S2O8 (0.575 g, 2.52 mmol) and AgNO3 (4 mg) are added to a solution of 4-butyl-6-chloro-3-phenyl-pyridazine (0.526 g, 2.1 mmol) in MeOH (12 mL) and water (6 mL). The mixture is heated at 75° C. for 3 h and the solvent is then evaporated in vacuo. The residue is partitioned between saturated aqueous NaHCO3 solution (30 mL) and EtOAc (30 mL) and the organic layer is washed with water (25 mL), brine (25 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Flash column chromatography (silica gel, 2:1 hexane, EtOAc) provides the product as a light yellow solid. LC-MS (M+1) 277. 1H NMR (δ, CDCl3) 7.42-7.50 (m, 5H), 4.87 (s, 2H), 2.75 (t, J=8.1 Hz, 2H), 2.40 (s, 1H), 1.34-1.43 (m, 2H), 1.17-1.25 (m, 2H), 0.74 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[CH:12][C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C1N=C[N:48]([C:51](N2C=NC=C2)=O)[CH:47]=1.C1CCN2C(=NCCC2)CC1.CN[N:71](NC)[SH:72](=[O:74])=[O:73].Cl>C1COCC1.O1CCOCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:71][S:72]([N:48]([CH3:51])[CH3:47])(=[O:74])=[O:73])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[CH:12][C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: CNN(NC)[SH](=O)=O
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)N(C)C)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Temperature: 65 °C
Yield: 9.2 %

Procedure:
A mixture of 17-[2-(4-isopropyl-thiazol-2-yl)-7-methoxy-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (35, 39.8 mg, 0.063 mmol) and CDI (22 mg, 0.136 mmol) in dry THF (4 mL) was heated at 65° C. in a reflux setup. After 1.75 h the reaction mixture was cooled to room temperature. The formation of the stable intermediate 36 was observed. Then, a solution of DBU (30 μL, 0.20 mmol) and N,N-dimethylaminosulfonamide (23.4 mg, 0.19 mmol) in THF (1 mL), was added. The reaction was heated overnight at 55° C., then acidified with a 4 M solution of HCl (200 μL) in dioxane and evaporated. Purification by flash chromatography (YMC silica, gradient MeOH/AcOEt, 1:100 to 5:95) gave 4.3 mg of the title product 37 as light yellow solids: LCMS: tR=3.64 min, >99% (Method Flow: 0.8 mL/min. UV 220 nm, ACE C8 3×50 mm; Mobile phase A: 10 mM NH4Ac in 90% water, B: 10 mM NH4Ac in 90% MeCN; Gradient: 5 to 99% B in 3 min, then 99% B for 2 min), m/z=739 (M+H)+. 1H NMR (500 MHz, CDCl3) major rotamer 1.2-1.4 (m, 3H), 1.39 (d, 6H, J=6.0 Hz), 1.46 (dd, 1H, J=9.7, 6.2 Hz), 1.66-1.80 (m, 2H), 1.87 (m, 1H), 1.99 (m, 1H), 2.22-2.32 (m, 1H), 2.32-2.46 (m, 2H), 2.50-2.62 (m, 2H), 2.80-2.84 (m, 1H), 2.98 (s, 3H), 3.04 (s, 3H), 3.20 (m, 1H), 3.40-3.44 (m, 2H), 3.77 (s, 3H), 3.97 (s, 3H), 4.6 (m, 1H), 5.05 (m, 1H), 5.37 (m, 1H), 5.68 (m, 1H), 6.39 (s, 1H), 7.05 (d, 1H, J=1.0 Hz), 7.13 (dd, 1H, J=9.0, 2.5 Hz), 7.38 (d, 1H, J=2.5 Hz), 7.51 (s, 1H), 8.04 (d, 1H, J=9.0 Hz), 10.62 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:15])[O-])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH3:32])[N:24]=[CH:23][N:22]=[C:21]2[S:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[C:34]([S:33][C:21]3[C:20]4[C:25](=[CH:26][C:27]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:18]([O:17][CH3:16])[CH:19]=4)[N:24]=[CH:23][N:22]=3)[CH:35]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: O=C([O-])Nc1ccc(C(F)(F)F)c(F)c1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4ccc(C(F)(F)F)c(F)c4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react 3-fluoro-4-(trifluoromethyl)phenylcarbamate as described in Example 150 (138 mg, 0.46 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (110 mg, 0.31 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction was concentrated to dryness and triturated with dichloromethane to give 122 mg. 1H (DMSO-d6) 9.43 (s, 1H), 9.15 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.70 (m, 2H), 7.60 (m, 1H), 7.50 (m, 1H), 7.40 (m, 4H), 4.34 (m, 2H), 4.00 (s, 3H), 3.78 (m, 2H), 3.38 (m, 3H). LCMS (ESI) m/z 563 (M+H)
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:35]=[CH:34][C:18]2/[C:19](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([C:24]=1[F:29])[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[N:5]=[C:4]3[CH2:1][CH2:2][CH3:3])[CH:35]=[CH:34][C:18]=1/[C:19]/2=[C:30](/[CH3:33])\[C:31]#[N:32]
Reactant: CCCc1nc2ccccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2c1ccc(F)c2F
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)COc1c(ccc(F)c1F)/C2=C(\C)C#N
Yield: 90 %

Procedure:
Using 2-propyl-1H-benzo[d]imidazole (Synthetic Communication, 2002, vol. 32, p 3703; 17 mg, 0.10 mmol) and (E)-2-[8-(bromomethyl)-3,4-difluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (40 mg, 0.12 mmol) obtained in Reference Example 4, and in the same manner as in Reference Example 1A, the title compound (41 mg, 87%) was obtained.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH2:22]([NH2:25])[CH:23]=[CH2:24].C(N(CC)CC)C>C(O)C>[CH2:22]([NH:25][S:18]([C:4]1[CH:5]=[C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])[CH:7]=[CH:8][C:3]=1[Cl:2])(=[O:20])=[O:19])[CH:23]=[CH2:24]
Reactant: C=CCN
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCNS(=O)(=O)c1cc(C2(O)CSC(=NC)N2C)ccc1Cl

Procedure:
8.7 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of allyl amine and 4 g of triethyl amine in 50 ml of ethanol and worked up. The water was decanted and the amorphous end product was crystallized under diethyl ether. Colorless solid body, melting point: 146° C (decomposition).
Reaction SMILES: [CH3:1][C:2]([NH:12][C:13](=O)[CH:14]=[CH2:15])([CH3:11])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:17]([CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)#[N:18]>>[NH2:18][CH2:17][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:15][CH2:14][CH2:13][NH:12][C:2]([CH3:11])([CH3:1])[CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:24]=1
Reactant: C=CC(=O)NC(C)(C)COc1ccccc1
Reactant: N#CCc1c[nH]cn1
Product: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1

Procedure:
The title compound was prepared in a similar manner to the Example immediately above from N-(1,1-dimethyl-2phenoxyethyl)acrylamide and 4-cyanomethyl-imidazole.
Reaction SMILES: C(NC(C)C)(C)C.[Li].Cl[Si](C)(C)C.[CH3:14][C:15]1([CH3:22])[C:20](=[O:21])[CH2:19][CH2:18][O:17][CH2:16]1.C(N(CC)CC)C.[Br:30]N1C(=O)CCC1=O>C1COCC1>[Br:30][CH:19]1[CH2:18][O:17][CH2:16][C:15]([CH3:22])([CH3:14])[C:20]1=[O:21]
Reactant: CC1(C)COCCC1=O
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)Cl
Agent: [Li]
Solvent: CCN(CC)CC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(C)COCC(Br)C1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 18.6 %

Procedure:
A solution of lithium diisopropylamine (2.0 M in heptanes/THF/ethylbenzene) (2.5 ml, 5.1 mmol) diluted with THF (10 mL) under argon was cooled to −78° C. Chlorotrimethylsilane (2.5 mL, 19.5 mmol) was added followed by 3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1, 500 mg, 3.9 mmol) in THF (5 mL) and triethylamine (8.0 mL, 57 mmol). The resulting mixture was stirred at −78° C. for 5 minutes and then quenched with saturated NaHCO3 (20 mL). The mixture was extracted with ether (30 mL) and the organics was washed with 1M citric acid (50 mL), dried (K2CO3), filtered and concentrated in vacuo. The residue was dissolved in THF (5 mL) and cooled to 0° C. N-Bromosuccinimide (694 mg, 3.9 mmol) was added and the resulting mixture was stirred at room temperature for 2 hrs and then quenched with saturated NaHCO3 (10 mL). The mixture was extracted with ether (2×20 mL) and the organics was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (8% ethyl acetate in hexane) to yield the title compound as an oil (150 mg, 18%).
Reaction SMILES: [Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[N:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.N1CCCCC1.CCOCC>CO>[Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[CH:31][C:30]1[CH:29]=[CH:28][C:27]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:34][CH:33]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC[n+]1ccccc1C
Reactant: O=Cc1ccc(N2CCCCC2)cc1
Agent: [Br-]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC[n+]1ccccc1C=Cc1ccc(N2CCCCC2)cc1
Yield: 24.7 %

Procedure:
1-Dodecyl-2-methylpyridinium bromide (2.3 g, 0.0067 mole) and 4-piperidinobenzaldehyde (1.27 g, 0.0067 mole) were refluxed in methanol (20 ml) in the presence of piperdine (0.1 ml) under nitrogen for three hours. The solution was cooled and addition of ether gave a crystalline solid which was collected giving 1-dodecyl-2-[(4-piperidino)styryl]pyridinium bromide (0.85 g), melting point 203°-205° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)C(OCC)=O)C.O.Cl.[OH-].[Na+]>[OH-].[Na+].C1COCC1>[CH3:18][O:17][C:14]1[N:13]=[CH:12][C:11]([CH2:5][C:4]([OH:19])=[O:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(6-Methoxy-pyridin-3-yl)-malonic acid diethyl ester (5.6 g, 21.0 mmoL) prepared in Example 3 was dissolved in 2N NaOH/THF:H2O (1:1) (20 mL). The resulting mixture was heated to reflux for 3 hours. The reaction mixture was then adjusted to pH=1 by concentrated HCl and stirred at room temperature for another 1 hour. The solution was then adjusted to pH=13 by 1N NaOH and extracted with ether. The aqueous phase was acidified to pH=5 by 1N HCl and extracted 3× by ethyl acetate. The combined organic phase was then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound a white solid (2.45, 70%).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:13]([C:19](=O)[CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=O)=[CH:7][CH:6]=1.O>C(O)C>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[C:19]([CH3:20])=[N:2][NH:3][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: COC(=O)Cc1c(C)n[nH]c1-c1ccc(Cl)cc1

Procedure:
2.236 g (45 mmol) of hydrazine hydrate were added to a solution of 10 g (37 mmol) of methyl 3-[(4-chlorophenyl)carbonyl]-4-oxopentanoate in ethanol (100 ml). The mixture was heated under reflux for 6 hours and then added to water and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtered and concentrated. This gave 6.9 g of product (63% of theory); NMR (CDCl3, 400 MHz): 2.28 (s, 3H); 3.5 (s, 2H); 3.7 (s, 3H); 7.39 (d, 2H); 7.5 (d, 2H).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]I.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[I-:1].[I-:1].[CH2:2]([N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ICCCCCI
Reactant: c1ccncc1
Product: [I-]
Product: c1cc[n+](CCCCC[n+]2ccccc2)cc1
Temperature: 65 °C
Yield: 90 %

Procedure:
1,5-Diiodopentane (mmol) was added to a solution (30 mL) of dry pyridine, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated in a 90% yield. 1H NMR (300 MHz, DMSO-D6) δ 9.14 (2H, d, C2&C6-H), 8.62 (1H, t, C4-H), 8.19 (2H, t, C3&C5-H), 4.62 (2H, t, C′1-CH2), 1.92 (2H, m, C′2-CH2), 1.25 (1H, m, C′3-CH2).
Reaction SMILES: ClCCl.[C:4]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:7])([CH3:6])[CH3:5].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:15]([NH:22][CH:11]1[CH2:12][CH2:13][N:8]([C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)N1CCC(NCc2ccccc2)CC1

Procedure:
A dichloromethane solution (3 mL) containing 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) (120 mg, 0.77 mmol), benzyl amine (0.17 mL, 1.56 mmol), acetic acid (0.05 mL) and sodium triacetoxy borohydride (246 mg, 1.16 mmol) was stirred for several days. The solution was concentrated and the residue partitioned between aqueous potassium carbonate and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using CHCl3/MeOH/NH4OH (87/12/1) as eluent to give N-benzyl-1-tert-butylpiperidin-4-amine. Mass spectrum (ESI) 247 (M+1). 1H NMR (500 MHz, CD3OD): δ 1.09(s, 9H); 1.38-1.48(m, 2H); 1.91-1.97(m, 2H); 2.11-2.18(m, 2H); 2.40-2.48(m, 1H); 3.02-3.08(m, 2H); 3.76(s, 2H); 4.87(s, 1H); 7.21-7.26(m, 1H); 7.29-7.36(m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1.N1C=CC=CC=1.Cl.[NH2:34][OH:35]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH:25]=[N:34][OH:35])=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: NO
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(COCc2ccccn2)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=Cc1ccc2c(c1)ncn2-c1cccc(COCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of compound 12a (220 mg, 0.64 mmol) and pyridine (0.08 mL, 1.5 equiv) in ethanol (2 mL) was added hydroxylamine hydrochloride (500 mg) and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (100 mL), washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate and pet-ether as the eluent to afford compound 14a (180 mg, 78%) as a solid. Mp 154-154.8° C. In analogy herewith, the following compounds were prepared: 1-[3-(1-Methyl-1H-imidazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14b) from 12b. Mp 209.8-211.7° C. and 1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14c) from 12c. Mp 145.8-147.7° C. O-Methyl 1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14h) from 12c and O-methyl hydroxylamine. LC-ESI-HRMS of [M+H]+ shows 377.1724 Da. Calc. 377.172525 Da, dev. −0.3 ppm 1-[3-(2-Methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14e) from 12e. LC-ESI-HRMS of [M+H]+ shows 362.1603 Da. Calc. 362.161625 Da, dev. −3.7 ppm O-Methyl 1-[3-(2-methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14i) from 12e and O-methyl hydroxyl amine. LC-ESI-HRMS of [M+H]+ shows 376.1755 Da. Calc. 376.177325 Da, dev. −4:9 ppm 1-[3-(1,3-Thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14j) from 12g. LC-ESI-HRMS of [M+H]+ shows 365.1074 Da. Calc. 365.107225 Da, dev. 0.5 ppm O-Methyl 1-[3-(1,3-thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14g) from 12g and O-methyl hydroxylamine. LC-ESI-HRMS of [M+H]+ shows 379.1238 Da. Calc. 379.122825 Da, dev. 2.6 ppm and 1-[3-(Pyridin-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14d) 1-[3-(Pyrimidin-4-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14f) are prepared likewise.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[NH2:7][C:8]1[N:13]=[C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([C:24]([O:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[CH2:21]3)=[CH:16][CH:15]=2)[CH:11]=[C:10]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:9]=1>>[NH2:7][C:8]1[N:13]=[C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([C:24]([O:26][CH:27]4[CH2:32][CH2:31][N:30]([C:2]([O:4][CH3:5])=[O:3])[CH2:29][CH2:28]4)=[O:25])[CH2:21]3)=[CH:16][CH:15]=2)[CH:11]=[C:10]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:9]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)N1CCC(OC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from methyl chloroformate and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=510.2.