Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[S:8]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[OH:19])(=[O:10])=[O:9].[CH:37](=O)[CH:38]([CH3:40])[CH3:39].[BH4-].[Na+]>CO>[Cl:18][C:13]1[C:12]([OH:19])=[C:11]([S:8]([N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[C:3]([CH2:2][NH:1][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:4]=2)(=[O:10])=[O:9])[CH:16]=[C:15]([Cl:17])[CH:14]=1
Reactant: CC(C)C=O
Reactant: NCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
N-(3-(Aminomethyl)benzyl)-3,5-dichloro-N-((4′-fluorobiphenyl-4-yl)methyl)-2-hydroxybenzenesulfonamide (1.0 g, 1.8 mmol, 1.0 eq) was dissolved in dry methanol. The solution was stirred for 10 minutes and treated with isobutyraldehyde (145 mg, 2 mmol, 1.1 eq). The resulting mixture was stirred for 10 minutes at ambient temperature, refluxed for 3 h, cooled to 0° C. and treated with NaBH4 (210 mg, 5.5 mmol, 3 eq). The mixture was stirred for 30 min at 0° C., quenched by the addition of 10% aq. NaHCO3 solution and stirred for 1 h at ambient temperature. The solvent was evaporated under reduced pressure and ethyl acetate was added. The organic layer was washed with water and dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel (240-280) column chromatography using 10-20% ethyl acetate/hexane as the eluent to afford the desired product (1 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 0.92-0.94 (s, 6H), 2.0 (t, 1H), 2.67-2.69 (d, 2H), 4.0 (s, 2H), 4.43-4.44 (s, 4H), 7.15-7.16 (d, 2H), 7.22-7.30 (m, 6H), 7.35 (s, 1H), 7.48-7.53 (d, 2H), 7.63-7.64 (d, 1H), 7.65-7.67 (t, 2H). MS (ESI): 602.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5].[NH3:10]>>[CH3:5][O:4][Si:3]([CH2:2][NH:10][CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5])([O:8][CH3:9])[O:6][CH3:7]
Reactant: CO[Si](CCl)(OC)OC
Reactant: N
Product: CO[Si](CNC[Si](OC)(OC)OC)(OC)OC
Temperature: 100 °C

Procedure:
Chloromethyltrimethoxysilane (50.0 g., 0.29 mole) and ammonia (98.6 g., 5.80 mole) were charged to a 300 ml. stainless steel pressure vessel. The mixture was heated to 100° C. at 800 psi pressure for 8 hours and then cooled. The mixture was filtered. The crude product was distilled at 60° C. and 0.2 mm Hg pressure to produce N,N-bis-(trimethoxysilylmethyl)amine. The N,N-bis-(trimethoxysilylmethyl)amine so produced (3.0 g., 0.01 mole) was found to be greater than 95% pure by gas chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[C:16]([Cl:24])[CH:17]=[C:18]([Cl:23])[CH:19]=2)[NH:14][C:13]=1[S:25][CH3:26])=[O:11].[OH:27]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[C:16]([Cl:24])[CH:17]=[C:18]([Cl:23])[CH:19]=2)[NH:14][C:13]=1[S:25]([CH3:26])=[O:27])=[O:11]
Reactant: CSc1[nH]c2c(Cl)cc(Cl)cc2c(=O)c1C(=O)Nc1ccc(Cl)cc1Cl
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1[nH]c2c(Cl)cc(Cl)cc2c(=O)c1C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 75 °C

Procedure:
6,8-Dichloro-2-methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (2,4-dichloro-phenyl)-amide (Compound 3 in Scheme, 1.13 g, 2.52 mmol) in acetic acid was mixed with 30% hydrogen peroxide (0.57 g, 2 eq) and heated at 70-80° C. for 2 days upon agitation. The reactants were poured into iced water, filtered, washed with water and normal hexane and dried under vacuum. The resultant was used without further purification for next steps (yield: 1.1 g, 94%): 1H NMR (DMSO-d6) δ12.66 (bs, 1H) 8.54-8.19 (m, 4H) 7.61-7.41 (m, 2H) 3.10 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14]O)[C:10](=[O:16])[O:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][Cl:19])[C:10](=[O:16])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-n2oc(=O)n(CO)c2=O)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2oc(=O)n(CCl)c2=O)cc1

Procedure:
2-(4-Methylphenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(4-methylphenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][C:13]=3[CH3:20])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:21].B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[CH3:20])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: COc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)c(C)c1
Agent: BrB(Br)Br
Product: Cc1cc(O)ccc1-c1ccc2c(Cl)c(O)ccc2c1

Procedure:
The title compound was prepared by reacting 1-chloro-6-(4-methoxy-2-methylphenyl)-2-naphthol (400 mg, 1.41 mmol) with boron tribromide (4.0 mL of 1.0 M solution in CH2Cl2, 4.0 mmol) according to method D to yield 310 mg (77%) of a yellowish solid: mp 216-218° C.; 1H NMR (DMDO-d6): δ 2.20 (1H, s), 6.68 (1H, dd, J=8.19 Hz, J=2.42 Hz), 6.72 (1H, d, J=2.13 Hz), 7.10 (1H, d, J=8.16 Hz), 7.29 (1H, d, J=8.89 Hz), 7.29 (1H, d, J=8.89 Hz), 7.53 (1H, dd, J=8.78 Hz, J=1.62 Hz), 7.76 (1H, d, J=1.38 Hz), 7.80 (1H, d, J=8.94 Hz), 8.02 (1H, d, J=8.72 Hz), 9.4 (1H, s), 10.43 (1H, s); 13 NMR (DMDO-d6): δ 20.47, 112.20, 112.99, 117.00, 118.66, 121.85, 127.83, 128.09, 128.38, 129.47, 130.00, 130.88, 131.65, 136.09, 136.51, 150.88, 156.62; MS (ESI) m/z283/285(M−H)−.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH2:23])[CH2:16][CH2:15][CH2:14]1>O1CCCC1>[NH:23]1[C:21]2=[C:22]3[C:17](=[CH:18][CH:19]=[CH:20]2)[CH2:16][CH2:15][CH2:14][N:13]3[C:1]1=[O:2]
Reactant: Nc1cccc2c1NCCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc3c2n1CCC3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1,1′-carbonyldiimidazole in tetrahydrofuran was added to a solution of 1,2,3,4-tetrahydro-8-quinolineamine (10 g) obtained in Reference Example 130 in tetrahydrofuran (100 ml), and the mixture was stirred at room temperature at 4 hours. The reaction mixture was concentrated to give a brown solid (11 g). Further recrystallization from water-ethyl estate afforded the title compound as colorless crystals (10 g).
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[NH2:20][CH2:21][CH2:22][SH:23].C(N(CC)CC)C.S(=O)(=O)(O)O>CO>[S:23]1[CH2:22][CH2:21][NH:20][CH:1]1[CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NCCS
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(C)=O)C1NCCS1
Yield: 73.8 %

Procedure:
In 20 ml of methanol was dissolved 2.0 g of N-acetyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 16-(c), and 800 mg of 2-aminoethanethiol, 1.0 ml of triethylamine, and a catalytic amount of concentrated sulfuric acid were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 1.8 g of the titled compound as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].Cl.[CH3:17][NH:18][O:19][CH3:20].N1C=CC=CC=1>C(O)C>[CH3:20][O:19][N:18]([CH3:17])[C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: CNOC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cc(C(=O)N(C)OC)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Dissolve 3,4,5-trimethoxybenzoyl chloride (2.3 g, 10 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.10 g, 11 mmol) in ethanol-free chloroform at room temperature. Cool the solution to 0° C. and add pyridine (1.85 g, 22 mmol). Stir at ambient temperature for 1 hour and evaporate the solvent in vacuo. Partition the residue between aqueous sodium chloride and a 1:1 mixture of ethyl ether and methylene chloride. Separate the organic phase, dry (Na2SO4), and evaporate the solvent in vacuo to yield an oil. Filter the oil through silica gel eluting with 65% ethyl acetate/hexane to yield 2.5 g of N-methoxy-N-methyl-(3,4,5-trimethoxy)benzamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=1.Cl.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[O:30]=[C:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][S:12]([C:10]3[S:11][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:8][CH:9]=3)(=[O:14])=[O:13])=[CH:19][CH:20]=2)[CH2:25][CH2:26]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: Cl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2)CC1

Procedure:
The title compound was prepared from 5-pyridin-2-yl-thiophene-2-sulphonyl chloride and 1-(4-amino-phenyl)-piperidin-4-one (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (t, J=6.0 Hz, 4 H), 3.52 (t, J=6.0 Hz, 4 H), 6.89 (d, J=9.0 Hz, 2 H), 7.02 (d, J=9.0 Hz, 2 H), 7.39 (dd, J=4.2, 1.5 Hz, 1 H), 7.42 (d, J=2.1 Hz, 1 H), 7.76 (d, J=2.1 Hz, 1 H), 7.90 (dd, J=7.8, 1.5 Hz, 1 H), 8.00 (d, J=7.8 Hz, 1 H), 8.53 (d, J=4.2 Hz, 1 H), 10.05 (s, 1 H); MS (ES) m/z: 413.9 (MH+); HRMS Calcd. for C20H19N3O3S2 (M+): 413.0867. Found: 413.0877.
Reaction SMILES: [CH2:1]([C:8]1(O)[CH2:20][CH2:19][C:11]2(OCC(C)(C)C[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:8]1[CH2:20][CH2:19][C:11](=[O:12])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COC2(CCC(O)(Cc3ccccc3)CC2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.1 %

Procedure:
To a solution in toluene (44.0 mL) of the compound (1.28 g) obtained in step (1) above, p-toluenesulfonic acid monohydrate (84.0 mg) was added and thereafter the mixture was refluxed for 3 hours with a Dean-Stark apparatus. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50). A suspension of the resulting purified product (935 mg) and 20% palladium hydroxide/carbon (93.5 mg) in methanol (11.3 mL) was stirred at room temperature for 5 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure. To a solution of the resulting residue (938 mg) in tetrahydrofuran (34.3 mL), 1 mol/L hydrochloric acid (9.30 mL) was added at 0° C. and the mixture was stirred at room temperature for 14.5 hours. After concentrating the stirred mixture under reduced pressure, three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine. After passage through a phase separator, the washed organic layers were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-50:50) to give the titled compound as a colorless oil (225 mg).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:19]([CH:16]3[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][O:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:2])=[O:29])[CH2:18][CH2:17]3)=[CH:20]2)[CH2:34][CH2:33]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CC3CC3)c3cc(F)ccc23)CC1

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 2 g (5.1 mmol) of 2-{2-[4-(6-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester, 0.51 g (12.8 mmol) of NaH 60% in mineral oil and 0.99 mL (10.2 mmol) of cyclopropylmethyl bromide. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by flash chromatography over silica gel affording 0.32 g (18% of yield) of the desired product.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=[C:32]([CH2:34][OH:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:35][CH2:34][C:32]1[CH:33]=[C:28]([NH:27][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=1
Reactant: COC(=O)CCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1cc(CO)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCNc1cc(CO)cc(CO)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To a mixture of methyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (263a) (250 mg, 0.640 mmol) and (5-amino-1,3-phenylene)dimethanol (26) (108 mg, 0.704 mmol) in anhydrous DMF (1.4 ml) was added potassium carbonate (133 mg, 0.960 mmol). The reaction stirred for 18 hours at 80° C. and then was allowed to cool to room temperature. The mixture was quenched with water and extracted two times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% Methanol/methylene chloride) yielded methyl 3-(2-(2-(2-(3,5-bis(hydroxymethyl)phenylamino)ethoxy)ethoxy)ethoxy)propanoate (264a) (61 mg, 25%); 1H NMR (400 Hz, CDCl3): δ 6.58 (s, 1H), 6.47 (s, 2H), 4.49 (s, 4H), 3.67 (t, J=6.4 Hz, 2H), 3.62 (s, 3H), 3.64-3.54 (m, 10H), 3.21 (t, J=5.2 Hz, 2H), 2.51 (t, J=6.4 Hz, 2H); MS (m/z). found 394.3 (M+Na)+.
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: O
Solvent: CN(C)C=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: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCCCCC.[C:16]1([C:26](Cl)=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>O1CCCC1.C([Li])CCC>[C:16]1([C:26]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[CH:5][C:6]=2[Cl:8])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Cc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(C(=O)c2cccc3ccccc23)c(Cl)c1
Temperature: -60 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
To a stirred, cold (-60° C.) solution of 3,5-dichlorotoluene (3.5 g, 21.7 mmol) in dry tetrahydrofuran (30 ml), 2.6 M n-butyllithium in hexane (8.78 ml, 22.8 mmol) was added dropwise over 15 minutes. The reaction mixture was stirred for one hour at -60° C. and then treated with a solution of 1-naphthoyl chloride (4.14 g, 21.7 mmol) in 15 ml of dry tetrahydrofuran over a period of 15 minutes. The mixture was stirred for 3.5 hours at -60° C. and then quenched with 4.8 ml of saturated NH4Cl solution. The mixture was permitted to warm to room temperature and then diluted with 30 ml of water and 30 ml of ether. The layers were thoroughly mixed and then separated. The etheral layer was backed-washed with brine and dried with anhydrous magnesium sulfate. Concentration afforded 7.12 g of crude product which was chromatographed on silica gel (20:1 hexane:ethyl acetate) to give 1.59 g (23 %).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][C@@H:13]([CH3:15])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:9]2=3)=[N:6][CH:7]=1.Br[C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][C@@H:13]([CH3:15])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][C:22]([C:34]4[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=4)=[CH:23][C:9]2=3)=[N:6][CH:7]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1nnc2n1-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3cnc(N)cn3)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
To a solution of (R)-6-(5-chloropyridin-2-yl)-1,4-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine in 1,4-dioxane/H2O (10:1, 5 mL) were added 5-bromopyrazin-2-amine (69.33 mg, 0.40 mmol), Cs2CO3 (197.3 mg, 0.61 mmol) and Tetrakis(triphenylphosphine)palladium(0) (24.1 mg, 0.033 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 20 min. The reaction solution was concentrated and purified by prep-TLC (elute: DCM:CH3OH=15:1) to give (R)-5-(6-(5-chloropyridin-2-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyrazin-2-amine (110 mg, 59%).
Reaction SMILES: C(#N)C.[CH2:4]([OH:7])[C:5]#[CH:6].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([F:18])[C:16]=1F)[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>O>[F:18][C:15]1[CH:14]=[C:11]([CH:10]=[C:9]([F:8])[C:16]=1[O:7][CH2:4][C:5]#[CH:6])[CH:12]=[O:13]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: C#CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCOc1c(F)cc(C=O)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 102 %

Procedure:
To 50 ml of acetonitrile were added 12 g of propargyl alcohol, 16 g of 3,4,5-trifluorobenzaldehyde and 15 g of potassium carbonate, and the mixture obtained was stirred at room temperature for 1 day. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 20 g of 3,5-difluoro-4-(2-propynyloxy)benzaldehyde represented by the formula:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[CH:9][CH:8]=2)=[C:4]([CH3:24])[CH:3]=1.[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].CCN(CC)CC>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:6][C:2]([CH2:26][CH2:25][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:3][C:4]=2[CH3:24])=[CH:8][CH:9]=1)=[O:23]
Reactant: Cc1cc(Br)sc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CCc2cccnc2)sc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1

Procedure:
N-(4-(5-bromo-3-methylthiophen-2-yl)phenyl)-2,6-difluorobenzamide (a, 1 mmol), 3-ethynylpyridine (1 mmol), CuI (0.05 mmol), PdCl2(PPh3)2 (0.05 mmol) in THF (6 mL), and Et3N (3 mL) was heated in sealed tube at 100° C. for 1 h. The mixture was filtered through celite and purified by column chromatography to give a white solid (b, 46 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[CH:13][C:14](F)=[C:15]([CH:18]=1)[C:16]#[N:17]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OC1CCOCC1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To a solution of tetrahydro-pyran-4-ol (3.3 g, 33.0 mmol) in DMF (60 ml) at 0° C. is added sodium hydride (1.4 g, 33.0 mmol). 5-Bromo-2-fluoro-benzonitrile (5.5 g, 27.5 mmol) in DMF (30 ml) is added dropwise at 0° C. The reaction is stirred at 45° C. for 16 h. The reaction is cooled to room temperature and quenched by pouring the reaction into water (500 ml). The precipitate is filtered and dried under vacuum; yield: 6.8 g 5-bromo-2-(tetrahydro-pyran-4-yloxy)-benzonitrile; HPLC/MS: 2.27 min, [M+H]=283.