Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[N:13]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:20]=[CH:19][C:17]([NH:18][C:29](=[O:31])[CH3:30])=[CH:16][CH:15]=2)[N:13]=1
Reactant: Nc1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of compound (156) (0.20 g, 0.63 mmol) in dichloromethane (3 ml) were added pyridine (0.05 ml, 0.63 mmol) and acetyl chloride (0.04 ml, 0.63 mmol) under ice-cooling. The reaction mixture was warmed to room temperature and, after stirring for one hr., partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, and the extracts were combined and dried (MgSO4). The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give white crystals (0.17 g, 76%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[NH:8][C:7]2=[O:17].[CH3:18]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=[O:16])[N:8]([CH3:18])[C:7]2=[O:17]
Reactant: CI
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2cc(Cl)c([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
NaH (5.30 g, 0.132 mol) was added in portions to a solution of 5-chloro-6-nitroisoindoline-1,3-dione (20.0 g, 88.27 mmol) in 100 mL of anhydrous DMF at 0° C. under argon. The reaction mixture was then stirred at rt for 3 h. MeI (15.0 g, 106 mol) was added dropwise via a syringe at rt under argon. The resulted mixture was stirred for 6 h at rt, hydrolyzed by adding 200 mL of water. The brown precipitate was isolated, washed with water and dried under vacuum. The solid was purified by column chromatography (silica-gel, CH2Cl2/Acetone=19/1 v/v) to give a yellow solid product, 15.6 g, 73.6% yield. MS: 239.2 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 8.54 (s, 1H), 8.32 (s, 1H), 3.07 (s, 3H).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH3:23])(=[O:22])=[O:21].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1C=CC=CC=1.O>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CCOC(=O)C(C)CCCCCBr
Reactant: CCCCCC(CCCNS(C)(=O)=O)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC(CCCN(CCCCCC(C)C(=O)OCC)S(C)(=O)=O)OC1CCCCO1
Reaction time: 1 h

Procedure:
A stirred suspension of sodium hydride (57%) (5.0 g., excess) in a solvent mixture of benzene (75 ml.) and dimethylformamide (75 ml.) is treated, over 30 minutes, with N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamide (Example N, Step 4) (32.1 g., 0.1 mole) dissolved in benzene (20 ml.). Stirring is continued for one hour. Then ethyl 7-bromo-2-methylheptanoate (Example L, Step 4) (25.3 g., 0.1 mole) is added dropwise, and the reaction is heated on the steam bath for 6 hours. The cooled reaction mixture is poured into water (400 ml.) and extracted with ethyl acetate (2× 200 ml.). The organic fractions are combined, washed with brine, then dried over sodium sulfate. The solvents are removed in vacuo to give ethyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamido}-2-methylheptanoate as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C(O)(=O)C.C1(C)C=CC=CC=1>O>[CH3:9][N:10]1[CH2:15][CH2:14][C:13]2([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2)[CH2:12][CH2:11]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccccc1S
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCC2(CC1)Nc1ccccc1S2

Procedure:
A mixture of 125.5 g 2-amino-thiophenol, 147 g N-methyl-4-piperidone, 2 ml acetic acid and 400 ml toluene is refluxed with a water separator for 2 hours. The mixture is evaporated in vacuo. The residue is recrystallised from methylene chloride/ether/petroleum ether to give the heading compound, m.p. 135°-140°.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[OH:22][N:23]=[C:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.FC(F)(F)C([O-])=O.CS(C)=O>C(O)(C)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:26]4[CH2:27][CH2:28][C:24](=[N:23][OH:22])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: ON=C1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=C([O-])C(F)(F)F
Solvent: CC(C)O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(=NO)C3)c(F)c(F)c2c1=O
Yield: 44.6 %

Procedure:
The reaction was conducted at room temperature for 3 hours in the same manner as in Example 3 except that 300 mg (1 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 535 mg (2.5 mmol) of 3-hydroxyiminopyrrolidine-trifluoroacetate were used as starting materials and 5 ml of dimethyl sulfoxide was used as the solvent for reaction. 7 ml of isopropanol was added to the reaction mixture, and the precipitate thereby formed was collected by filtration and recrystallized from a mixture of 6 ml of dimethyl sulfoxide and 6 ml of isopropanol to give 170 mg of the desired product as pale yellow powder.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]([O:11][CH3:12])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]([O:15]C)=O.[H-].[Na+].[CH3:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21].Cl.[O:26]1CCC[CH2:27]1>O.C(O)(C)C>[CH:22]1([C:20](=[O:21])[CH2:19][C:13]([C:3]2[CH:4]=[CH:5][C:6]3[S:7][CH:8]=[C:9]([O:11][CH3:12])[C:10]=3[C:2]=2[O:26][CH3:27])=[O:15])[CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc2scc(OC)c2c1Cl
Reactant: C1CCOC1
Reactant: CC(=O)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1csc2ccc(C(=O)CC(=O)C3CC3)c(OC)c12

Procedure:
A solution of methyl 4-chloro-3-methoxybenzo[b]thiophene-5-carboxylate (3.95 g) in dry tetrahydrofuran was added to sodium hydride (60%, 1.355 g) and stirred under an inert atmosphere with warming to 50°-60° C. Cyclopropyl methyl ketone (2.59 g) was added with stirring at 50°-60° C. for 3 hours. After this time the reaction exothermed and was heated at 50°-60° C. for a further 1.5 hours. After cooling, isopropanol (5 ml) was cautiously added, followed by water (5 ml). The mixture was poured onto 2N hydrochloric acid and extracted with ether. The ether extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ether/cyclohexane to yield 5-(3-cyclopropyl-1,3-dioxoprop-1-yl)-3,4-dimethoxybenzo[b]thiophene as a yellow solid (1.47 g), m.p. 77.5°-80° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([CH3:13])[CH2:11][NH2:12])=[CH:2]1.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])[C:15]([CH3:17])=O>>[CH3:13][CH:10]1[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[NH:1][C:2]=2[C:15]([C:14]([O:19][CH2:20][CH3:21])=[O:18])=[CH:17][NH:12][CH2:11]1
Reactant: CCOC(=O)C(C)=O
Reactant: CC(CN)c1c[nH]c2ccccc12
Product: CCOC(=O)C1=CNCC(C)c2c1[nH]c1ccccc21

Procedure:
In a manner similar to Example 1, the title compound was prepared from 2-(1H-indol-3-yl)propylamine and ethyl pyruvate. MS(ESI): 271 (MH+).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([C:23](OCC)=[O:24])[C:19](=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CC(O)(C)C>[NH2:7][C:6]1[N:8]=[C:23]([OH:24])[C:20]2[CH2:21][CH2:22][N:17]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:18][C:19]=2[N:5]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: O=C(O)O
Solvent: CC(C)(C)O
Product: Nc1nc(O)c2c(n1)CN(Cc1ccccc1)CC2
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
Guanidine carbonate (343 mg, 1.87 mmol) was added to a solution of 1-benzyl-4-ethoxycarbonyl-3-piperidone hydrochloride (488 mg, 1.87 mmol) in tBuOH (18 mL). The reaction was heated to reflux for 2 hours and then was acidified with 1N HCl to pH 5 and stirred for 30 minutes. The mixture was filtered and the solids were dried to obtain 2-amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol as a yellow solid (320 mg, 67%). MS (ESI): mass calcd. for C14H16N4O 256.3 m/z found, 257.2[M+H]+. 1H NMR (500 MHz, MeOD) δ 7.40-7.26 (m, 5H), 3.71 (s, 2H), 3.25 (s, 2H), 2.73 (t, J=5.9 Hz, 2H), 2.46 (t, J=5.9 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][CH:6]=1.CN.[CH2:16]([N:18](CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:18][CH3:16])=[CH:7][CH:6]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: CN
Solvent: C1CCOC1
Product: CNCc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 15 in tetrahydrofuran (0.4 M) at room temperature under nitrogen was added methylamine (7.5 eq) and triethylamine (12.0 eq). The reaction was stirred at room temperature overnight. The tetrahydrofuran was removed under reduced pressure and the resulting oil was diluted with H2O. The aqueous layer was acidified with 6N hydrochloric acid, extracted with ethyl acetate (3×), made basic with saturated sodium bicarbonate and extracted with dichloromethane (3×). The dichloromethane was dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (66%) 1H NMR (400 MHz, CDCl3) δ 7.31 (d, 2H), 7.25 (d, 2H), 3.77 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.45 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:27][C:28]2[O:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH:32]=2)[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:25][CH:24]([CH3:26])[CH2:23][CH2:22][N:21]([CH2:27][C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[CH:32]=1)[CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)CCN(Cc1cc2ccccc2o1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCN(Cc1cc2ccccc2o1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Trifluoroacetic acid (15 ml, 195 mmol) is added to a solution of 4-{[(benzofuran-2-yl)methyl]-(3-methylbutyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.17 g, 2.92 mmol) in dichloromethane (15 ml). The reaction is stirred overnight at room temperature. The reaction is concentrated and water added to the residue. The solution is loaded onto a SCX-2 (10 g) column and washed with water (20 ml) and methanol (20 ml). The product is then eluted off with 2M ammonia in methanol (30 ml) and concentrated on a rotary evaporator to yield (0.77 g) of N-(3-methylbutyl)-N-[(benzofuran-2-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=301 (M+1); 1H NMR (CDCl3): δ=7.52-7.43 (2H, m), 7.25-7.16 (2H, m), 6.56 (1H, s), 3.81 (2H, s), 3.14 (2H, brd), 2.72-2.52 (5H, m), 1.86-1.75 (3H, brm), 1.64-1.34 (5H, m), 0.92-0.83 (6H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:22]([O:24]CC)=[O:23])[C:5]2=[O:27].Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH:7]=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:27]
Reactant: CCOC(=O)c1cn(-c2ccc(OC)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)cc1
Temperature: 120 °C
Yield: 87.6 %

Procedure:
A mixture of ethyl 6,7,8-trifluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.37 g), conc. hydrochloric acid (1 ml) and 90% acetic acid (4 ml) is heated at 120° C. for one hour. After cooling, the precipitated crystals are separated by filtration, washed well with water and with a mixture of ethanol and ether to give 6,7,8-trifluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.3 g) as white crystals, m.p. 252°-254° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])=[C:17]([Cl:28])[CH:16]=1)#[N:2].Br[CH2:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>>[Cl:28][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[NH:21][C:22]([NH:24][CH:25]1[CH2:26][CH2:27]1)=[O:23])[O:14][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:30][CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:33][CH2:32]3)=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)c3cc2C#N)CC1
Yield: 14.6 %

Procedure:
The title compound (275.8 mg, 0.466 mmol, 14.6%) was obtained as white crystals from an N-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-chlorophenyl)-N′-cyclopropylurea crude product (1.00 g, 3.20 mmol) and tert-butyl 4-(bromomethyl)-1-piperidinecarboxylate, by the same procedure as in Example 7.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH2:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:14]=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[CH2:16]2.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:10][C:11]1[CH:12]=[C:13]([CH2:33][CH:34]2[CH2:35][CH2:36][N:37]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:38][CH2:39]2)[CH:14]=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=1)[CH2:16]2
Reactant: ClCc1ccccn1
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(CC2CCN(Cc3ccccn3)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a mixture of 2-chloromethylpyridine hydrochloride salt (16.9 mg, 0.103 mmol), 7-methyl-5-piperidin-4-ylmethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (50.0 mg, 0.120 mmol) and potassium carbonate (71.2 mg, 0.515 mmol) was added acetonitrile (3.0 mL). The mixture was allowed to stir at room temperature overnight. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography provided the title compound as a yellow oil (34.1 mg, 65%). 1H NMR (300 MHz, CDCl3): δ 8.56 (d, 1H), 7.65 (t, 1H), 7.34 (m, 3H), 7.18 (m, 3H), 6.98 (d, 2H), 4.76 (s, 2H), 4.20 (s, 2H), 3.64 (s, 2H), 2.90 (d, 2H), 2.73 (s, 3H), 2.57 (d, 2H), 2.03 (t, 2H), 1.62 (m, 2H), 1.35 (m, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH:20][S:21]([O-:23])=[O:22].[Na+:24]>CCO.O>[Na+:24].[OH:17][CH:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:19][CH:18]=1)[S:21]([O-:23])(=[O:22])=[O:20]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)N1CCN(C(=O)c2ccc(C(O)S(=O)(=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (20.0 g, 76.9 mmol) in EtOH (200 mL) was stirred at room temperature for 15 min. To the resulting solution was added a solution of NaHSO3 (9.6 g) in H2O (25 mL), dropwise over 30 min. The resulting suspension was stirred at room temperature for 2 h, then cooled to 0° C. and stirred for 3 h, adding EtOH periodically (total 200 mL) to aid stirring. A precipitate formed and was collected by suction filtration through a glass frit lined with filter paper. The filter cake was washed with hexane (1×50 mL), and dried under vacuum for 16 h to yield the title compound as a white solid.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ClCI.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]=[CH2:25])=[CH:19][CH:18]=1.Cl>C(Cl)Cl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:1][CH2:25]2)=[CH:19][CH:18]=1
Reactant: C=COc1ccc(Br)cc1
Reactant: CC[Zn]CC
Agent: Cl
Agent: ClCI
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(OC2CC2)cc1
Reaction time: 1 h
Yield: 102.4 %

Procedure:
The following cyclopropanation was conducted according to the description in the document (Tetrahedron Lett., (1998), 39, 8621-8624). Diethylzinc (1.0 M n-hexane solution, 250 mL, 250 mmol) was added to methylene chloride (250 mL), and a methylene chloride (120 mL) solution of trifluoroacetic acid (19.2 mL, 249 mmol) was added thereto under ice-cooling over 100 minutes. The mixture was further stirred for 1 hour. Then, a methylene chloride (100 mL) solution of chloroiodomethane (20.1 mL, 250 mmol) was added thereto under ice-cooling over 40 minutes. At the same temperature, a methylene chloride (120 mL) solution of 1-bromo-4-(vinyloxy)benzene (32.8 g, 165 mmol) prepared in Example 5 (5b) was added thereto over 20 minutes. The resulting mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added 0.1 N hydrochloric acid (400 mL). The mixture was stirred for 30 minutes, filtered through Celite, and further washed with n-hexane (200 mL). The filtrate and the n-hexane washing solution were combined, and the organic layer was washed with 0.1 N hydrochloric acid (100 mL) and saturated brine (100 mL) containing about 1 g of sodium sulfite twice. This organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated to give 36.0 g of 1-bromo-4-(cyclopropyloxy)benzene (yellow oil).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][CH2:32][CH3:33])[C:26](=[O:34])[CH:25]=2)=[CH:18][N:17]=1)([O-])=O>N1C=CC=CC=1>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][CH2:32][CH3:33])[C:26](=[O:34])[CH:25]=2)=[CH:18][N:17]=1
Reactant: CCCCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Reactant: Cc1[nH]cnc1CSCCN
Solvent: c1ccncc1
Product: CCCCn1ccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cc1=O

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethylamine (1.37 g) and 2-nitroamino-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (2.39 g) were refluxed in pyridine (12 ml) for 17 hours. The reaction mixture was evaporated under reduced pressure and the residue washed with hot water. The mixture was allowed to cool and the water was decanted to give the title compound as a residue. Ethanolic HCl was added with warming and on subsequent cooling the trihydrochloride salt of 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one was obtained as a solid (2.50 g); recrystallisation from ethanolic HCl afforded material, m.p. 170°-173.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH2:5][CH:6]([C:8](=[CH:10][CH:11]=1)[OH:9])[OH:7].N1C=C(C2CCCN2C)C=CC=1>>[NH2:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: NCCC1=CC=C(O)C(O)C1
Agent: CN1CCCC1c1cccnc1
Product: NCCc1ccc(O)c(O)c1
Reaction time: 0.17 h

Procedure:
The synaptosomal suspension was incubated for 10 min at 37° C. to restore metabolic activity. [3H]Dopamine ([3H]DA, specific activity=28.0 Ci/mmol, NEN Research Products) was added at a final concentration of 0.1 μM and the suspension was incubated at 37° C. for another 10 min. Aliquots of tissue (50 μl) and perfusion buffer (100 μl) were loaded into the suprafusion chambers of a Brandel Suprafusion System (series 2500, Gaithersburg, Md.). Perfusion buffer (room temperature) was pumped into the chambers at a rate of 3 ml/min for a wash period of 8 min. Test compound (10 μM) or nicotine (10 μM) was then applied in the perfusion stream for 40 sec. Fractions (12 sec each) were continuously collected from each chamber throughout the experiment to capture basal release and agonist-induced peak release and to re-establish the baseline after the agonist application. The perfusate was collected directly into scintillation vials, to which scintillation fluid was added. [3H]DA released was quantified by scintillation counting. For each chamber, the integrated area of the peak was normalized to its baseline.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13].[I:22]Cl>CO>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9]([I:22])[C:8](=[O:12])[NH:7][C:6]1=[O:13]
Reactant: ClI
Reactant: Cc1cc(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: CO
Product: Cc1c(I)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 50 °C
Yield: 91.8 %

Procedure:
To a 250 mL three-neck round bottom flask was charged 1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1a (25.0 g) and methanol (250 mL). Iodine monochloride (30.9 g) was charged over 2.5 min. The mixture was heated at 50° C. for 3 hours. After cooling to ambient temperature, the mixture was filtered. The cake was re-slurried in methanol (250 mL) and heated to 50° C. for 3 hours. After cooling to ambient temperature, the mixture was filtered and the filter cake was washed with methanol (50 mL). The off-white solid was dried in a vacuum oven at 50° C. to provide 1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione 1b (32.5 g, 90% yield). LCMS (ESI) m/z 429.3 (MH+). The material may be re-slurried in MeOH as needed.
Reaction SMILES: [CH3:1][CH:2]1[CH2:3][C:4](=[O:19])[CH2:5][CH2:6][CH:7]([CH3:18])[CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17]1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[CH3:1][CH:2]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([CH3:18])[CH2:6][CH2:5][C:4](=[O:19])[CH2:3]1
Reactant: CC1C=CCCCCCCC=CC(C)CC(=O)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC1/C=C/CCCCCC/C=C/C(C)CC(=O)CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1CCCCCCCCCCC(C)CC(=O)CC1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A Parr bottle was charged with 3,14-dimethylcyclohexadeca-4E,12E-dien-one (0.203 g, 0.77 mmole), ethyl acetate (36 ml), ethanol (4 ml) and 5% palladium-on-carbon (0.050 g). The vessel was pressurized to 43 psi with hydrogen gas and the solution was shaken vigorously for 2 hours. The pressure was brought down to atmospheric pressure and the reaction mixture was filtered through a pad of Celite and the solvents were removed by distillation under reduced pressure to afford 3,14-dimethylcyclohexadecan-1-one (0.206 g, 100% yield). C18H34O (266.47 g/mole). 1HNMR (500 MHz, CDCl3): 0.861 (dd, 3H), 0.909 (dd, 3H), 1.38-1.03 (m, 20H), 1.62-1.38 (m, 3H), 2.10-1.98 (m, 1H), 2.18-2.11 (m, 1H), 2.43-2.33 (m, 3H) ppm. 13CNMR (125 MHz, CDCl3): 20.44, 20.80, 24.15, 25.21, 26.47, 26.50, 26.76, 27.06, 27.47, 29.10, 29.45, 31.31, 34.50, 35.61, 40.24, 50.48, 211.86 ppm. IR (νmax(cm−1)): 2930(s), 2910(s), 2856(s), 1713(s), 1460(s), 1412(w), 1375(m), 1146(w), 1096(w), 1059(w). MS (m/z): 266(M+), 251, 237, 223, 208, 152, 139, 125, 109, 97, 85, 69, 55, 41.