Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].O1CCCC1.B.CO>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(F)cc(Br)c1
Temperature: 0 °C

Procedure:
3-Bromo-5-fluorobenzoic acid (1.0 g, 4.52 mmol) was suspended in tetrahydrofuran (8 mL) and cooled to 0° C. To this solution was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 9 mL, 9.0 mmol) cautiously over 15 min. The reaction mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0° C., treated with excess methanol, diluted with ethyl acetate, washed with 1 N sodium hydroxide (2×), then brine (2×), dried over sodium sulfate, and concentrated to afford 0.88 g (95%) as a white powder. 1H-NMR (CDCl3, 500 MHz) 7.29 (s, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 4.66 (s, 2H).
Reaction SMILES: C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29](C=O)[CH:30]=2)[CH:25]=1)=[O:23].C(Cl)Cl.[H][H]>O1CCCC1>[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:23]
Reactant: COC(=O)c1ccc2cc(C=O)ccc2c1
Reactant: [H][H]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc2ccccc2c1

Procedure:
For example, 4'-alkoxy-4-bromobiphenyl (17) is reacted with triphenylphosphin to obtain triphenylphosphonium salt of 4'-alkoxybiphenyl (21). The thus obtained triphenylphosphonium salt of 4'-alkoxybiphenyl (21) is reacted with 6-formyl-2-naphthalenecarboxylic acid methyl ester as a solution in such as methylene chloride and then the resulting compound is reacted with hydrogen in the presence of the reducing catalyst such as paradium carbon in a solvent such as tetrahydrofuran (THF) to obtain 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid methyl ester. The resulting 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid methyl ester is hydrolysised to obtain 6-[4'-alkoxy-4-biphenyl)ethyl]-2-naphthalenecarboxylic acid (22).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([Cl:9])=[C:7](Cl)[S:6](=[O:11])[N:5]=1)[CH3:2].[CH3:12][O-:13].[Na+]>CO>[CH2:1]([O:3][C:4]1[C:8]([Cl:9])=[C:7]([O:13][CH3:12])[S:6](=[O:11])[N:5]=1)[CH3:2]
Reactant: C[O-]
Reactant: CCOC1=NS(=O)C(Cl)=C1Cl
Agent: [Na+]
Solvent: CO
Product: CCOC1=NS(=O)C(OC)=C1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.2 %

Procedure:
To the solution of 3-ethoxy-4,5-dichloroisothiazole-1-oxide (0.12 g, 0.00056 mol) in methanol (1 ml) cooled in an ice-bath was added a solution of sodium methoxide (0.032 g, 0.00060 mol) methanol (1 ml). The solution was warmed to ambient temperature and stirred overnight. The solution was concentrated to dryness in vacuo and the residue was partitioned between chloroform (10 ml) and water (5 ml). The aqueous layer was washed with chloroform (10 ml) and the combined organic layers were washed with saturated sodium chlorate solution (2 ml) dried over sodium sulfate, filtered, and concentrated to dryness to give 0.14 g orange liquid. This liquid was chromatographed on a column of E. Merck silica gel 60. From the fraction eluted with n-butylchloride, there was obtained 0.06 g of a mixture of starting material and 3-methoxy-4,5-dichloroisothiazole-1-oxide. From the fractions eluted with methylene chloride, there was obtained 0.03 g (25%) of the title compound. TLC (methylene chloride silica): Rf=0.43 (identical to product of Step B above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)cc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2,4-dichlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 233.0-234.0° C. 1H NMR (acetone-d6 /300 MHz) 7.90 (s, 1H), 7.73 (s, 1H), 7.69 (d, 1H, J=2.6 Hz), 7.47 (dd, 1H, J=8.7 Hz, 2.6 Hz), 7.23 (d, 1H, J=8.7 Hz), 6.57 (s, 1H), 5.81 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=6.5 Hz). FABLRMS m/z 437 (M-H). ESHRMS m/z 436.9379 (M-H, Calc'd 436.9362). Anal. Calc'd for C17H8Cl3F3O4 : C, 46.45; H, 1.83; Cl, 24.19. Found: C, 46.38; H, 1.59; Cl, 24.46.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1>C(O)C.[C].[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]([CH3:1])[O:3][C:4]2=[O:5])=[CH:10][CH:9]=1
Reactant: CC1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CC1OC(=O)c2cc(N)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
78.00 g of 3-methyl-6-nitrophthalide (3-3) was dissolved in 1.2 l of ethanol and 4.0 g of 5% palladium carbon was added thereto, and under a hydrogen atmosphere, the resulting mixture was stirred at a room temperature for 5 hours. The catalyst was filtered off, and thereafter, the filtrate was concentrated under reduced pressure, and the precipitated crystal was purified by recrystallizing (ethanol:water) to obtain 58.21 g of 6-amino-3-methylphtalide (3-4).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.[I-].CS[C:16]1[S:17][CH2:18][C@@H:19]2[CH2:27][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:20]=12>>[CH3:12][C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:1]=[C:16]1[N:20]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH2:27][C@H:19]3[CH2:18][S:17]1)[CH:11]=[CH:10][CH:9]=2
Reactant: CSC1=[N+]2c3ccccc3C[C@H]2CS1
Reactant: Cc1cc2c(N)cccc2cn1
Agent: [I-]
Product: Cc1cc2c(N=C3SC[C@@H]4Cc5ccccc5N34)cccc2cn1
Yield: 72.9 %

Procedure:
Following the procedure of Example 1 but starting with 5-amino-3-methylisoquinoline (6.0 g) and (S)-3-methylthio-9,9a-dihydrothiazolo[3,4-a]indolium iodide (12.0 g), (S)-3-[(3-methylisoquinol-5-yl)imino]-9,9a-dihydrothiazolo[3,4-a]indole (8.3 g) is obtained, after recrystallisation from ethanol, in the form of white crystals melting at 182° C. [α]D20 =-92.5±1.5° (c=1, chloroform)
Reaction SMILES: CN(C)CCO.[Li]CCCC.[CH3:12][N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>CCCCCC.O>[CH3:12][N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])[N:15]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CN(C)c1ccccn1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(N(C)C)n1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-dimethylaminoethanol (0.65 mL, 9.60 mmol) in hexane (10.0 mL, HPLC grade) cooled at −5° C. was added drop wise n-BuLi (1.60 M, 11.38 mL, 18.20 mmol) under nitrogen atmosphere. After 30 min at 0° C., dimethyl-pyridin-2-yl-amine (0.40 g, 3.20 mmol) in hexane (5.0 mL) was added drop wise. After stirring the reaction mixture for 1 h at 0-5° C., the reaction medium was cooled to −78° C. followed by drop wise addition of tributyl tin chloride (1.55 mL, 8.0 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then allowed to stir at 0-5° C. for 1 h. The reaction mixture was then allowed to stir at room temperature for 16 h. After the completion of reaction (TLC monitoring), the reaction mass was cooled to 0° C. and water was added slowly. The aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness. The crude residue was carried foreard to the next step without further purification. MS: 413.22.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:10][CH2:9][CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5]1)[CH3:3]>C(O)C.[Pd]>[CH3:1][CH:2]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:3]
Reactant: CC(C)N1CCCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1CCCNCC1
Yield: 99.8 %

Procedure:
Benzyl 4-propan-2-yl-1,4-diazepane-1-carboxylate (3.00 g, 10.85 mmol) and palladium, 10% on carbon (0.289 g, 2.71 mmol) in ethanol (54.3 ml) were stirred under an atmosphere of hydrogen at atmospheric pressure and ambient temperature for 18 h. The reaction mixture was filtered through celite, washing with ethanol, methanol and dichloromethane and the filtrate concentrated under reduced pressure to afford 1-propan-2-yl-1,4-diazepane (1.54 g, 100%) as a yellow liquid. This was used directly with no further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=3)[S:8][C:7]=2[CH:39]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[S:8][C:7]=2[CH:39]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCOC(=O)c3ccccc3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: O=C(OCCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1)c1ccccc1
Yield: 20 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl][4-(benzoyloxyethoxy)phenyl]methanone (1.14 g, 2.10 mmol) was converted to the title compound by the procedure of Example 3 using 400 mg (7.0 mmol) of ethanethiol and 920 mg (7.0 mmol) of aluminum chloride.
Reaction SMILES: C(NC1CCCCC1)(C)C.[Li]CCCC.[S:16]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17]1.Cl.[CH3:25][CH2:26][O:27][C:28]([CH3:30])=[O:29]>C1COCC1.[Cl-].[Na+].O>[O:22]=[C:21]([C:18]1[CH:19]=[CH:20][S:16][CH:17]=1)[CH2:30][C:28]([O:27][CH2:26][CH3:25])=[O:29]
Reactant: O=C(Cl)c1ccsc1
Reactant: CCOC(C)=O
Agent: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccsc1
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (5.64 g) in THF (80 mL) cooled to -78° C. under nitrogen was added nBuLi (25 mL, 1.6M in hexane) and the mixture was stirred for 30 min. EtOAc (1.95 mL) was added and after a further 30 min., 3-thiophene carbonyl chloride (from Step 1) dissolved in 3 mL THF was added. After 30 min., 1N HCl (75 mL) was added followed by brine and EtOAc. The organic layer was separated, dried and concentrated. Purification by column chromatography (5% EtOAc/hexane) afforded the title compound as an oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16](=[O:25])[C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[CH:26]=[CH2:27])(O)=[O:2].C(Cl)(=O)C(C)(C)C.[NH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>C(N(CC)CC)C>[Cl:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:24])[C:17]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([CH:26]=[CH2:27])=[C:5]2[CH2:4][C:1](=[O:2])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)=[O:25]
Reactant: NCc1ccccn1
Reactant: C=Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C=Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)NCc1ccccn1
Reaction time: 1 h
Yield: 14.8 %

Procedure:
To a solution of 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)-3-vinylquinoline (190.1 mg) were added pivaloyl chloride (62.8 mg) and triethylamine (52.7 mg) at 0° C., and the mixture was stirred for 1 hour at the same temperature. To the mixture was added 2-aminomethylpyridine (154 mg) at 0° C., and the mixture was stirred for 30 minutes at the same temperature and for 1 hour at ambient temperature. The mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (methanol-dichloromethane) to give 8-(2,6-dichlorobenzoylamino)-4-[(pyridin-2-ylmethyl)carbamoylmethyl]-3-vinylquinoline (34.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:24][CH:25]=1)[CH:6]=[CH:7][CH:8]=[C:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]>[C].[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[O:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:24][CH:25]=1
Reactant: COc1cc(C=CC=C2OC(=O)NC2=O)ccc1OCc1csc(-c2ccccc2)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1csc(-c2ccccc2)n1
Yield: 32.6 %

Procedure:
A mixture of 5-[3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)cinnamylidene]-2,4-oxazolidinedione (0.76 g), palladium-carbon (5%, 1.0 g) and tetrahydrofuran (THF) (100 ml) was subjected to catalytic hydrogenation under 1 atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-ethyl acetate (4:1), 5-[3-[3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione (0.25 g, 32%) was obtained. Recrystallization of the product from ethyl acetate-hexane gave colorless prisms, m.p.96-97° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[H][H].[C:11]([OH:14])(=[O:13])[CH3:12]>[Rh]>[C:11]([OH:14])(=[O:13])[CH3:12].[NH:1]=[C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][NH:3]1
Reactant: [H][H]
Reactant: Cc1ccnc(N)c1
Agent: [Rh]
Solvent: CC(=O)O
Product: CC1CCNC(=N)C1

Procedure:
2-Amino-4-methylpyridine (1.56 g; 15 mmoles) and 5% rhodium on carbon (0.51 g, wet, Degussa type G10) in glacial acetic acid (30 mL) were shaken on a Parr hydrogenation apparatus at 55 psi of hydrogen overnight. The catalyst was removed by filtration and the filtrate was diluted with water to 250 mL, and lyophilized to yield a light tan powder. The powder was recrystallized from warm ethanol/ether to give 0.3 g of white solid. mp 181°-182° C. A second crop of white solid was obtained (0.85 g; mp 180°-182° C.). MH+=113; 1H NMR (D2O): δ3.32-3.16 (m, 2H); 2.54-2.46 (m, 1H); 2.10-2.00 (m, 1H); 1.80-1.70 (m, 2H); 1.74 (s, 3H); 1.32-1.25 (m, 1H); 0.87 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([NH2:14])([CH3:13])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[N:15]1[N:16]=[N:17][N:18]2[CH:23]=[C:22]([C@@H:24]3[CH2:26][O:25]3)[CH:21]=[CH:20][C:19]=12>C(O)C>[CH3:13][C:2]([NH:14][CH2:26][C@@H:24]([C:22]1[CH:21]=[CH:20][C:19]2[N:18]([N:17]=[N:16][N:15]=2)[CH:23]=1)[OH:25])([CH3:1])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: CC(C)(N)Cc1c[nH]c2ccccc12
Solvent: CCO
Product: CC(C)(Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc2nnnn2c1

Procedure:
A solution of 670 mg (3.58 mmol) of (1,1-dimethyl-2-(1H-indol-3-yl)ethyl amine (B. Heath-Brown and P. G. Philpott, J. Chem. Soc., 7165 (1965)) and 598 mg (3.69 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane in 12 ml of absolute ethanol was heated at reflux for 15 hours. The reaction mixture was concentrated and the residue (1.24 g) chromatographed on silica gel (95:5:1 CH2Cl2 :MeOH:conc. NH4OH) to give 808 mg of (R)-α-[[(1,1-dimethyl-2-(1H-indol-3-yl)ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20]([OH:22])=O)[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>>[CH2:23]([N:25]([CH2:26][CH3:27])[C:20](=[O:22])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:10])=[O:9])[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[CH3:24]
Reactant: CCNCC
Reactant: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)c1
Product: CCN(CC)C(=O)CN(c1cccc(C)c1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with diethylamine
Reaction SMILES: [NH2:1][C:2]1[C:3](C(N)=O)=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:7]=1.[OH-].[Na+].Cl>O1CCOCC1.ClC1C=CC=CC=1Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[N:4][CH:3]=1
Reactant: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2-c2ccccn2)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Clc1ccccc1Cl
Product: CC(C)n1cc(-c2ncc(N)nc2-c2ccccn2)ccc1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 11 %

Procedure:
To a suspention of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(2-pyridyl)-2-pyrazinecarboxamide (52 mg) in dioxane (0.5 ml) was added an aq. NaOH (2M, 1 ml) and this solution was heated at 100° C. for 4 hours. This reaction mixture was cooled to room temperature and the pH of this solution was adjusted to 2.5 with 2N aq. HCl. This solution was evaporated under reduced pressure to give yellow solid. A suspension of this yellow solid in 1,2-dichlorobenzene (2 ml) was heated at 200° C. and stirred for 4 hours. This reaction mixture was cooled to room temperature. To this solution was added IPE and stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with IPE. The residual solid was placed on a column of silica-gel and eluted with CHCl3—MeOH—28% aq. ammonia (15:1:0.1). The eluent was evaporated and the residue was purified by recrystallization from EtOAc-IPE to give 5-[5-amino-3-(2-pyridyl)-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (5 mg) as a pale yellow crystal.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[S:9])=[CH:3][CH:2]=1.[CH3:11][C:12]([CH3:19])([CH:17]=[CH2:18])[CH2:13][CH2:14][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([NH:7][C:8](=[S:9])[CH2:18][CH2:17][C:12]([CH3:19])([CH3:11])[CH:13]=[CH2:14])=[CH:3][CH:2]=1
Reactant: Cc1ccc(N=C=S)cc1
Reactant: C=CC(C)(C)CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C)(C)CCC(=S)Nc1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a dehydrated tetrahydrofuran (30 ml) solution of p-tolyl isothiocyanate (1.8 g), a tetrahydrofuran solution of the above (3,3-dimethyl-4-pentenyl)magnesium bromide was added dropwise at 0° C., followed by stirring at 0° C. for 30 minutes. After raising the temperature to room temperature and further stirring for 30 minutes, an aqueous saturated ammonium chloride solution was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.2 g of the target compound.
Reaction SMILES: [CH2:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][C:7](=[C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=1)[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:8]2)[CH:2]=[CH2:3].B(Br)(Br)Br.C([O-])(O)=O.[Na+].C(O)C>ClCCl>[CH2:1]([N:4]1[CH:5]2[CH2:11][CH2:10][CH:9]1[CH2:8][C:7](=[C:12]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)[CH2:6]2)[CH:2]=[CH2:3]
Reactant: C=CCN1C2CCC1CC(=C(c1ccsc1)c1cccc(OC)c1)C2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: C=CCN1C2CCC1CC(=C(c1ccsc1)c1cccc(O)c1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.8 %

Procedure:
To 72 mg (0.20 mmol) of 8-allyl-3-[(3-methoxy-phenyl)-thiophen-3-yl-methylene]-8-aza-bicyclo[3.2.1]octane in 2 mL of dichloromethane at −78° C. was added 1.68 mL ([1 M] in DCM) of boron tribromide drop wise. The reaction solution was slowly warmed to room temperature over 1 hr and allowed to stir 3 hr at room temperature. After 3 hr, to the reaction solution was added 4 mL of a saturated solution of NaHCO3, and 4 mL of 20% ethanol in DCM. The aqueous phase was removed. The organic phase was washed with 4 mL of brine, dried over MgSO4, and concentrated. The concentrated sample was purified by reverse phase chromatography (20×100 mm J'sphere H-80 YMC column using a gradient of 0.1% TFA/water to 5% water/0.1% TFA/acetonitrile). The eluent corresponding to 3-[(8-allyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-thiophen-3-yl-methyl]-phenol was evaporated to yield 12 mg of the title compound as a white solid; MS m/z (MH+) 338.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])[CH:3]=[N:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](=[O:26])[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:4]3[CH:5]=[N:1][NH:2][CH:3]=3)[CH:7]=2)=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(-c2cn[nH]c2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2cn[nH]c2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(1H-pyrazol-4-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([3-(1H-pyrazol-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 72%).
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH:1]1[C:10]2[C@@H:11]3[CH2:16][N:15]([CH2:28][CH2:27][CH2:26][C:25]([C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[NH2:17])=[O:30])[CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Product: Nc1cc(F)ccc1C(=O)CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 402 as a yellow oil (35 mg, 20%) from (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (100 mg, 0.47 mmol) and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (202 mg, 0.93 mmol). The title compound was spectroscopically identical to Example 415.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][CH:7]=1)=[O:16]
Reactant: CCc1ccc(C(Cl)C(=O)C(=O)OC)cc1
Reactant: CC(N)=S
Product: CCc1ccc(-c2sc(C)nc2C(=O)OC)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-ethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.98 min; [M+H]+=262.1.