Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][N:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(N(CC)CC)C.[F:31][C:32]1[CH:45]=[CH:44][C:35]([C:36]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:37])=[CH:34][CH:33]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CS(C)=O.CO.CCOCC.CC(C)=O>[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([CH:38]2[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][N:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[S:5]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)(=[O:7])=[O:6])[CH2:40][CH2:39]2)=[O:37])=[CH:44][CH:45]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1ccc(S(=O)(=O)N(CCO)c2ccccc2OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(S(=O)(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
In an atmosphere of argon at room temperature, N-hydroxyethyl-4-methoxy-N-(2-methoxyphenyl)benzene sulfonamide (235 mg, 0.697 mmol) was dissolved in DMSO (3 ml) to which were subsequently added dropwise triethylamine (0.48 ml, 3.44 mmol) and sulfur trioxide-pyridine complex (558 mg, 3.44 mmol) which has been dissolved in DMSO (3 ml). After 20 minutes of stirring at the same temperature, ice water (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate and then washed with water and saturated brine. The resulting organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by evaporation to obtain a light yellow oily material. The thus obtained residue was dissolved in methanol (5 ml) to which were subsequently added 4-(4-fluorobenzoyl)piperidine (108 mg, 0.52 mmol) and molecular sieve 4A (200 mg) at room temperature. After 45 minutes of stirring at the same temperature, sodium cyanoborohydride (11 mg, 0.166 mmol) was added to the reaction mixture which was stirred for additional 30 minutes, followed by the addition of acetone (1 ml). The resulting reaction solution was diluted with ether (10 ml) and filtered through cerite, followed by the removal of the solvent by evaporation. The thus obtained colorless oily residue was dissolved in ether (10 ml) and extracted with 2N hydrochloric acid (10 ml). After removing the ether layer, the resulting reaction solution was adjusted to pH 9 to 10 with 10% sodium hydroxide aqueous solution and extracted with methylene chloride, the resulting organic layer was dried on potassium carbonate and then the solvent was removed by evaporation. Thereafter, the resulting yellow oily residue was purified by subjecting it to a silica gel column chromatography and PTLC (ether:hexane=7:1) to obtain 56.7 mg (15.4%) of the title compound in the form of colorless oil.
Reaction SMILES: [F:1][CH2:2][C:3]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])([CH2:6][CH2:7][CH2:8][CH2:9][O:10]CC1C=CC=CC=1)[C:4]#[N:5].C[Si](I)(C)C.C(N(CC)CC)C.Cl>ClCCl.C(Cl)(Cl)Cl>[F:1][CH2:2][C:3]([N:18]1[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]2[C:22]1=[O:23])([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[C:4]#[N:5]
Reactant: N#CC(CF)(CCCCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#CC(CF)(CCCCO)N1C(=O)c2ccccc2C1=O
Yield: 76 %

Procedure:
A solution of 2-fluoromethyl-2-phthalimido-6-benzyloxyhexanenitrile (15.5 g, 40.8 mmol) and trimethylsilyliodide (13 ml, 2.2 equivalents) in dry dichloromethane (100 ml) is stirred at room temperature under nitrogen overnight. After removing the solvent under vacuum, the residue is dissolved in dry chloroform, triethylamine (17 ml, 3 equivalents) is added, and the mixture is refluxed for 30 minutes. Upon cooling, the solution is stirred with 2N HCl (250 ml) for 15 minutes, the phases are separated, and the organic layer is washed with sodium bicarbonate and with water. After evaporation, the residue is dissolved in THF and water (20 ml). Drops of 6N HCl are added, and the resulting mixture is stirred for several minutes. The solvent is removed by evaporation, and the residue obtained in dissolved in chloroform, washed with water, and dried. Removal of solvent gives the crude title compound as an oil (12 g). Chromatography on silica (300 g, eluant: ethylacetate) gives 2-fluoromethyl-2-phthalimido-6-hydroxyhexanenitrile (9.0 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>ClCCl>[Si:21]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(-c2ccc(CO)cc2OC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2OC)cc1

Procedure:
A solution of Example 417A (136 mg, 0.50 mmol), tert-butyldimethylsilyl chloride (91 mg, 0.60 mmol), and N,N-diisopropylethylamine (129 mg, 1.0 mmol) in dichloromethane (5 mL) at room temperature was stirred for 3 hours, and filtered through a pad of silica gel. The pad was rinsed with ether and the combined solutions were concentrated to provide the desired product.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O[C:9]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:19][C:18]1[C:9]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc(C)c1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(C)c1C(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
Pivaloyl chloride is added dropwise at 10°-15° C. to a stirred mixture of methyl 2-hydroxy-3-methylbenzoate and 4-dimethylaminopyridine in 25 ml of dichloromethane. After 2 hours at room temperature, the reaction is quenched with 200 ml of water. The organic layer is washed with 5% sodium bicarbonate, dried on anhydrous sodium sulfate and evaporated in vacuo. The product is purified by flash chromatography on silica gel.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([Cl:15])[N:7]=1.[H+].[B-](F)(F)(F)[F:18].[OH-].[Na+]>>[Cl:15][C:8]1[N:7]=[C:6]([F:18])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][NH:12]2
Reactant: F[B-](F)(F)F
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: Fc1nc(Cl)c2nc[nH]c2n1
Reaction time: 0.33 h

Procedure:
A 0.3 M aqueous solution of NaNO2 (200 mL, 60 mmol) was added dropwise to a cooled (−15° C.), vigorously stirred suspension of 2-amino-6-chloro-9H-purine (6.0 g, 35.4 mmol) in 120 mL HBF4 (48 w % in H20, 0.92 mol) over 75 min. The pale yellow reaction was stirred at r. t. for 20 min and then recooled to −15° C. and neutralized to PH=6.0 with aqueous NaOH (50 w % in H2O). The water was removed in vacuo and the resulting orange solid chromatographed on silica gel (90:10 CH2Cl2:MeOH, Rf 0.50). The final product was obtained as white solid (3.0 g, 49.1%).
Reaction SMILES: C([O:8][C:9](=[O:40])[C@H:10]([CH:37]([CH3:39])[CH3:38])[N:11]([C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1.C(OC(=O)[C@H](C(C)C)N(C(OCCCC)=O)CC1C=CC(C2C=CC=CC=2C#N)=CC=1)C1C=CC=CC=1.C([Sn](N=[N+]=[N-])(CCCC)CCCC)CCC>>[CH2:33]([O:32][C:30]([N:11]([C@H:10]([C:9]([OH:40])=[O:8])[CH:37]([CH3:38])[CH3:39])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1)=[O:31])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCOC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: CCCCOC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Product: CCCCOC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C

Procedure:
N-Carbobutoxy-N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine benzyl ester starting from 1.05 g of N-carbobutoxy-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester and 1.05 g of tributyltin azide and subsequent flash chromatography using the system N6. Amorphous product. TLC (system N6) Rf : 0.17.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>C(O)C>[CH2:12]([NH:14][C:15]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])=[S:16])[CH3:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CCN=C=S
Solvent: CCO
Product: CCNC(=S)NCCSCc1[nH]cnc1C
Yield: 86.4 %

Procedure:
(i) A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (6.9 g.) and ethyl isothiocyanate (3.84 g.) in ethanol was heated under reflux for 2 hours. Concentration followed by recrystallisation of the residue from aqueous ethanol gave N-ethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (9.0 g.), m.p. 140°-141°. (Found: C, 46.5; H, 7.1; N, 21.7; S, 25.1. C10H18N4S2 requries: C, 46.5; H, 7.0; N, 21.7; S, 24.8).
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:11]2[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl>CN(C)C=O>[C:29]1([S:35]([NH:38][C:26]([C:23]2[CH:24]=[CH:25][C:10]3[N:9]=[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:12]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=4[Cl:21])[C:11]=3[CH:22]=2)=[O:27])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc2nc(Cc3ccccc3)n(Cc3ccc(Cl)cc3Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc2nc(Cc3ccccc3)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
N,N′-carbonyldiimidazole (0.248 g) was added at a time to a solution of 0.315 g of 2-benzyl-6-carboxy-1-(2,4-dichlorobenzyl)benzimidazole in 5 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 0.240 g of benzenesulfonamide and 0.233 g of diazabicycloundecene in 4 ml of N,N-dimethylformamide was added thereto, and the mixture was stirred at 100° C. for 62 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. Water and chloroform were added to the residue, and 10% hydrochloric acid was added thereto while being mixed until the aqueous layer was acidified. The solution was extracted twice with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, and a part of the solvent was distilled off under reduced pressure. To the residue were added 4 ml of methanol and 4 ml of a 20% potassium hydrogencarbonate aqueous solution to form a uniform solution. This solution was then adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were separated through filtration, and were dried to give 0.310 g of 6-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)benzimidazole (244).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[C:19]([OH:21])(=[O:20])[CH3:18].[NH:11]1[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: CCOC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)COC1CCNCC1
Yield: 192.1 %

Procedure:
In a similar manner to Example 2, starting material step (c), the product from step (a) (2.3 g), ethanol (200 ml), glacial acetic acid (0.6 ml), 10% Pd on C (200 mg) and hydrogen gas were reacted to give ethyl piperidin-4-yloxyacetate, acetate salt (1.7 g), as a brown oil: NMR Spectrum (DMSO-d6) 1.20 (3H, t), 1.41 (2H, m), 1.82 (3H, s), 1.86 (2H, m), 2.58 (2H, m), 2.95 (2H, m), 3.46 (1H, m), 4.11 (4H, m); Mass Spectrum m/Z 188 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.[CH2:21]([Mg]Br)[CH3:22].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:21][CH3:22])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C=O)cnc21
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (117 mg, 0.360 mmol) in tetrahydrofuran (2 mL) was mixed with ethylmagnesium bromide-tetrahydrofuran solution (1.0 M, 1.0 mL, 1.0 mmol) under cooling with ice and stirred at room temperature for one day. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 (v/v)) to give the title compound as a colorless oil (75.6 mg, yield 62%).
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][CH2:28][NH2:29])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:29][CH2:28][CH2:27][C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Product: CCCCCCCCC#Cc1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-dec-1-ynylbenzaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 416.3. HPLC (Condition A), Rt: 4.91 min (HPLC purity: 72.4%).
Reaction SMILES: [Cl:1][N:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:15](OCC)=[O:16])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[ClH:1].[Cl:1][N:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH2:15][OH:16])[CH2:3]1
Reactant: CCOC(=O)C1=Cc2cc3c(cc2N(Cl)C1)OCO3
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1=Cc2cc3c(cc2N(Cl)C1)OCO3
Temperature: -5 °C
Reaction time: 2.5 h

Procedure:
56 g of Ethyl 5-chloro-1,3-dioxolo[4,5-g]quinoline-7-carboxylate (0.2 mol) are dissolved in 400 ml of anhydrous tetrahydrofuran. Nitrogen is passed through the flask and while stirring and cooling to -5° C., 5.7 g of lithium aluminum hydride are added a bit at a time in order to keep the reaction temperature below 0° C. Stirring is continued for an additional 2.5 hours. Then 360 ml of aqueous hydrochloric acid (3 N) are added while keeping the reaction temperature below 10° C. The precipitated title compound (40.5 g) is recrystallized from aqueous hydrochloric acid (3 N). Yield 38.1 g (70%), m.p. >300° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[C:15]([CH3:27])[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].[Br:36][CH2:37][CH2:38][CH2:39]Br.O>CN(C)C=O>[Br:36][CH2:37][CH2:38][CH2:39][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[C:15]([CH3:27])[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: BrCCCBr
Reactant: CCCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(O)c(OC)cc23)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1cc(C)c(Oc2ccnc3cc(OCCCBr)c(OC)cc23)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 1,3-dibromopropane(0.10 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-N′-propylurea). The intermediate, potassium carbonate (138 mg), and 1-methylpiperazine (0.055 ml) were dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 33 mg (yield 31%) of the title compound.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][O:6][CH2:5]1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[C:14]1([C:4]2([CH2:3][CH2:2][N:24]3[C:23](=[O:25])[C:22]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]4[C:20]3=[O:30])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][O:6][CH2:5]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ICCC1(c2ccccc2)COCc2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC1(c2ccccc2)COCc2ccccc21
Temperature: 0 °C
Reaction time: 14 h
Yield: 22.8 %

Procedure:
A mixture of synthesized 4-(2-iodoethyl)-4-phenylisochroman (0.5 g) and potassium phthalimide (0.51 g) was heated in DMF (10 ml) at 60° C. with stirring for 14 hours. The reaction mixture was then poured in ice-water and the syrup separating out was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate-hexane to provide the title compound (0.12 g) as colorless needless.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].[ClH:28]>C(OCC)(=O)C.O1CCOCC1>[ClH:28].[ClH:28].[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([N:12]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:13])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N(C)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CNCC[C@H]1N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of trans-4-(benzyl-methyl-amino)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (235 mg, 624 μmol) in ethyl acetate (2 mL) was stirred on an ice bath and treated with 4.0 N hydrogen chloride in dioxane (6 mL). The bath was removed, and the mixture was stirred at room temperature for 18 hours. The mixture was then concentrated under vacuum, and the residue was stirred in ether, and the ether was decanted. The ether treatment was repeated twice more, and the residue was dried under vacuum to provide a white powder (231 mg) which was used without purification. 1H NMR (300 MHz, methanol-d4) δ7.60 (m, 2H), 7.54 (m, 3H), 4.6-3.8 (m, 6H), 3.68 (m, 2H), 3.4-3.0 (m, 2H), 2.90 (s, 3H), 2.52 (m, 1H), 2.28 (m, 1H), 1.35 (m, 3H).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=[NH:23]>>[CH3:20][C:21]([C:22]1[N:23]=[CH:4][C:5]2[CH2:6][C:7](=[O:18])[NH:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[N:24]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Agent: Cl
Product: CC(C)(C)c1ncc2c(n1)-c1cc(F)ccc1NC(=O)C2
Yield: 54 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and 2,2-dimethylpropionamidine hydrochloride. Yield: 54%.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5](C#N)[C:6](=[O:12])[NH:7]2.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2
Reactant: Cc1nccc2[nH]c(=O)c(C#N)cc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1nccc2[nH]c(=O)ccc12

Procedure:
5-Methyl-1,6-naphthyridin-2(1H)-one also was prepared directly from the corresponding 3-cyano compound, as follows: A 650 g portion of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile was added with stirring at room temperature to a solution of 2100 ml 8 M sulfuric acid in 350 ml of water. The reaction mixture was stirred mechanically and refluxed (internal temperature at 215°-220° C.) for 24 hours. The dark solution was allowed to come to ambient temperature and poured on ice. The solution was stirred and basified with 6 l of concentrated ammonium hydroxide to pH 10.5, the internal temperature being maintained at 20°-30° C. during this addition. The dark beige solid was collected by filtration, washed with a minimum of cold water and dried in an oven chamber at 65° overnight. The crude product was recrystallized twice from water with decolorizing charcoal treatment to produce 330 g of 5-methyl-1,6-naphthyridin-2(1H)-one, m.p. 245°-246° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([OH:6])=O.OS(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:4](=[O:6])[CH2:3]1
Reactant: Cc1cccc(CC(C)CC(=O)O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)CC(C)CC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Methyl-4-m-tolylbutanoic acid (20.6 g, 107 mmol, dissolved in 125 mL DCM) was added slowly to triflic acid (250 g, 1.7 mol) that was pre-cooled to 0° C. under an Ar atmosphere. After 30 minutes, the volume of the reaction is doubled with DCM and poured slowly onto 1.5 L crushed ice. The resulting icy slurry is allowed to stir and come to room temperature over 1 hour. The resulting aqueous layer was extracted with DCM and the combined organics dried over anhydrous MgSO4, filtered and concentrated in vacuo. The procedure was repeated once and the two lots of crude product were combined and purified via elution on Isco silica gel column chromatography (0-15% EtOAc/hex) to afford 3,6-dimethyl-3,4-dihydronaphthalen-1(2H)-one. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H15O: 175.3. found: 175.4.