Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[O:9]([C:8]1[CH:7]=[CH:6][C:5]([B:16]2[O:20][C:19]([CH3:21])([CH3:22])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:4][C:3]=1[OH:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Oc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(Oc3ccccc3)c(O)c2)OC1(C)C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-methoxy-4-phenoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (50 mg, 0.0002 mol) in DCM (3 mL) was slowly added boron tribromide (0.145 mL, 0.00153 mol) at −20° C. The reaction was stirred at that temperature for 2 h. The reaction mixture was concentrated in vacuo and dried on the pump. The crude reaction mixture was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][C:31]([CH3:36])([CH2:34][OH:35])[CH2:32][OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:30][C:31]([CH2:34][OH:35])([CH3:36])[CH2:32][OH:33])[N:13]=1
Reactant: CC(N)(CO)CO
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Product: CC(CO)(CO)Nc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
The product of Example 47, and 2-amino-2-methylpropane 1,3-diol were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 1.01 (s, 3H), 3.43 (m, 2H), 3.62 (m, 2H), 6.03 (br s, 1H), 6.41 (d, 1H, J=9.6 Hz), 7.27-7.65 (m, 9H). LC MS (m/e)=471 (MH+).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6]1([CH3:15])[CH:11]=[CH:10][C:9]([C:12](Cl)=[O:13])=[CH:8][CH:7]=1.[Si]([C:20]#[N:21])(C)(C)C>C(Cl)Cl>[C:6]1([CH3:15])[CH:11]=[CH:10][C:9]([C:12]([C:20]#[N:21])=[O:13])=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)C#N)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
A 1 M solution of tin chloride in CH2Cl2 (1.3 mL, 1.3 mmol) was added dropwise to an ice water cooled solution of p-toluoyl chloride (10.00 g, 65 mmol) and TMSCN (9.00 mL, 68 mmol). The reaction was monitored to completion over 4 hours by disappearance of the IR acid chloride carbonyl stretch, then quenched by addition of ice water (20 mL) and extracted with CH2Cl2. The organic solution was dried (MgSO4) and concentrated to afford 8.80 g of p-toluoyl cyanide as an orange solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C1CCN2C(=NCCC2)CC1.[CH2:39]([O:46][C:47](Cl)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CO>[CH2:39]([O:46][C:47]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: O=C(O)CCCCCCCCCCCCCCCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To D6 (0.500 g, 1.30 mmol) and DBU (794 mg, 5.21 mmol) in refluxing methanol (100 ml) was added neat benzylchloroformate and the reaction refluxed for 3 hours until complete conversion of D6 to either the protected amino acid D19 or its methyl ester was observed. The solvent was removed and the residues taken up into dioxane (60 ml) and water (2 ml) and lithium hydroxide (1 g) added. The reaction was then refluxed for 2 hours until hydrolysis of the methyl ester derivative to D19 was complete. The solvent was removed, the residues suspended in 1M HCl (100 ml) and extracted with hot ethyl acetate (300 ml). The hot ethyl acetate was dried (MgSO4) and the solvent volume reduced to 40 ml. The solution/suspension was left at −10° C. for 1 hour, allowed to warm to room temperature and the resulting white precipitates filtered off and dried under vacuum to yield the title compound (585 mg, 87%). M.Pt 102-104° C. C32H55NO4 requires 517.4. Found ES−: MCI−, 552.6. δH (d6DMSO), 1.32 (38H, s, (CH2)19(CH2)2N), 1.52 (2H, p, CH2CH2CO2H), 1.65 (2H, p, CH2CH2NH), 2.35 (2H, t, CH2CO2H), 3.18 (2H, t, CH2N), 5.14 (2H, s, CH2Ph), 7.35 (5H, m, Ph).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[N:12](OCCC(C)C)=[O:13].Cl.O1CCOCC1>C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12][OH:13])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)CCON=O
Reactant: Cc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)C(=O)C(=NO)C2

Procedure:
6-Methyl-1-indanone (40.4 g) and isoamyl nitrite (40.6 mL) were dissolved in ethanol (300 mL), and 4N hydrogen chloride-dioxane (10 mL) was added dropwise under ice-cooling. After the completion of the reaction, the precipitated crystals were collected by filtration and washed with ether to give 6-methyl-2-hydroxyimino-1-indanone (37 g).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:22][CH2:23][CH:24]([OH:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCC(O)c1ccccc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: OC(CNC[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1)c1ccccc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-amino-1-phenylethanol in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=423.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:33]3[CH:32]=[N:31][C:30]([CH3:29])=[N:35][CH:34]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)([CH3:13])[CH3:12]
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cnc(C)nc2)cc2c1cnn2C(C)C
Temperature: 110 °C
Yield: 41.7 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.23 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (64.2 mg, 0.29 mmol) in dioxane/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 adduct (9.2 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (56.6 mg, 0.67 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 110° C. for min. The mixture was evaporated, DCM/MeOH (1:1) was added, and the contents pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was suspended in acetonitrile along with a few drops of EtOH and some hexanes. The contents were sonicated, and solids that precipitated were filtered and dried to afford the title compound as an off-white solid (44 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H) 9.21 (s, 2H) 8.63 (t, J=4.80 Hz, 1H) 8.43 (s, 1H) 8.32 (s, 1H) 7.94-7.96 (m, 1H) 5.92 (s, 1H) 5.17 (quin, J=6.63 Hz, 1H) 4.43 (br. s., 1H) 4.42 (br. s., 1H) 2.69 (s, 3H) 2.52-2.56 (m, 2H) 2.14 (s, 3H) 1.49-1.55 (m, 8H) 0.88 (t, J=7.33 Hz, 3H); LC-MS (ES) m/z=459.2
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1F
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1F

Procedure:
1-(5-(4-Fluoro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was prepared from 2-(4-fluoro-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a pale yellow solid (0.072 g, 16% yield). MS: m/z 456.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1B(O)O.[NH2:13][C:14]1[C:19](Br)=[N:18][CH:17]=[C:16]([Cl:21])[N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC=CC=1>[NH2:13][C:14]1[C:19]([C:3]2[CH:4]=[C:5]([Cl:9])[CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[N:18][CH:17]=[C:16]([Cl:21])[N:15]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Reactant: Nc1nc(Cl)cnc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Nc1nc(Cl)cnc1-c1cc(Cl)cc(Cl)c1Cl

Procedure:
A solution of 2,3,5-trichlorobenzeneboronic acid (1.62 g, 7.18×10−3 mole) in absolute ethanol (2.05 ml) was added slowly to a mixture of 2-amino-3-bromo-6-chloropyrazine (1 g, 5.1×10−3 mole) and tetrakis(triphenylphospine)palladium(0) (0.334 g,2.89×1−4 mole) in benzene (10.20 ml)/2M aqueous sodium carbonate (5.50 ml). The mixture was refluxed for 17 hrs. The cooled reaction mixture was evaporated in vacuo and then extracted with chloroform (50 ml). The chloroform layer was washed with water (2×30 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo. The residue was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 0.205 g (14%), M.p. 211-214° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([OH:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:11][C:10]([C:7]1[S:6][C:5]2[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][C:4]=2[C:8]=1[CH3:9])=[O:12])[CH3:21]
Reactant: Cc1c(C(=O)O)sc2ccc(Br)cc12
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1sc2ccc(Br)cc2c1C

Procedure:
A mixture of 5-bromo-3-methylbenzo[b]thiophene-2-carboxylic acid (5.80 g.), ethanol (500 ml.) and concentrated sulphuric acid (2 ml.) was heated under reflux for 48 hours, and then evaporated. Dilute aqueous ammonia solution was added and the solid was filtered off, washed well with water and dried to give 5-bromo-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (5.70 g.), m.p. 87°-88° C., raised to 88°-89° on crystallization from petrol (b.p. 80°-100°).
Reaction SMILES: [C:1]1([C:7]#[C:8]C#C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].BrC1C=CC(C=C)=CC=1.Cl[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH:7]([C:1]1[CH:2]=[CH:3][C:4]([P:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][CH:6]=1)=[CH2:8]
Reactant: C#CC#Cc1ccccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: C=Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Polymerizable Gold Complex (3-1) was synthesized by reacting the gold complex obtained by the reaction between sodium tetrachloroaurate (III) and triphenylphosphine having a polymerizable functional group, with phenylbutadiyne synthesized by a known method (see, P. Cadiot and W. Chodkiewicz, Chemistry of Acetylenes, H. G. Viehe, ed., Marcel Dekker, New York (1969)). More specifically, 20 ml of dried THF was added to 341 mg (14 mmol) of magnesium and thereto, a 10 ml THF solution containing 2.70 g (15 mmol) of 4-bromostyrene was added dropwise to prepare a Grignard reagent. To the resulting solution, a 10 ml THF solution containing 2.50 g (11 mmol) of chlorodiphenylphosphine was added dropwise and stirred at room temperature of 1.5 hours. After removing the solvent by distillation under reduced pressure, the residue was purified by silica gel column chromatography and recrystallized from a hexane solution to obtain 2.30 g (8.3 mmol) of (4-vinylphenyl)diphenylphosphine Compound (B).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:30][O:31][C:32](=[O:46])[C:33]1[CH:38]=[CH:37][C:36]([NH:39][CH:40]([CH2:43][CH3:44])[CH2:41][CH3:42])=[C:35]([NH2:45])[CH:34]=1>CN(C=O)C.O.C(Cl)CCl>[CH3:30][O:31][C:32](=[O:46])[C:33]1[CH:38]=[CH:37][C:36]([NH:39][CH:40]([CH2:41][CH3:42])[CH2:43][CH3:44])=[C:35]([NH:45][C:8](=[O:10])[CH2:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:34]=1
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1N
Reactant: O=C(O)Cc1ccc(Cl)s1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 1.00 g of 5-Chlorothiophen-2-yl-acetic acid in 15 ml of dry DMF 0.84 g of HOBT, 1.19 g of EDC and 1.5 ml of DIPEA were added at 0° C. After 30 min 1.33 g of 3-amino-4-(1-ethyl-propylamino)-benzoic acid methyl ester and 1.5 ml of DIPEA were added and the reaction was stirred at rt for 16 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. The crude product was purified by crystallization from diethylether to yield 2.00 g (89%) of 3-[2-(5-Chloro-thiophen-2-yl)-acetylamino]-4-(1-ethyl-propylamino)-benzoic acid methyl ester.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:4]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([NH:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:4]1)(=[O:33])=[O:34]
Reactant: NC1CCN(C(=O)C2CCN(c3ccncc3)CC2)C1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCC(NS(=O)(=O)c2ccc3ccccc3c2)C1
Yield: 37 %

Procedure:
Using an analogous procedure to that described in Example 2, 3-amino-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]pyrrolidine hydrochloride salt was reacted with 2-naphthylsulphonyl chloride to give 3-(2-naphthalenesulphonamido)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]pyrrolidine in 37% yield;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.N=CO[CH2:34][NH:35][C:36](=[O:39])[O:37][CH3:38].C(O)(=O)C>ClC(Cl)Cl>[C:19]1([CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][N:8]3[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[N:1]=[C:34]3[NH:35][C:36](=[O:39])[O:37][CH3:38])[CH2:17][CH2:16]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COC(=O)NCOC=N
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 60 parts of N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine, 20 parts of methyl (iminomethoxymethyl)carbamate, 42 parts of acetic acid and 450 parts of trichloromethane is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is stirred in water. The latter is decanted and the residue is taken up again in water. The whole is alkalized with a diluted ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding methyl [1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1H-benzimidazol-2-yl]carbamate; mp. 137.8° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23.ClCCl.C(N(CC)CC)C.[C:30](Cl)(=[O:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>O.CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:36])[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23
Reactant: NCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 0 °C
Reaction time: 10 h
Yield: 21.1 %

Procedure:
To a solution of 9-bromo-5-aminomethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione hydrochloride (300 mg, 0.866 mmol)in a 1:1 mixture of dichloromethane and DMF (10 mL)in the presence of triethylamine (0.3 mL, 2.16 mmol) was added ethyl chlorooxalate (0.102 mL, 0.909 mmol) at 0° C. The mixture was stirred for 15 min at 0° C. and for 10 h at room temperature and then water was added. The mixture was extracted with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid to pH 1 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residual solid was recrystallized from ethanol-ether to give 75 mg of the title compound (21%): mp 214.5~220.5° C.; 1H NMR (270 MHz, DMSO-d6) δ12.01 (s, 1H), 9.11 and 9.04 (two triplet, 1H, J=6 Hz), 7.19 (s, 1H), 7.14 (s, 1H), 4.98~5.07 (m, 1H), 4.21 (q, 2H, J=7.5 Hz), 3.17~3.57 (m, 2H), 3.01 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.79, (dm, 1H, J=17.1 Hz), 2.10 (dm, 1H, 13.5 Hz), 1.70~1.85 (m, 1H), 1.26 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[N:18]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CCO>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:26][CH2:25][CH2:24][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCN1CCOCC1
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCCN2CCOCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (1.00 g, 4.16 mmol), 2-(4-morpholinyl)ethanamine (0.600 mL, 4.58 mmol) in 80% aq. EtOH (50 mL) was refluxed for 4 hours. The reaction was then concentrated in vacuo, and the residue was taken up into EtOAc (40 mL). The organic phase was washed with saturated NaHCO3 (2×10 mL), and the combined aqueous phases were extracted with additional EtOAc (2×20 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound. The crude product was purified by silica gel column chromatography (100% EtOAc to 5% triethylamine/EtOAc) to provide the title compound (1.12 g, 77%) as a bright yellow solid. 1H-NMR (CDCl3): δ 8.67 (s, 1H), 8.28 (d, J=1.2 Hz, 1H), 7.56 (dd, J=8.8 Hz, J=1.6 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 3.77 (t, J=5.2 Hz, 4H), 3.55–3.20 (br m, 6H), 2.74 (t, J=6.4 Hz, 2H), 2.53 (br s, 4H), 1.22 (t, J=6.8 Hz, 6H). MS (ESI) (M+H)+=351.
Reaction SMILES: C([O-])(C)(C)C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]=[C:18](Cl)[C:19]([F:22])([F:21])[F:20]>C(O)(C)(C)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[C:17]#[C:18][C:19]([F:20])([F:22])[F:21]
Reactant: COc1cccc(OC)c1C=C(Cl)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1cccc(OC)c1C#CC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
30.7 g of potassium tertiary butanolate in 900 ml of tertiary butanol are introduced into a 1.5 l sulfonating flask with a thermometer, condenser, bubble counter and dropping funnel. 63.7 g (0.25 mole) of 1,3-dimethoxy-2-(2-chloro-3,3,3-trifluoroprop-1-enyl)-benzene in 100 ml of tertiary butanol are added dropwise to this clear, colourless solution (weakly exothermic) and the reaction is brought to completion by stirring at room temperature for 24 hours. The orange suspension is poured onto ice and extracted with ether and the extract is washed with water, N bicarbonate solution and brine, dried over magnesium sulfate and concentrated until crystals precipitate. The crystal mass is cooled, filtered cold and washed with a little ice-cold petroleum ether. 1,3-Dimethoxy-2-(3,3,3-trifluoroprop-1-ynyl)-benzene is obtained in the form of pale beige, fine crystals of melting point 110°-111° (yield 73%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]([O:18][CH2:19][C@@:20]1([CH2:34][CH2:35]Br)[CH2:24][N:23]([C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[C:22](=[O:33])[CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:38]([O:40][CH3:41])=[O:39].[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[CH3:41][O:40][C:38]([C@@:21]12[CH2:35][CH2:34][C@:20]1([CH2:19][O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:24][N:23]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[C:22]2=[O:33])=[O:39]
Reactant: COC(=O)Cl
Reactant: C[C@H](c1ccccc1)N1C[C@](CCBr)(COCc2ccccc2)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@]12CC[C@]1(COCc1ccccc1)CN([C@H](C)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
A 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (14.5 mL, 14.5 mmol) was added to a solution of (4S)-4-benzyloxymethyl-4-(2-bromoethyl)-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (2.75 g, 6.60 mmol) and methyl chloroformate (0.54 mL, 6.93 mmol) in tetrahydrofuran (20 mL) in a nitrogen atmosphere at 0° C. The mixture was stirred for 12 hours while gradually heating to room temperature. The reaction solution was cooled to 0° C. A saturated ammonium chloride solution (5 mL) was added, and the mixture was stirred for 10 minutes. Then, the reaction solution was poured into a mixture of ethyl acetate (100 mL) and water (50 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL) and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→2:1→1:1) to give 2.12 g (82%) of the title compound as a pale yellow oil.