Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[Cl:18][CH2:19][C:20](Cl)=[O:21]>ClCCl.C(OCC)C>[CH2:1]([N:5]([CH:6]1[CH2:7][C:8]([CH3:16])([CH3:17])[N:9]([O:14][CH3:15])[C:10]([CH3:13])([CH3:12])[CH2:11]1)[C:20](=[O:21])[CH2:19][Cl:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC1CC(C)(C)N(OC)C(C)(C)C1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCN(C(=O)CCl)C1CC(C)(C)N(OC)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A solution of 48.5 g (0.200 mol) of 4-butylamino-1-methoxy-2,2,6,6-tetramethylpiperidine in 150 ml of dichloromethane is added over a one hour interval at -10° C. to a solution of 11.3 g (0.100 mol) of chloroacetyl chloride in 100 ml of dichloromethane. The reaction mixture is then stirred at ambient temperature for 1 hour. The mixture is diluted with diethyl ether (500 ml), and solids are removed by filtration. The filtrate is washed with 1N hydrochloric acid (2×75 ml) and saturated sodium bicarbonate (100 ml), then dried over magnesium sulfate and concentrated to afford 27.8 g (87% yield) of the title compound, a pale yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[N+:32]([O-])([O-:34])=[O:33].[Na+]>C(O)(C(F)(F)F)=O.O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:15]([N+:32]([O-:34])=[O:33])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine (Example 14, 10 mmol, 4.24 g) in TFA (10 mL) was added sodium nitrate (12 mmol, 1.02 g) at 0° C. The mixture was allowed to warm up to room temperature and stirred for 8 hours. The mixture was then diluted with water/EtOAc, neutralized slowly with NaHCO3 powder. The organic layers were combined, dried, and condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% MeOH) to give a pale-yellow solid, 3-butyl-4-(4-cyclohexyloxy-3-nitro-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine (3.09 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][CH2:24][N:25]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:26][CH2:27]2)[CH:17]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2cccc(-c3ccccc3)c2)CC1
Yield: 58.5 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (249 mg, 0.923 mmol), 1-biphenyl-3-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. To the reaction solution was added water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and then recrystallized from a mixed solvent of hexane and ethyl acetate to give the titled compound (176 mg, 58.6%) as solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=2[F:17])[C:5]2[N:6]([C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:26]([CH3:28])[N:8]=2)[CH:7]=1
Reactant: Nc1ncc(Cl)cc1OCc1c(F)cccc1F
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Cl)cn12

Procedure:
40 g of 5-chloro-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 17A; 147.8 mmol; 1 equivalent) were initially charged in 800 ml of ethanol, 30 g of powdered molecular sieve 3 Å and 128 g of ethyl 2-chloroacetoacetate (739 mmol, 5 equivalents) were added and the mixture was heated at reflux overnight. The reaction mixture was concentrated and the residue was taken up in ethyl acetate and filtered. The ethyl acetate phase was washed with water, dried, filtered and concentrated. This gave 44 g (78% of theory) of the title compound.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:36]=[C:35]([C:37]([O:39][CH3:40])=[O:38])[CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C.C(Cl)Cl.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>[N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:31]5[N:36]=[C:35]([C:37]([O:39][CH3:40])=[O:38])[CH:34]=[CH:33][CH:32]=5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(Br)n1
Reactant: CC1(C)OB(c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)n1
Temperature: 80 °C

Procedure:
A vial containing (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (Example 64A, 30 mg, 0.072 mmol), methyl 6-bromo-2-pyridinecarboxylate (16 mg, 0.072 mmol), K2CO3 (30 mg, 0.22 mmol) and bis(triphenylphosphine)palladium(II) chloride (5 mg, 7 μmol) in tert-butanol (0.5 mL) was heated to 80° C. for 1 hour and cooled. The mixture was diluted with CH2Cl2 (5 mL), filtered, and concentrated. The residue was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm) as described in Example 65. The title compound was obtained as the bis trifluoroacetate salt. 1H NMR (300 MHz, CD3OD) δ ppm 1.52-1.65 (m, 1H), 1.74-1.93 (m, 3H), 1.96-2.09 (m, 2H), 2.34-2.48 (m, 1H), 2.63-2.76 (m, 1H), 3.04-3.20 (m, 2H), 3.52-3.77 (m, 3H), 3.81-3.95 (m, 2H), 4.01 (s, 3H), 4.08-4.21 (m, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.98-8.07 (m, 2H), 8.08-8.15 (m, 2H), 8.57 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 423 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][CH:7]([CH:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8].S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:8][CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]2[CH2:4][CH2:5][N:1]=[C:2]2[NH:6]1
Reactant: CC(NC1=NCCN1)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1NC2=NCCN2C1c1ccccc1

Procedure:
A solution of 12 parts of the oily α-[1-(2imidazolin-2-ylamino)ethyl]benzyl alcohol in 40 parts of sulfuric acid solution 80% is stirred for 3 hours at room temperature. The reaction mixture is poured onto crushed ice. The whole is alkalized with sodium hydroxide solution and the product is extracted with toluene. The extract is dried, filtered and evaporated. The residue is washed with acetone and dried, yielding 2,3,5,6-tetrahydro-2-methyl-3-phenyl-1H-imidazo[1,2-a]imidazole; m.p. 179.4°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@H:27]([OH:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40].[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH3:41][S:42]([O:38][C@@H:27]1[C@@H:26]([CH3:39])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:40])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29][C@H:28]1[NH2:30])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@@H]1OS(C)(=O)=O
Reaction time: 0.08 h
Yield: 31 %

Procedure:
To a solution of tert-butyl (1R,2R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in CH2Cl2 was added TEA (4.0 equiv.) and MsCl (2.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo, the residue was dissolved in DMSO, purified by RP HPLC and the product fractions were lyophilized directly. The Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles were removed in vacuo and the residue was dissolved in DMSO and purified by RP-HPLC. The product fractions were lyophilized directly to yield (1R,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate in 31% yield. LC/MS (m/z)=535.2 (MH+), Rt=0.61 min.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:6](O)=[O:7])(=[O:3])[CH3:2].[CH3:17][O:18][C:19](=[O:30])[CH:20]([NH2:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:17][O:18][C:19](=[O:30])[CH:20]([NH:29][C:6](=[O:7])[CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: CC(=O)NC(Cc1ccc(O)cc1)C(=O)O
Reactant: COC(=O)C(N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)C(Cc1ccc(O)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-acetylamino-3-(4-hydroxy-phenyl)-propionic acid 20 (13.4 grams, 60.09 mmol) and 2-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester 1 (11.7 grams, 60.00 mmol) in anhydrous dichloro methane (100 mL) under a nitrogen atmosphere at 0° C. is added dropwise to a solution of 1,3-dicyclohexyl carbodiimide (31 grams, 150.24 mmol) in dichloro methane (75 mL). The mixture is stirred at room temperature for 6 hours. The resulting solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 21, which can be purified in appropriate solvent.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6](=[O:13])[CH:5]([NH:14]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].Cl.[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1>C1COCC1.OC1C=CC([N+]([O-])=O)=CC=1C=O>[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([O-:37])=[O:36])=[CH:33][CH:32]=1.[CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:11])([F:12])[F:10])[C:6](=[O:13])[C@@H:5]([NH3+:14])[CH2:4][C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccccc1[C@@H]1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(F)(F)F)[C@@H]1C
Agent: Cl
Agent: O=Cc1cc([N+](=O)[O-])ccc1O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)[O-])cc1
Product: Cc1ccccc1[C@@H]1C[C@H]([NH3+])C(=O)N(CC(F)(F)F)[C@@H]1C
Temperature: 50 °C
Reaction time: 5 h
Yield: 43.5 %

Procedure:
To a solution of 38 (2.0 g, 5.0 mol) in THF (10 mL) was added 6N HCl (10 mL, 59.9 mmol) dropwise. The reaction was aged at 20-25° C. for 5 h then concentrated to remove THF. The residue was diluted with MTBE and basified with K2CO3. A total of 3 mL of H2O was added to dissolve all solids. The organic layer was separated, washed with brine, and solvent-switched to IPAC. To one-third of the organic layer was added 4-methylbenzoic acid (0.27 g, 2.00 mmol). The solution was heated to 50° C. and 2-hydroxy-5-nitrobenzaldehyde (0.0028 g, 0.017 mmol) was added. The reaction was aged at 20-25° C. for 16 h. The resulting slurry was chilled in an ice bath to 2° C. and filtered. The solids were washed with IPAC and dried to give product 39 (0.38 g, 52%) as crystals. 1H NMR (500 MHz, DMSO-d6): δ 7.82 (d, J=8.0 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 7.18-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 4.67 (dq, J=15.2, 9.7 Hz, 1H), 3.72-3.74 (m, 2H), 3.61-3.63 (m, 1H), 3.55 (dd, J=11.3, 6.7 Hz, 1H), 2.40 (dd, J=25.2, 12.9 Hz, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 2.02 (dd, J=12.6, 6.7 Hz, 1H), 0.91 (d, J=6.4 Hz; 3H); 13C NMR (100 MHz, DMSO-d6): δ 172.7, 168.3, 142.4, 139.1, 136.1, 130.9, 130.5, 129.7, 129.3, 127.4, 127.2, 126.5, 125.6 (q, J=281 Hz), 56.2, 52.1, 45.0 (q, J=32.3 Hz), 38.5, 29.1, 21.5, 18.7, 14.2
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:37][CH:38]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41]O>CN(C)C=O.C(OCC)C>[CH3:37][CH:38]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][N:15]=2)=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCC(C)CCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCC(C)CCCC)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.38 g of 55% sodium hydride and 10 ml of dimethylformamide were weighed out and a solution of 2 g of 2-(4-hydroxyphenyl)-5-n-decylpyrimidine in 3 ml of dimethylformamide was added dropwise thereto under ice cooling. After the completion of the addition, the resulting mixture was stirred at room temperature for one hour. Then p-toluene-sulfonate of optically active 4-methyloctanol was added dropwise thereto and the resulting mixture was stirred at 90° C. for two hours. After cooling, the reaction mixture was poured into ice/water, extractd with diethyl ether and dried followed by removal of the solvent. The residue was purified on a silica gel column to thereby give 1.5 g of optically active 2-(4-(4-methyloctoxy)phenyl)-5-n-decylpyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.O>[Br:1][C:2]1[C:7]([CH2:8][Br:17])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Cl)cc1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Clc1cc(Br)c(CBr)cn1
Temperature: 25 °C

Procedure:
A flask was charged with 4-bromo-2-chloro-5-methylpyridine (513 mg, 2.48 mmol), (PhCO2)2 (32 mg, 0.13 mmol), and NBS (452 mg, 2.54 mmol) then diluted with CCl4 (9 mL). The reaction mixture was heated to reflux for 2 hours and then allowed to cool to room temperature and diluted with CH2Cl2 and H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-20% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C6H5Br2ClN 283.9 (M+H+); Found: 283.9 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[O:13])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:23]=[C:22](C3C=CC=CC=3)[S:21][C:7]=12.[Cr](Cl)([O-])(=O)=O.[NH+]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:41](Cl)Cl>>[O:1]=[C:2]1[C:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:10][C:9]([C:12]([N:14]2[CH2:15][CH2:16][C:17](=[O:20])[CH2:18][CH2:19]2)=[O:13])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:23]=[CH:22][S:21][C:7]=12
Reactant: ClCCl
Reactant: c1cc[nH+]cc1
Reactant: O=C(c1ccc(=O)n2c1-c1sc(-c3ccccc3)cc1CC2)N1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Product: O=C1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2sccc2CC3)CC1

Procedure:
A solution of 100 mg of 1-[(4,5-dihydro-7-oxo-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)carbonyl]-4-piperidinol in 5 ml of methylene chloride was treated with 51 mg of pyridinium chlorochromate. After the reaction was completed, the solvent was evaporated in vacuo and the residue was chromatographed over silica gel. The product was recrystallized from diethyl ether and there was obtained 1-[(4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]-quinolizin-10-yl)carbonyl]-4-piperidinone of m.p. 218°-220°.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:20][CH2:21][CH:22]([CH3:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH:22]([CH3:32])[CH2:21][O:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:31][CH:30]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCOCC(C)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCOCC(C)Oc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 1.7 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 2.8 g of 4-(2-hexyloxy-1-methylethoxy)-benzyl bromide, and the resulting solution was stirred overnight at room temperature. The crude product which had been obtained similarly to the procedures in Preparation Example 3 was isolated through column chromatography [eluting with benzene/ethyl acetate (18/1)] to give 3.4 g of the aimed product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][Cl:14])[C:9]#N)=[CH:4][CH:3]=1.[OH:15]S(O)(=O)=O.[OH2:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][Cl:14])[C:9]([OH:15])=[O:20])=[CH:4][CH:3]=1
Reactant: N#CC(CCCCl)c1ccc(Br)cc1
Reactant: O=S(=O)(O)O
Reactant: O
Product: O=C(O)C(CCCCl)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
The 2-(4-bromophenyl)-5-chloropentane nitrile (4 g, 14.7 mmol) was hydrolyzed by refluxing for 12 h with a 3:5:3 mixture of concentrated H2SO4, glacial acietic acid, and water (33 mL). The reaction mixture was cooled to room temperature, diluted with water, and extracted with CHCl3. The organic layer was washed with brine (3 times), then dried with MgSO4, the solution was evaporated to dryness under reduced pressure, giving an oil (3.8 g, 90%). MS: calc'd 290 (MH+), exp 290 (MH+). 1H NMR (400 MHz, CDCl3), 7.46-7.56 (2H), 7.10-7.20 (2H), 3.84 (1H), 3.52 (3H), 1.60-2.20 (4H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:27])[CH2:12][N:13]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:51][C@H:52]1[CH2:56][CH2:55][C@@H:54]([CH2:57]O)[O:53]1>CN(C)C=O>[CH2:3]([O:10][C:11]([C:12]1([N:13]=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:57][CH:54]2[O:53][CH:52]([CH2:56][CH2:55]2)[CH2:51]1)=[O:27])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC[C@@H]1CC[C@H](CO)O1
Reactant: O=C(CN=C(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1(N=C(c2ccccc2)c2ccccc2)CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.41 grams, 17.1 mmole) in N,N-dimethylformamide (50 mL) at 0° C. is added dropwise a solution of N-diphenylmethylene glycine benzyl ester (7.8 mmole) in N,N-dimethylformamide (50 mL). After stirring for 30 minutes at room temperature, a solution of cis-2,5-bis(hydroxymethyl)-tetrahydrofuran ditosylate (4.1 grams, 9.3 mmole) (prepared by literature methods such as those described in JOC, 47, 2429-2435 (1982)) in N,N-dimethylformamide (50 mL) is added dropwise. The reaction mixture is gradually heated to 100° C. in an oil bath and stirred at this temperature overnight. The solvent is evaporated under vacuum and the residue is taken up in water and extracted twice with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate and concentrated to a crude product.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH2:1]([NH:3][C:4]([NH:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCN=C=S
Solvent: c1ccccc1
Product: CCNC(=S)NCc1ccccc1
Yield: 94.4 %

Procedure:
To a mixture of 1.74 grams (0.02 mole) of ethyl isothiocyanate and 25 milliliters of benzene was added 2.14 grams (0.02 mole) of benzylamine. The temperature rose from 25° C. to 41° C. The reaction mixture was then refluxed on a steam bath for about 20 minutes to bring the reaction to completion. The mixture was evaporated under vacuum to give 3.67 grams of 1-ethyl-3-benzyl thiourea.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[C:17]([CH3:24])=[C:16]([CH3:25])[N:15]=1.C(N(CC)CC)C.C(=O)([O-])N>CN(C)C=O>[Cl:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[C:17]([CH3:24])=[C:16]([CH3:25])[N:15]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Agent: NC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.2 %

Procedure:
A solution of tert-butyl 3-aminopropylcarbamate (121.39 g, 697 mmol) in N,N-dimethylformamide (200 mL) was slowly added to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (110 g, 498 mmol) and triethylamine (104 mL, 746 mmol) in N,N-dimethylformamide (900 mL). After stirring at ambient temperature for 20 hours the reaction mixture was heated to 55° C. At 24 hours 0.1 equivalents of the carbamate was added. The reaction mixture was allowed to cool to ambient temperature overnight and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (3 L). The solution was divided into 3 aliquots (1 L each). Each aliquot was washed with water (2×1 L). The pH of the aqueous washes was adjusted to 10 with potassium carbonate and then they were extracted with ethyl acetate. All of the ethyl acetate layers were combined, dried over sodium sulfate and then concentrated under reduced pressure to provide 181 g of crude product. This material was recrystallized from acetonitrile to provide 138 g of tert-butyl 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propylcarbamate as a yellow solid.