Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[O:11][CH:12]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[O:11][CH:12]=1
Reactant: COC(=O)CCCCc1coc(-c2ccccc2OC)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CCCCc1coc(-c2ccccc2O)n1
Yield: 48.4 %

Procedure:
Using a method similar to that described in Example 165, 5-[2-(2-methoxy-phenyl)-oxazol-4-yl]-pentanoic acid methyl ester (1.65 g, 5.7 mmol) with boron tribromide (1.0 M in CH2Cl2, 17.2 m/L) in CH2Cl2 gives 5-[2-(2-hydroxy-phenyl)-oxazol-4-yl]-pentanoic acid methyl ester (0.76 g, 48%). MS (ES): (M+1)+ 276.1, 277.2 m/z.
Reaction SMILES: Cl[C:2]1[C:3]([S:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])([N+]([O-])=O)[CH2:6][CH:7]=1.[NH2:22][CH2:23][CH2:24][NH2:25]>C(O)(C)C>[NH2:22][CH2:23][CH2:24][NH:25][C:2]1[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[S:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15]
Reactant: NCCN
Reactant: O=C(O)CCS(=O)(=O)C1=CC([N+](=O)[O-])([N+](=O)[O-])CC=C1Cl
Solvent: CC(C)O
Product: NCCNc1ccc([N+](=O)[O-])cc1S(=O)(=O)CCC(=O)O
Temperature: 0 °C

Procedure:
29.5 g of 3-(2-chloro-5-nitro-5-nitrophenylsulphonyl)propionic acid and 15 g of 1,2-diaminoethane are refluxed in 150 ml of isopropanol for two hours. The reaction mixture is cooled down to 0° C. and filtered with suction. The isolation is suspended in 100 ml of water, the suspension is brought to pH 3.5, and 15 g of sodium chloride are added for salting out. The precipitated betaine is filtered off with suction and dried. The yield of 3-[2-(-aminoethyl)amino-5-nitrophenylsulphonyl]-propionic acid is 28.5 g.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=2)[N:3]=1.Cl.[CH3:24][NH2:25].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=3)[N:3]=[C:2]([NH:25][CH3:24])[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(C)cc23)cc1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CNc1nc(N(C)c2ccc(OC)cc2)c2cc(C)ccc2n1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
A solution of (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxyphenyl)-methyl-amine (62.9 mg, 0.20 mmol), methylamine hydrochloride (145.8 mg, 2.2 mmol) and Na2CO3 (234.5 mg, 2.2 mmol) in i-PrOH (2 mL) was heated to 100° C. overnight. After cooling to room temperature the reaction mixture was concentrated onto SiO2 and purified by gradient MPLC (SiO2, 0 to 20% MeOH/CH2Cl2 with 0.1% NH4OH, 20 min). 20.3 mg (33%) of the title compound was obtained: 1H NMR (DMSO-d6, 90° C.) δ 7.93 (br s, 1 H), 7.38-7.52 (m, 2 H), 7.33 (d, 2 H), 7.08 (d, 2 H), 6.39 (s, 1 H), 3.83 (s, 3 H), 3.62 (s, 3 H), 3.06 (s, 3 H), 1.96 (s, 3 H). HRMS (ES) calcd for C18H21N4O [(M+H)] 309.1710, found 309.1714.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[N:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[N:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=c1cnc(Br)cn1Cc1ccc(Cl)cc1
Product: COc1ccc(-c2cn(Cc3ccc(Cl)cc3)c(=O)cn2)cc1
Yield: 70.1 %

Procedure:
According to Scheme 27 Step 2: The title compound was prepared from 1-(4-chlorobenzyl)-5-bromopyrazin-2(1H)-one (1 eq, 0.67 mmol, 0.20 g) and 4-methoxyphenylboronic acid (1.5 eq, 1.00 mmol, 0.15 g) according to the procedure described for Example 1 Step 3. Reaction conditions: 1 hour at 80° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/MeOH (98/2) as the eluent to afford 1-(4-chlorobenzyl)-5-(4-methoxyphenyl)pyrazin-2(1H)-one (0.47 mmol, 0.15 g, 71%) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4cccc(Cl)c4)CC3)c(OC)nc2c1
Yield: 85 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 4H), 3.74 (s, 4H), 3.90 (s, 3H), 4.13 (s, 4H), 6.78-6.89 (m, 3H), 7.15-7.27 (m, 4H), 7.73 (d, J=9.7 Hz, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.[Br:55][C:56]1[CH:61]=[CH:60][C:59](I)=[CH:58][N:57]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[Br:55][C:56]1[N:57]=[CH:58][C:59]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[CH:60][CH:61]=1
Reactant: Brc1ccc(I)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tris(dibenzylideneacetone)dipalladium (840 mg) and 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (1.6 g) and sodium tert-butoxide (6.6 g) were added to a solution of morpholine (2 ml) and 2-bromo-5-iodo-pyridine (7.8 g) in toluene (230 ml), and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Water and ethyl acetate were added to the mixture and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give the titled compound (5.07 g). MS (m/z): 243/245 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:13](OCC)=[O:14])[NH:10]2)=[CH:6][C:5]=1[Cl:24].O.C(O)(=O)C.[CH3:30][S:31]([CH3:33])=[O:32]>C1C=CC=CC=1>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:13](=[O:14])[CH2:30][S:31]([CH3:33])=[O:32])[NH:10]2)=[CH:6][C:5]=1[Cl:24]
Reactant: CS(C)=O
Reactant: CCOC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)CC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Stir sodium hydride (13 g) in a mixture of dimethylsulfoxide (100 ml) and benzene (100 ml), and heat at 65°-75° for 2 hours under nitrogen. To this mixture add ethyl 6-bromo-5-chloro-3-phenylindole-2-carboxylate in dimethylsulfoxide (50 ml) and benzene (30 ml) at 15°-20° and stir the mixture at room temperature for one hour. Cool the resulting mixture to 15° C. add 50 ml of water (very slowly) and then add an additional 550 ml of water. Add 25 ml of acetic acid, stir and then filter. Wash the resulting solid with water and then hexane. Crystallize the desired product from methanol-methylene chloride to obtain 6-bromo-5-chloro-2[(methylsulfinyl)acetyl]-3-phenylindole, m.p. 169°-170°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21])[C:16](O)=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:46][C:47]1[NH:51][N:50]=[N:49][N:48]=1>ClCCl.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH2:25]([O:24][C:22](=[O:23])[C@@H:20]([NH:19][C@H:15]([C:16](=[O:17])[NH:46][C:47]1[NH:51][N:50]=[N:49][N:48]=1)[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:21])[CH3:26]
Reactant: Nc1nnn[nH]1
Reactant: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a suspension of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid (4.0 g, 10.84 mmol) in dichloromethane (60 mL) and saturated aqueous NaHCO3 (10 mL) was added triphosgene (1.90 g, 6.39 mmol). After vigorously stirred for 0.5 hour, the reaction mixture was diluted with EtOAc and partially concentrated under reduced pressure. Excess of triphosgene was quenched by adding saturated aqueous NaHCO3 and stirred for 0.5 hour. The mixture was extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (50 mL). To the mixture was added triethylamine (1.93 mL, 13.8 mmol) and 5-amino-1H-tetrazole (1.18 g, 13.84 mmol) at 0° C., and the reaction mixture was gradually warmed to room temperature. After stirred for 2 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (eluent: 10% MeOH in dichloromethane) to give a mixture of the desired trans isomer product and the cis isomer. The obtained material was re-crystallized from CH3CN three times to give (S)-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester (3.92 g). 1H NMR (400 MHz, DMSO-d6) δ 1.11 (t, 3H, J=7.1 Hz), 1.15 (d, 3H, J=6.8 Hz), 2.89 (dd, 1H, J=8.1, 13.7 Hz), 3.02 (dd, 1H, J=5.8, 14.0 Hz), 3.27-3.36 (m, 1H), 3.75-3.83 (m, 1H), 4.01 (q, 2H, J=7.1 Hz), 7.34 (d, 2H, J=8.3 Hz), 7.38-7.42 (m, 1H), 7.47 (dd, 1H, J=7.8, 7.8 Hz), 7.60-7.65 (m, 3H), 7.69 (dd, 1H, J=1.8, 1.8 Hz); MS: m/z (MH+) 443; HRMS: calculated for C22H23ClN6O3 (M)+ 442.1, found 442.1; EA: Calculated for C21H23ClN6O3: C, 56.95; H, 5.23; N, 18.97. Found: C, 56.88; H, 5.07; N, 19.1.
Reaction SMILES: [NH4+].[OH-].C([N:6](C(C)C)CC)(C)C.[Cl:12][C:13]1[N:14]=[N:15][C:16]([Cl:22])=[CH:17][C:18]=1[C:19](Cl)=[O:20]>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[N:14]=[N:15][C:16]([Cl:22])=[CH:17][C:18]=1[C:19]([NH2:6])=[O:20]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1cc(Cl)nnc1Cl
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
A solution of NH4OH (1.1 mL, 17 mmol, 1.2 equiv) and diisopropylethylamine (6.2 mL, 36 mmol, 2.1 equiv) in THF (57 mL) was sonicated until homogeneous after which was added DMAP (1.0 g, 14 mmol, 1.0 equiv). 3,6-dichloropyridazine-4-carbonyl chloride (3.0 g, 14 mmol, 1.0 equiv) was then added and the solution was stirred at room temperature for 20 minutes. The solution was filtered and partitioned between EtOAc and 1M KHSO4 solution. The organic layer was washed once more with 1M KHSO4 and saturated NaCl, dried over Na2SO4, and evaporated to dryness to give the desired product (2.6 g, 96%).
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:7]=1N.[C-:14]#[N:15].[K+].C(=O)(O)[O-].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].C1C=CC=CC=1.C(O)(=O)C>[C:14]([C:7]1[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:6]=1[F:5])#[N:15]
Reactant: Nc1ccc(I)cc1F
Reactant: [C-]#N
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
27 g of sodium nitrite was dissolved in 205 ml of sulfuric acid and cooled to 10° C. or less, and then 238 ml of acetic acid was added. At 20° to 25° C., 65 g of 2-fluoro-4-iodoaniline was added to the solution, and then the solution was agitated for one hour. A second solution was made by dissolving 83 g of copper sulfate pentahydrate in 20.5 ml of water, to which was added 140 g of ice, and this solution was added to the first. A third solution containing 88 g of potassium cyanide dissolved in 200 ml of water, 500 g of sodium bicarbonate, and 200 ml of benzene was added to the first solution, and a diazonium salt sulfuric acid solution was added therein. After agitation at room temperature for 3 hours, a sodium hydroxide aqueous solution was added to dissolve the crystals. After being extracted with chloroform, the crystals were washed three times alternating with a 10% sodium hydroxide solution and water. After distillation of the chloroform, the residue was extracted with hexane, and the hexane was distilled off. This residue was subjected to vacuum distillation (95° to 110° C./15 mmHg), and further recrystallized to obtain 20 g of 1-cyano-2-fluoro-4-iodobenzene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([Cl:16])=[CH:10][N:9]=1>O>[Cl:16][C:11]1[CH:12]=[C:13]([O:14][CH3:15])[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: COc1cc(Cl)cnc1Br
Solvent: O
Product: COc1cc(Cl)cnc1N1CCNCC1
Yield: 32.7 %

Procedure:
Anhydrous piperazine (13.41 g) and 2-bromo-5-chloro-3-methoxypridine (3.50 g) were heated in an autoclave at 100° C. for 20 h. The mixture was dissolved in water (10 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with a saturated NaCl soution, dried with K2CO3, filtered and concentrated under reduced pressure. Silica gel chromatography (CH2Cl2 /MeOH; 90:10) of the residue yielded product (1.17 g, 33%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[N:1]1([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(CN2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1csc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
Ethyl 2-(4-morpholinylmethyl)-1,3-thiazole-4-carboxylate (260 mg) was dissolved in methanol (5 ml). Sodium hydroxide (5 ml) was added and the mixture was stirred at RT for 18 h. The solvent was removed in vacuo and water (10 ml) added. The pH was adjusted to pH 5-6 by the addition of 2M hydrochloric acid. The aqueous layer was washed with DCM (3×25 ml). The aqueous layer was loaded onto a SCX SPE cartridge (20 g) and allowed to stand for 15 min. Elution with ethanol (100 ml) followed by 2M ammonia in ethanol (100 ml) gave the title compound (121 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22]C)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[S:8][C:7]=2[CH:32]=1.C1COCC1.O.[Li+].[OH-]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[S:8][C:7]=2[CH:32]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a 30 mL vial containing (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (110 mg, 0.25 mmol) was added THF (2.00 mL), MeOH (1.00 mL). H2O (1.00 mL) and LiOH (29.5 mg, 1.23 mmol). The resulting mixture was stirred at room temperature for 60 min after which the reaction was concentrated in vacuo, diluted with water, and acidified to pH 2 with 6 M HCl causing a precipitate to form. The mixture was diluted with 20 mL DCM and 2 mL MeOH and the organic layer was collected (phase separator) and concentrated in vacuo to afford (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (98 mg, 0.23 mmol, 92% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.51-7.69 (m, 5 H), 7.43 (d, J=2.02 Hz, 1H), 7.25 (d, J=9.09 Hz, 1 H), 6.88-7.02 (m, 5 H), 6.37 (d, J=15.66 Hz, 1 H), 3.89 (s, 3 H), 3.80 (s, 3 H), LC/MS (m/z, MH+): 433.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8]
Reactant: BrCc1ccccc1
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
A solution of 2-chloro-3-methyl-4-nitrophenol (30.0g, 0.160 mol) in sieve-dried DMF (650 ml) was treated with sodium hydride (50%, 8.44g, 0.176 mol) and then benzyl bromide (30.1 g, 0.176 mol), while stirring at 0° C. The mixture was stirred at room temperature for 16 hours, then poured into 3 litres of water to precipitate an orange-coloured solid, which was recrystallised from ethanol to give 2-chloro-3-benzyloxy-6-nitrotoluene (31.3 g) m.p. 73°-74.5° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([N:9]2[C:13]3=[C:14]4[CH:20]=[CH:19][NH:18][C:15]4=[N:16][CH:17]=[C:12]3[NH:11][C:10]2=[O:21])[CH2:4]1.C(N(CC)CC)C.[N:29]([Si](C)(C)C)=[C:30]=[O:31]>CN1CCN(C)C1=O>[O:21]=[C:10]1[N:9]([C@@H:5]2[CH2:6][CH2:7][CH2:8][N:3]([C:30]([NH2:29])=[O:31])[CH2:4]2)[C:13]2=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=[C:12]2[NH:11]1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1[C@@H]1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: NC(=O)N1CCC[C@@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-[(3R)-3-piperidinyl]-3,6-dihydroimidazo-[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one dihydrochloride (20 mg) in 1,3-dimethyl-2-imidazolidinone (1 ml) was added triethylamine (51 μl) and isocyanato(trimethyl)silane (24 μl) which was stirred at 110° C. for 1 hour. The solvent was evaporated and purified by column chromatography on Hi-Flash™ (NH2)*(YAMAZEN CORPORATION) eluting with chloroform:methanol=100:0-85:15 to give (3R)-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)-1-piperidinecarboxamide (12 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.ClC1C=CC(C[CH:17]2[C:22](=[O:23])[O:21][C:20]([CH3:25])([CH3:24])[O:19][C:18]2=[O:26])=CC=1.BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(Cl)=CC=1)=C2Cl>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:17]2[C:22](=[O:23])[O:21][C:20]([CH3:25])([CH3:24])[O:19][C:18]2=[O:26])=[CH:5][CH:4]=1
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Reactant: COc1ccc(C=O)cc1
Agent: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: COc1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1

Procedure:
The title compound was prepared using 4-methoxybenzaldehyde in place of 4-chlorobenzaldehyde using the procedure described for the preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1.BrC1C=C(C)C=CN=1.[F:24][C:25]([F:52])([F:51])[C:26]1[CH:27]=[C:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][N:42]([C:45]3[C:49](Cl)=[N:48][S:47][N:46]=3)[CH2:41][CH2:40]2)=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(O)(C)(C)C>[F:52][C:25]([F:24])([F:51])[C:26]1[CH:27]=[C:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][N:42]([C:45]3[C:49]([O:15][CH2:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([Br:7])[CH:13]=4)=[N:48][S:47][N:46]=3)[CH2:41][CH2:40]2)=[O:38])[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1
Reactant: OCc1ccnc(Br)c1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: Cc1ccnc(Br)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCc2ccnc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium t-butoxide (0.070 g, 0.63 mmol) and t-butanol (0.5 mL) was added dropwise with stirring (2-bromo-pyridin-4-yl)-methanol (0.078 g, 0.42 mmol, prepared in the similar fashion as Example 16a from 2-Bromo-4-methyl-pyridine), followed by 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (0.100 g, 0.21 mmol; prepared in Example 10b). The mixture was stirred at room temperature overnight. LC/MS analysis indicated formation of the desired product. The mixture was concentrated in vacuo, and the crude product was purified on preparative HPLC to afford N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-bromopyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide (13 mg, 10% yield). 1H NMR (CDCl3) 8.40 (s, 1H), 7.95 (s, 2H), 7.45 (s, 2H), 7.25 (m, 1H), 6.6 (s, 1H), 5.45 (m, 2H), 3.6 (m, 4H), 1.6 (m, 4H) ppm.
Reaction SMILES: CCCCCC.[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:9].[Br:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29](F)=[C:30]([N+:33]([O-])=O)[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:19]=[CH:20][CH:21]=1.CCOC(C)=O>C1COCC1.C(Cl)Cl.CCCCCC.CO.CCOC(C)=O>[NH2:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:14][CH2:13][CH2:12][CH2:11][CH2:10][N:8]([CH3:9])[CH3:7])[N:26]=[CH:25][N:24]=[C:23]2[NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Br:15])[CH:17]=1
Reactant: CN(C)CCCCO
Reactant: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1F
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCCCOc1cc2ncnc(Nc3cccc(Br)c3)c2cc1N
Temperature: 20 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a suspension of hexane prewashed sodium hydride (11.0 mmol, 440 mg of a 60% dispersion in mineral oil) in THF (20 mL) was cannulated a solution of 4-(N,N-dimethylamino)butan-1-ol (8.80 mmol, 1.03 g) in THF (30 mL). The resulting suspension was stirred at 20° C. under N2 for 2 hours and then cannulated into a solution of 4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline (J Med Chem, 1996;39:918-928) (0.80 g, 2.20 mmol) in THF (30 mL) under N2. The dark red solution was then heated at reflux overnight. Identical workup as above gave, after chromatography on grade III alumina eluting with EtOAc to MeOH/EtOAc (5:95) to give 6-amino-4-[(3-bromophenyl)amino]-7-[4(N,N-dimethylamino)butyloxy]quinazoline (310 mg, 33%) as a pale brown powder, mp (CH2Cl2/hexane) 155-156° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Br:23][CH2:24][C:25](Br)=[O:26].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Br:23][CH2:24][C:25]([NH:21][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:22])=[O:26]
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CBr)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine (2.0 g, 5.54 mmol) in ethyl acetate (50 ml) were added bromoacetyl bromide (723 ml, 8.30 mmol) and saturated aqueous sodium hydrogen carbonate (50 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (2.0 g, 83%).