Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:15](S(Cl)(=O)=O)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1>CCCCCC.O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:15]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCCN1
Reactant: COc1cccc(S(=O)(=O)S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(S(=O)(=O)N2CCCC2=O)c1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
15.75 cm3 of a 1.6M solution of M-butyllithium in hexane is added to 2.22 g of 2-pyrrolidinone in solution in 80 cm3 of tetrahydrofuran and cooled to -25° C., the temperature being maintained between -25° C. and -20° C. After agitation for 30 minutes at -25° C., a solution of 5.40 g of 3-methoxybenzenesulphonyl sulphonyl chloride [J. Chem. Soc. P.T.2., 579 (1982)] in 40 cm3 of tetrahydrofuran is poured drop by drop into the mixture, operating between -25° C. and -20° C. After agitation for 30 minutes at -25° C., the whole is allowed to return to ambient temperature. The solvent is evaporated under reduced pressure; the residue is taken up in water, filtered and crystallized from isopropanol. 3.5 g of expected product is obtained.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH:11]([CH3:13])[CH3:12])[CH2:4][CH2:5][CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])#[N:2]>CS(C)=O.C(N(CC)CC)C>[C:1]([C:3]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH:11]([CH3:13])[CH3:12])[CH2:4][CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])#[N:2]
Reactant: CCCC(O)CCC(C#N)(c1ccccc1)C(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCC(=O)CCC(C#N)(c1ccccc1)C(C)C
Reaction time: 1 h

Procedure:
7-Cyano-8-methyl-7-phenylnonane-4-ol, 70 mg 0.27 mmol, was dissolved in dimethyl sulfoxide 3.00 ml and triethylamine 0.70 ml. A sulfur trioxide-pyridine complex 64.7 mg was added thereto. After 1 hour, an additional sulfur trioxide-pyridine complex 80.0 mg was added thereto. The reaction mixture was partitioned by adding aqueous saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with aqueous ammonium chloride and then with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound, 50 mg 0.19 mmol, 72.0%, was obtained as a colorless syrup.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:23]([OH:25])=O)[CH:17]=3)=[C:9]([CH3:26])[CH:8]=1)=[O:4].[NH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[I-].C[NH+]1CCN(CCC)C1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH3:26])[C:10]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:23](=[O:25])[NH:27][C:28]2[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=2)[CH:17]=3)=[C:11]([CH3:13])[CH:12]=1
Reactant: Nc1ccc2ccccc2n1
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Agent: CCCN1CC[NH+](C)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1
Temperature: 150 °C

Procedure:
A mixture of 2-[4-(2-methoxycarbonylethyl)-2,6-dimethylphenyl]-1H-indole-6-carboxylic acid (600 mg, 1.71 mmol), 2-aminoquinoline (246 mg, 1.71 mmol), EDCI (491 mg, 2.56 mmol), HOBT (254 mg, 1.88 mmol) and 1-methyl-3-propylimidazolinium iodide (140 mg, 560 μmol) in THF (10 mL) was heated in a microwave apparatus at 150° C. for 3 h then the mixture was poured into ethyl acetate and extracted with water twice and brine once. The ethyl acetate layer was dried, filtered, and removed under reduced pressure, and the residual material was chromatographed using a 20-50% gradient of heptane/ethyl acetate to afford 3-{3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-indol-2-yl]-phenyl}-propionic acid methyl ester. 1H NMR (DMSO-d6, 400 MHz): δ 11.56 (s, 1H), 11.00 (s, 1H), 8.39 (s, 2H), 8.16 (s, 1H), 7.95 (d, J=7.4 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.79 (dd, J=8.3, 1.5 Hz, 1H), 7.73 (TD, J=7.0, 1.4 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.52 (t, J=7.0 Hz, 1H), 7.05 (s, 2H), 6.41 (d, J=1.3 Hz, 1H), 3.62 (s, 3H), 2.85 (t, J=7.4 Hz, 2H), 2.67 (t, J=7.4 Hz, 2H), 2.12 (s, 6H). MS (m/z) 478.2 (M+1); Retention time=1.58 min (Method 10).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=2[F:48])[CH2:17][O:16][C@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:14]1[CH2:39][OH:40].CCOC(C)=O>C(Cl)Cl>[F:48][C:42]1[C:43]([F:47])=[CH:44][CH:45]=[CH:46][C:41]=1[C@@:13]1([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])[C@H:14]([CH2:39][OH:40])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:16][CH2:17]1
Reactant: N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1

Procedure:
Benzoyl isothiocyanate (6 g) was added dropwise to a solution containing ((2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl)methanol, obtained in Preparation Example 1-(3), (15.42 g) in CH2Cl2 (80 mL), and the mixture was stirred at RT for 18 h. EtOAc was added and the mixture was extracted with NaHCO3 (3×100 mL), dried over MgSO4, evaporated, and the residue was purified by silica gel column chromatography (0% to 30% EtOAc in hexanes) to obtain the title compound (19.06 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.00 (t, J=6.2 Hz, 1H), 3.08-3.17 (m, 1H), 3.26 (dd, J=10.2, 4.2 Hz, 1H), 3.38 (dd, J=10.2, 3.9 Hz, 1H), 3.73-3.95 (m, 2H), 4.04-4.12 (m, 1H), 4.54 (d, J=9.6 Hz, 1H), 4.69 (d, J=9.9 Hz, 1H), 7.05-7.68 (m, 21H) 7.88 (d, J=7.1 Hz, 2H), 8.88 (s, 1H), 11.83 (s, 1H)
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:28])[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14][C:15](=[O:27])[O:16][C@@H:17]1[CH2:22][C@H:21]([CH3:23])[CH2:20][CH2:19][C@H:18]1[CH:24]([CH3:26])[CH3:25])=O)(C)(C)C.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[NH2:8][C:9]1([CH3:28])[CH2:13][CH2:12][CH2:11][CH:10]1[NH:14][C:15](=[O:27])[O:16][C@@H:17]1[CH2:22][C@H:21]([CH3:23])[CH2:20][CH2:19][C@H:18]1[CH:24]([CH3:25])[CH3:26]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-{[(tert-butoxy)carbonyl]amino}-2-methylcyclopentyl)carbamate (25.2 g, 63.5 mmol) in DCM (100 ml) was added HCl in 1,4-dioxane (4 M, 60 ml, 240 mmol). The reaction mixture was stirred at room temperature for 18 hours and then further HCl in 1,4-dioxane (4 M, 20 ml, 80 mmol) was added and the stirred for an additional 24 hours at room temperature. The reaction was concentrated in vacuo and purified by SCX chromatography (2M ammonia in methanol). The resulting residue was suspended in DCM/methanol and to this was added HCl in 1,4-dioxane (4 M, 10 ml, 40 mmol) and stirred for 2 hours. The reaction was concentrated in vacuo and further evaporated from diethyl ether and then methanol to afford the title compound as a mixture of trans-amino compounds.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl.[CH3:23][NH:24][O:25][CH3:26].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:24]([O:25][CH3:26])[CH3:23])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.2 %

Procedure:
To a solution of Boc-Glu(OtBu)-OH (15 g) in dichloromethane (150 ml) was added N,O-dimethyl-hydroxylamine hydrochloride (5.3 g) and [2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate] (15.87 g) and the pH was adjusted to pH 8-8.5 by adding triethylamine. The reaction mixture was stirred for 16 h at room temperature. The mixture was washed successively with cold 0.3M hydrochloric acid solution, water, 5% aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (eluent: dichloromethane/methanol=98/2 v/v %) to yield Boc-Glu(OtBu)-NMeOMe (17.5 g).
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3](=[O:10])[O:2]1.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:3](=[O:10])[CH2:4][C:5]1([C:1]([OH:11])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CC2(CCCC2)C(=O)O1
Reactant: OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(CC1(C(=O)O)CCCC1)OCc1ccccc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 60.5 %

Procedure:
To a solution of 2-oxaspiro[4.4]nonane-1,3-dione (3 g, 19.46 mmol) in toluene (2 ml), BnOH (2.023 ml, 19.46 mmol) was added. The reaction mixture was allowed to stir at 100° C. for 19 hours, and the reaction mixture was concentrated under reduced pressure. The obtained residue was recrystallized in DCM (15 ml) and 2,2,4-trimethylpentane (100 ml). The obtained colorless crystal was washed with a 10% solution of DCM/heptane (20 ml). The obtained solid was dried under reduce pressure to give 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (3.09 g); Retention time=1.56 minutes (condition A); 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (t, J=7.2 Hz, 3H) 1.58-1.81 (m, 6H) 2.19-2.25 (m, 2H) 2.75 (s, 2H) 5.11 (s, 2H) 7.28-7.37 (m, 5H) 11.80 (br s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-:18])=[O:17])=[C:9]([NH:12]C(=O)C)[CH:10]=2)[C:5]([CH3:20])([CH3:19])[C:4]1=[O:21])[CH3:2].Cl>C(O)C>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:19])([CH3:20])[C:4](=[O:21])[N:3]2[CH2:1][CH3:2])=[CH:7][C:8]=1[N+:16]([O-:18])=[O:17]
Reactant: CCN1C(=O)C(C)(C)c2cc([N+](=O)[O-])c(NC(C)=O)cc21
Agent: Cl
Solvent: CCO
Product: CCN1C(=O)C(C)(C)c2cc([N+](=O)[O-])c(N)cc21
Temperature: 25 °C
Yield: 93.3 %

Procedure:
N-(1-ethyl-3,3-dimethyl-5-nitro-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide (5.2 g, 17.85 mmol) was dissolved in ethanol (40 ml). After addition of hydrochloric acid (25%, 8 ml, 81.44 mmol) the mixture was stirred under reflux for 3 h. The reaction mixture was allowed to cool down to room temperature and then quenched with water (80 ml). The yellow precipitate was isolated by suction and washed with ethanol/water (1:1). The solid was dissolved in ethyl acetate, dried over sodium sulfate and concentrated to yield 4.15 g (93%) 6-amino-1-ethyl-3,3-dimethyl-5-nitro-1,3-dihydro-indol-2-one as a orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=1[C:28]([OH:30])=[O:29]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=2[C:28]([OH:30])=[O:29])=[C:4]([F:9])[CH:3]=1
Reactant: O=C(O)c1nnc(Cl)cc1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1nnc(Cl)cc1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To the stirred solution of 4-bromo-2-fluorophenylamine (3.15 g, 16.58 mmol) in THF (50 ml) under argon at −78° C. is added dropwise LiHMDS (24.9 ml, 24.9 mmol, 1.0 M in hexane). After stirring for one hour at −78° C., a solution of 4,6-dichloropyridazine-3-carboxylic acid (1.6 g, 8.29 mmol) in THF (10 ml) is added dropwise. The resulting mixture is allowed to warm to room temperature slowly and was stirred continuously for 18 hours. The reaction is quenched by addition of 5 ml of water, diluted with ethyl acetate, acidified with aqueous 1.0 M HCl to pH 1-2. The layers are separated and aqueous layer is extracted with ethyl acetate (30 ml×3). The combined organic layers are washed with brine (30 ml×3), dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by flash column chromatography to give the product.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([NH2:26])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])C.O[Li].O>C1COCC1.O>[NH2:26][C:17]1[CH:16]=[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([NH:6][CH2:5][C:4]([OH:27])=[O:3])=[O:8])[CH2:10][CH2:11]2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]=1
Reactant: CCOC(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
As described example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine (1.5 g, 5.7 mmol), isocyanato-acetic acid-ethy ester (0.7 mL, 6.3 mmol) and diisopropylethyl amine (1.5 mL, 8.6 mmol) are reacted to give [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid-ethyl ester the product as a white solid (990 mg, 40%). A mixture of the ester (990 mg), LiOH.H2O (1 g) in THF-H2O (5:1, 45 mL) was stirred at rt for 3 h, then acidified with 1.0 N HC (aq.) to pH to 4–5. After the removal of THF in vacuo, crude product precipitated. 760 mg (76%) of the acid was obtained after drying under vacuum for 3 h. LC-MS: 363 (M++1).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[N:6]=[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][N:8]2[C:9](=[O:11])[CH:10]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:28]2C=CC=CC=2C=O)[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25]>C(O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:20](/[CH:28]=[CH:4]/[C:5]2[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][N:8]3[C:9](=[O:11])[CH:10]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:23]=1[O:24][CH3:25]
Reactant: COc1cc(-c2ccccc2C=O)cc(OC)c1OC
Reactant: Cc1cc(=O)n2ccccc2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(/C=C/c2cc(=O)n3ccccc3n2)cc(OC)c1OC

Procedure:
To a solution of 1.3g of sodium methoxide in 75ml of absolute ethanol is added 3.2g of 2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one, followed by 4.0g of 3,4,5-trimethoxyphenyl-benzaldehyde. The mixture is stirred and heated under reflux for 24 hours. The mixture is worked up as described in Example 3 to yield the title compound, melting point 212°-214°C, dec.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:31](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:31][O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:14][C:13]([F:27])=[CH:12][CH:11]=2)=[O:20]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Reaction time: 12 h
Yield: 48.2 %

Procedure:
2-Benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (400 mg) was dissolved in DMF (4 ml) and methyl iodide (0.14 ml) and potassium carbonate (300 mg) were added at room temperature. The mixture was stirred for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound (200 mg).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)[CH:17]=[CH:16]4)[CH:7]=2)=[O:24])[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2ccc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(1-oxo-1,2-dihydroisoquinolin-6-yl)benzamide (Example 11) (1.0 g), potassium carbonate (1.3 g) and methyl 4-(bromomethyl)benzoate (0.86 g) in DMF (10 mL) was stirred at room temperature for 17 hours.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:27]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2Cc1ccccc1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.42 mmol) was dissolved in DMF (2 mL) and K2CO3 (220 mg, 1.6 mmol) and benzyl bromide (71.8 mg, 0.42 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration and then purified further by silica gel chromatography (5% MeOH/CH2Cl2) to yield a white solid.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:25][CH:26]=1.O>CN(C)C=O>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=4)=[N:25][CH:26]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cn2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2ccc(COc3ccc(CCCCn4ccnn4)cc3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
23 mg (0.90 mmol) of 95% sodium hydride were added at 0° C. to a solution of 163 mg (0.75 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 204 mg (0.75 mmol) 5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyridine (WO 2005/049573) were given to the reaction mixture and stirring continued at r.t for 2 days. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether. The residue was purified by chromatography on silica (eluent: ethyl acetate) to give 240 mg 71% of the title compound as white powder.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][NH2:9])[C:3]([OH:5])=[O:4].[O-2].[Mg+2].[CH3:12][O:13][C:14]1[CH:26]=[CH:25][C:17]([CH2:18][O:19][C:20](N=[N+]=[N-])=[O:21])=[CH:16][CH:15]=1>O.O1CCOCC1>[CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][NH:9][C:20]([O:19][CH2:18][C:17]1[CH:25]=[CH:26][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[O:21])[C:3]([OH:5])=[O:4]
Reactant: C=C(CCCN)C(=O)O
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: C=C(CCCNC(=O)OCc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.4 %

Procedure:
To a solution of 8.8 g of 2-methylene-5-aminopentanoic acid hydrochloric in 100 ml of water is added with stirring 6.36 g of magnesium oxide, followed by a solution of 12.2 g of p-methoxybenzyloxycarbonyl azide in 100 ml of dioxane, and the resulting mixture is stirred at room temperature for two days. The reaction mixture is filtered, and the filtrate diluted with 200 ml of ethyl acetate, two equivalents of Dowex 50 ion exchange resin is added, and the mixture is stirred at room temperature for two hours. The resin is then filtered off and washed with water. The layers in the filtrate are separated and the aqueous layer is extracted twice with ethyl acetate. The combined organic layers are dried and concentrated in vacuo to give 18.2 g of 2-methylene-5-(p-methoxybenzyloxycarbonyl)aminopentanoic acid as an amber oil which crystallizes on standing. This is used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.IC.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1([CH2:16][N:17]([CH3:27])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NCC1(CC2OCCO2)CCc2ccccc21
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CC1(CC2OCCO2)CCc2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of tert-butyl [1-(1,3-dioxolan-2-ylmethyl)-2,3-dihydro-1H-inden-1-yl]methylcarbamate (13.50 g, 38.9 mmole) in THF was cooled to 0° C. To this was added iodomethane (7.27 ml, 117 mmole) followed by 1M NaHMDS in THF (58 ml, 58 mmole). The reaction was then warmed to room temperature and stirred until no U16370/185/2 remained by TLC. The THF was evaporated and the residue dissolved in Et2O. The ether was washed with water and evaporated to afford 14.33 g of tert-butyl [1-(1,3-dioxolan-2-ylmethyl)-2,3-dihydro-1H-inden-1-yl]methyl(methyl)carbamate as a crude oil, which was used, with no further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](F)(F)F)=[CH:4][CH:3]=1.C1C(O)=CC=C(C)C=1.Cl[C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:21]2[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cc1ccc(O)cc1
Product: COC(=O)c1cnc(Oc2ccc(C)cc2)cn1

Procedure:
Instead of 4-hydroxybenzotrifluoride and 6-bromo-3-pyridinecarboxyaldehyde, p-cresol (833 mg) and methyl 5-chloro-2-pyrazinecarboxylate (1.33 g) were respectively used and treated by the same technique as in Reference Example 13-1 to give methyl 5-(4-methylphenoxyl)pyrazine-2-carboxylate as a colorless solid (1.36 g).