Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2].[NH2:33][C@H:34]([CH3:37])[CH2:35][OH:36]>>[C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2]
Reactant: C[C@@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Product: CC(=O)N(C)CCn1c(=O)c(C(=O)N[C@H](C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-2-amino-1-propanol using methods similar to Example 574: step 2 to provide an off-white solid: 1H NMR (400 MHz, DMSO-d6@90° C.) δ ppm 1.23 (d, J=6.72 Hz, 3 H), 1.85 (s, 3 H), 2.80 (s, 1 H), 2.95 (s, 2 H), 3.50-3.55 (m, 4 H), 4.05-4.14 (m, 1 H), 4.18 (d, J=0.82 Hz, 2 H), 4.35 (s, 2 H), 4.70 (t, J=5.56 Hz, 1 H), 7.09-7.15 (m, 2 H), 7.36-7.42 (m, 2 H), 8.08 (s, 1 H), 8.55 (s, 1 H), 10.06-10.42 (m, 1 H), 17.06-17.18 (m, 1 H); ES− MS: 471 (M+H+).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C(=O)C)=[CH:8][N:7]=1)(=O)C.[ClH:16]>CC(CC)=O>[ClH:16].[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[N:7][CH:8]=1
Reactant: CC(=O)OCc1ccc(OC(C)=O)cn1
Agent: Cl
Solvent: CCC(C)=O
Product: OCc1ccc(O)cn1

Procedure:
220.0 g of the above ester is added to 2,200 ml of 6N-hydrochloric acid and the resulting solution is refluxed for 18 hours. Then, the solution is evaporated to leave an oily viscous residue. This residue is digested with ethyl methyl ketone to yield 5-hydroxy-2-pyridinemethanol hydrochloride melting at 122°-123°. (The corresponding free base is prepared by adding a saturated solution of potassium carbonate to the hydrochloride, extracting the resulting suspension with chloroform, drying the chloroform extract over sodium sulfate, filtering and evaporating the filtrate to yield the free base.)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](OCC)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1.C(OCC)(=O)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: CCOC(=O)c1ccc2c(cnn2C)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ncc2cc(CO)ccc21
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
Lithium aluminum hydride (300 mg, 7.83 mmol) was suspended in tetrahydrofuran (20 ml); and under an ice cooling, a solution (10 ml) of ethyl 1-methyl-1H-indazole-5-carboxylate (800 mg, 3.92 mmol) prepared in the Step 4-1-3-A in tetrahydrofuran was slowly added thereto. After the mixture was stirred under an ice cooling for 30 minutes, 5 drops of a saturated sodium bicarbonate solution were slowly added to the mixture. Ethyl acetate was added to the mixture, and 5 drops of a saturated sodium bicarbonate solution was further added thereto. The precipitate was removed by filtration, and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (420 mg, 66%) as a light-brown powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18](=[O:20])[CH3:19]>CN(C=O)C>[CH2:7]([O:17][C:15]1[CH:14]=[CH:13][C:12]([C:18](=[O:20])[CH3:19])=[C:11]([OH:10])[CH:16]=1)[CH3:8]
Reactant: CCI
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)=O)c(O)c1
Reaction time: 4 h
Yield: 69.4 %

Procedure:
Potassium carbonate (13.6 g, 99 mmol) followed by ethyl iodide (2.4 mL, 29.6 mmol) were added to a solution of 2′,4′-dihydroxyacetophenone (5 g, 33 mmol) in DMF (50 mL). The mixture was stirred for 4 hours and then partitioned between H2O and EtOAc. The organic layer was washed with satd NaHCO3, brine, dried over Na2SO4 and concentrated to a clear oil. Purification by column chromatography gave the product as a white solid (3.7 g, 63%). 1H NMR (400 MHz, CDCl3): δ 1.43 (t, J=6.8 Hz, 3 H), 2.55 (s, 3 H), 4.07 (d, J=7.1 Hz, 2 H), 6.40 (s, 1 H), 6.43 (d, J=8.8 Hz, 1 H), 7.62 (d, J=8.8 Hz, 1 H), 12.74 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:24][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C@@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:21]3)[CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]=[O:46].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:21][C@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:24]3)[CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=2)=[O:46])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=Cc1ccccn1
Reactant: C=CC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ccccn2)cc1Cl
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]pent-1-en-3-one (882 mg) in ethanol (5 mL) were added pyridine-2-carbaldehyde (183 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (47.5 mg) and triethylamine (96 μL), and the mixture was stirred with heating under reflux for 1.5 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (698 mg, yield 66%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([N:20]1[C:28]2[C:27](=[O:29])[N:26]([CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]([OH:36])[CH3:35])[C:25](=[O:37])[N:24]([CH3:38])[C:23]=2[N:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)([O-:41])=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:13]([N:20]1[C:28]2[C:27](=[O:29])[N:26]([CH2:30][CH2:31][CH2:32][CH2:33][C@@H:34]([O:36][C:46](=[O:47])[C:45]3[CH:44]=[CH:43][C:42]([N+:39]([O-:41])=[O:40])=[CH:50][CH:49]=3)[CH3:35])[C:25](=[O:37])[N:24]([CH3:38])[C:23]=2[N:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
Diethyl azodicarboxylate (14.63 g, 84 mmol) was added dropwise to a solution of (R)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (as prepared in Example 29) (20 g, 56 mmol), 4-nitrobenzoic acid (14 g, 84 mmol) and triphenylphosphine (22 g, 84 mmol) in tetrahydrofuran (200 ml). After stirring for 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 30% ethyl acetate-hexane to provide (S)-7-benzyl-1-(5-(4-nitrobenzoyloxy)hexyl)-3-methylxanthine (25 g).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:25]=[C:18]3[N:19]=[C:20]([Cl:24])[CH:21]=[C:22](Cl)[N:17]3[N:16]=2)[CH2:11][C:10]1=[C:26]=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCOCC1.O>[CH2:1]([O:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:25]=[C:18]3[N:19]=[C:20]([Cl:24])[CH:21]=[C:22]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:17]3[N:16]=2)[CH2:11][C:10]1=[C:26]=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=C1CC(c2cc3nc(Cl)cc(Cl)n3n2)CCN1OCc1ccccc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: O
Product: O=C=C1CC(c2cc3nc(Cl)cc(N4CCOCC4)n3n2)CCN1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 2-(1-benzyloxy-carbonyl-piperidin-4-yl)-5,7-dichloro-pyrazolo[1,5-a]-pyrimidine (192 mg, 0.474 mM), then morpholine (82.7 μL, 0.948 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the residue thus obtained was diluted with water and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (191 mg, yield: 88%).
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:14]/[C:15]1[NH:16][CH:17]=[C:18]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[C:19]=1[CH3:20])/[C:5](=[O:13])[NH:6]2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd]>[CH3:12][O:11][C:10]1[C:2]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:13])/[C:4]/2=[CH:14]\[C:15]1[NH:16][CH:17]=[C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:19]=1[CH3:20]
Reactant: COc1ccc2c(c1Br)/C(=C/c1[nH]cc(C(=O)N3CCOCC3)c1C)C(=O)N2
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2c(c1-c1ccccc1)/C(=C/c1[nH]cc(C(=O)N3CCOCC3)c1C)C(=O)N2
Temperature: 85 °C
Reaction time: 8 h
Yield: 9.5 %

Procedure:
To a mixture of 4-bromo-5-methoxy-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one (223 mg, 0.5 mmol) and phenylboronic acid (73 mg, 0.6 mmol) in DME/water (5 mL) were added Palladium catalyst Pd(PPh3)2Cl2 (10.5 mg) and sodium carbonate (106 mg, 1 mmol). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 85° C. oil bath for overnight. TLC showed some de-bromination of the starting material. The degass procedure was repeated for three more times and the heating was continued for 3 more days. The mixture was cooled to room temperature, the unreacted starting material was filtered off and the mother liquor was concentrated. The residue was purified on a silica gel column to give 21 mg of 5-methoxy-3-[1-[3-methyl 4 (morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-phenyl-1,3-dihydro-indol-2-one.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([N:13]1[CH2:21][CH2:20][CH2:19][C@H:14]1[C:15]([O:17]C)=[O:16])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3].[OH-].[Na+]>O.CC(C)=O>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([N:13]1[CH2:21][CH2:20][CH2:19][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
3 (4.2 g, 9.6 mmol) was dissolved in 30 ml of water/acetone (1/5 v/v) and 11.6 ml NaOH (1N) where added. After completion of the reaction the organic solvent was removed by evaporation and the resulting solution was diluted by 15 ml NaHCO3 solution (saturated). Then the mixture was extracted three times by 10 ml of acetic acid ethyl ester. After that the solution was brought to pH2 by adding HCl (15% in water). The resulting mixture was extracted three times by 30 ml of acetic acid ethyl ester. The organic layer was separated and washed three times with brine, dried (Na2SO4) and evaporated.
Reaction SMILES: [CH2:1]([CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH2:2][CH3:3].[OH-].[Na+]>>[CH2:1]([CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:34])[C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:26][CH:27]=2)=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Yield: 99.4 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-propyl-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (2.10 g), which is the product of Example 73, was reacted with aqueous sodium hydroxide solution (1N, 15.0 ml) and the reaction mixture was treated to give the title compound (1.96 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[C:25]([NH:28][NH2:29])(=[O:27])[CH3:26]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](/[C:22](=[N:29]/[NH:28][C:25](=[O:27])[CH3:26])/[CH3:23])[N:20]=2)[N:15]=[N:14]1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Reactant: CC(=O)NN
Product: CC(=O)N/N=C(\C)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 89.6 %

Procedure:
The title compound (30.5 mg, 82%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (30.0 mg, 0.09 mmol) and acetic acid hydrazide (23.0 mg, 0.28 mmol) using the same procedure as described in the synthesis of example 72. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.83 (bs, 1H), 9.46 (s, 1H), 8.93 (dd, 1H), 8.40 (d, 1H), 8.19 (d, 1H), 7.81 (d, 1H), 7.53 (dd, 1H), 6.22 (s, 2H), 2.34, 2.14 (s, 6H). LCMS (method A): [MH]+=379, tR=2.07 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH3:19])[CH:6]=[CH:5]2.[N:20]1[NH:21][C:22](=[O:26])[CH:23]=[CH:24][CH:25]=1>>[CH3:19][CH:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([N:21]1[C:22](=[O:26])[CH:23]=[CH:24][CH:25]=[N:20]1)[CH:11]=[CH:10]2
Reactant: O=c1cccn[nH]1
Reactant: CC1CCCN1CCc1ccc2cc(Br)ccc2c1
Product: CC1CCCN1CCc1ccc2cc(-n3ncccc3=O)ccc2c1

Procedure:
One process for the preparation of 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one, which demonstrates activity as a histamine-3 receptor ligand, involves treating an inexpensive and readily available starting material, 6-bromo-naphthalen-2-ol, to afford 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one. Briefly, the process involves providing 6-bromo-naphthalen-2-ol. Preparing the triflate, or trifluoromethansulfonic acid ester, of 6-bromo-naphthalen-2-ol (2) with trifluoromethanesulfonic anhydride or another suitable trifluoromethanesulfonic reagent. The resulting trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester (2) is converted to 2-bromo-6-vinyl-naphthalene (3) via a Pd-catalyzed Suzuki cross-coupling reaction. The 2-bromo-6-vinyl-naphthalene is reacted with a 2-methylpyrrolidine anion generated with n-butyllithium to provide 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine (4). Compound (4) is reacted with 2H-pyridazin-3-one to provide the desired 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one (5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]([NH2:26])=[S:25])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:29][C:30](=O)[CH3:31].[O-]S([O-])(=O)=O.[Mg+2].[Al]>CC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:29]=[C:30]([CH3:31])[N:26]=2)=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(NC(N)=S)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: CC(=O)CCl
Agent: O=S(=O)([O-])[O-]
Agent: [Al]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: COc1cc2c(Nc3nc(C)cs3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reaction time: 20 h

Procedure:
A solution of (6,7-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (50 mg, 0.127 mmol) and chloroacetone (13.0 mg, 0.140 mmol) in acetone (1.4 mL) in a conical vial was added MgSO4 (7.7 mg, 0.0637 mmol). The resulting suspension was placed in an aluminum block preheated to 60° C. and was allowed to stir for 20 h. The reaction was cooled and concentrated. The residue was purified using a 5 g silica cartridge (MeOH/CH2Cl2, 2:98) to give [6,7-dimethoxy-4-(4-methyl-thiazol-2-ylamino)isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester as a yellow solid (17.4 mg; 32%). MS: calculated for C21H26N4O4S+H 431.0; found: 431.0.
Reaction SMILES: [OH-].[Na+].[C:3]([O:18]CC)(=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][CH3:16].O.Cl>CO>[C:3]([OH:18])(=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][CH3:16]
Reactant: CCOC(=O)CCCCSCCCCCSCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCSCCCCCSCCCCC(=O)O
Reaction time: 4 h
Yield: 93.9 %

Procedure:
Sodium hydroxide (1 M, 6.2 mL, 6.2 mmol) was added to a solution of ethyl 6,12-dithiatetradecanoate (0.9 g, 3.1 mmol) in MeOH (15 mL). After stirring for 4 hours, water (20 mL) was added and the reaction mixture was acidified (pH 1, HCl) extracted with EtOAc (2×100 mL), and the organic phase was washed with water (20 mL), brine (20 mL), and then dried (Na2SO4). The product crystallized from n-hexane to yield the title compound as a white solid (0.77 g, 95%, mp 49.5° C.-50.0° C.). IR: 3000, 1720 cm-1 ; 1H NMR, 1.23 (t, 3H), 1.49 (quintet, 2H), 1.56-1.68 (m, 6H), 1.74 (quintet, 2H), 2.38 (t, 2H), 2.51 (t, 2H), 2.53 (t, 4H), 2.54 (q, 2H), and 10.45 (b, IH). Anal. Calcd for C12H24S2O2 : C, 54.50; H, 9.15%. Found: C, 54.59; H, 9.21%.
Reaction SMILES: [NH2:1][CH:2]([C:31]([O:33][CH3:34])=[O:32])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:5]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[CH:17]1([C:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:12]=3[N:4]3[CH2:3][CH:2]([C:31]([O:33][CH3:34])=[O:32])[NH:1][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:5]=23)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CC(N)C(=O)OC)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)NCc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(2-amino-3-methoxy-3-oxopropyl)-3-cyclohexyl-2-(2-formylphenyl)-1H-indole-6-carboxylate in 1,2-DCE (0.04 M), 2 eq of NaBH(OAc)3 was added and the solution stirred overnight at RT. The reaction mixture was diluted with EtOAc. The organic phase was washed with NaHCO3 (s.s.) and brine before being dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound (quant). MS (ES+) m/z 447 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.[C:10](Cl)(=[O:12])[CH3:11]>FC(F)(F)C(O)=O>[C:10]([C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1])(=[O:12])[CH3:11]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1c(O)cc(C)oc1=O
Yield: 34.7 %

Procedure:
Dissolve 4-hydroxy-6-methyl-pyran-2-one (12.6 g, 100 mmol) in trifluoroacetic acid (50 ml). and add 7.8 g (100 mml) of acetyl chloride dropwise. Heat this mixture at reflux for 5 hours. Evaporate the reaction mixture under reduced pressure. Add 50 ml of water, extract with ethyl acetate (50 ml×3) and combine the organic layers. Wash with brine and dry (sodium sulfate). Chromatograph on silica gel, eluting with chloroform to provide 5.8 g (34.5 mmol) of 3-acetyl-4-hydroxy-6-methyl-pyran-2-one.
Reaction SMILES: Cl.N[C@H]1C[CH2:7][C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[CH2:35]([N:37]([CH2:40]C)[CH2:38][CH3:39])C>ClCCl>[CH3:40][N:37]([CH3:35])[C@H:38]1[CH2:39][CH2:7][C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4]1
Reactant: CCN(CC)CC
Reactant: COC(=O)C[C@H]1CC[C@H](N)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](N(C)C)CC1
Temperature: 25 °C

Procedure:
Under ice-cooling, to a suspension of methyl trans-(4-aminocyclohexyl)acetate hydrochloride (895 mg) obtained in Reference Example 120(4) in dichloromethane (30 ml), triethylamine (1.2 ml) is added and the mixture is stirred. Aqueous 35% formaldehyde solution (1.71 ml) and sodium triacetoxy borohydride (2.74 g) are added thereto successively under ice-cooling. The reaction solution is warmed to room temperature and stirred for 6 hours. Saturated aqueous sodium hydrogen carbonate solution is poured into the mixture under ice-cooling and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and then the solvent is removed under reduced pressure to give methyl trans-[4-(dimethylamino)cyclohexyl]acetate (771 mg).