Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:9]([OH:30])[C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH:12](Br)[C@:11]1([S:26]([CH3:29])(=[O:28])=[O:27])[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>>[C:1]([CH:9]([OH:30])[C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@:11]1([S:26]([CH3:29])(=[O:28])=[O:27])[OH:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](C(O)C(=O)c3ccccc3)[C@](O)(S(C)(=O)=O)C2Br)c(=O)[nH]c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Product: Cc1cn([C@H]2C[C@@](O)(S(C)(=O)=O)[C@@H](C(O)C(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 50 ml round-bottom flask equipped with condenser, nitrogen inlet, and thermometer was added 5'-benzoyl-3'-methanesulfonyl-2'-bromo-thymidine (5) (3.0 g, 5.96 mmol) and 30 ml of the specified solvent (see the table below). Bu3SnH (3.0 ml, 11.15 mmol; 1.9 equiv) was then added. The reaction mixture was heated to reflux or to the temperature specified in the table, to give a clear, homogeneous solution. The reaction mixture was then cooled slightly and 300 mg AIBN was added. The mixture was heated to reflux or the temperature specified in table for 45 minutes at which time the reaction was complete by HPLC (or for a period of time as specified in the table). The mixture was then cooled to 25° C. and concentrated to give a residue. The residue was purified by silica gel column chromatography (Kiesgel 60, 230-400 mesh silica gel, 2.5×23 cm column, 3/1 EtOAc/hexane as eluent) or by methylene chloride trituration to afford 5'-benzoyl-3'-methanesulfonylthymidine (6). These results were summarized in the table.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C@H:4]1[CH2:6][O:5]1.[CH2:15](I)[CH:16]=[CH2:17]>C1(C)C=CC=CC=1.[Ag-]=O>[CH2:17]([O:1][CH2:2][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C@H:4]1[CH2:6][O:5]1)[CH:16]=[CH2:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)[C@H]1CO1
Reactant: C=CCI
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)[C@H]1CO1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl (S)-2-hydroxy-1-((S)-oxiran-2-yl)ethylcarbamate (0.125 g, 0.6 mmol; see: Kurokawa, N.; Ohfune, Y. Tetrahedron 1993, 49, 6195) in toluene (6 mL), was added allyliodide 0.3 mL, 3 mmol) followed by silver(I) oxide (0.7 g, 3 mmol). The solution was stirred at 65° C. in a darkened hood for a period of 15 h. The mixture was then cooled to ambient temperature, filtered through Celite, washed with CH2Cl2, and conc. in vacuo. Purification on SiO2 (10-20% EtoAc/Hexanes) gave the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10]C(=O)C2C=CC=CC=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].[OH-].[K+]>CO>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4]
Reactant: COC(=O)[C@@H]1[C@H](OC(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution of compound 1C (88.44 g, 0.253 mol) in anhydrous MeOH (700 mL) cooled to 0° C. was slowly added a freshly prepared 1N solution of KOH in anhydrous MeOH (367 mL, 0.367 mol) over 25 min through an addition funnel. After the addition, the light yellow solution was stirred at 0° C. for 2 h, and then the reaction was quenched by slow addition (over 25 min) of a solution of 1N HCl in dioxane/EtOAc (380 mL) through an addition funnel. The resulting white suspension was concentrated under reduced pressure to remove most of the solvent, and the remaining mixture was partitioned between water and EtOAc. The separated organic phase was washed with water (2×), saturated aqueous NaHCO3 (2×), water, brine, and then dried (Na2SO4). The filtrate was concentrated under reduced pressure to give a light yellow oily residue, which was chromatographed (silica gel) eluting first with 25-30% EtOAc/hexane, then 5% MeOH in 30% EtOAc/hexane to furnish compound 1D (44.6 g) as a pale yellow oil.
Reaction SMILES: Cl.Cl.NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3SC(CN5CCNCC5)=CC=3)=CC=CC=4)C)N=C(C3C=C(O)C=C(F)C=3)C=12.O[CH:47]([C:49]1[O:50][C:51](=[O:72])[C:52]2[C:57]([C:58]=1[C:59]1[S:60][C:61]([CH2:64][N:65]3[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]3)=[CH:62][CH:63]=1)=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH3:48].[F:73][C:74]1[CH:75]=[C:76]([C:82]2[C:90]3[C:85](=[N:86][CH:87]=[N:88][C:89]=3[NH2:91])[NH:84][N:83]=2)[CH:77]=[C:78]([O:80][CH3:81])[CH:79]=1>>[NH2:91][C:89]1[N:88]=[CH:87][N:86]=[C:85]2[N:84]([CH:47]([C:49]3[O:50][C:51](=[O:72])[C:52]4[C:57]([C:58]=3[C:59]3[S:60][C:61]([CH2:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[CH:62][CH:63]=3)=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH3:48])[N:83]=[C:82]([C:76]3[CH:77]=[C:78]([O:80][CH3:81])[CH:79]=[C:74]([F:73])[CH:75]=3)[C:90]=12
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCN(C)CC2)s1
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCNCC2)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: Cl
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCN(C)CC4)s3)c3ncnc(N)c23)c1
Yield: 62.8 %

Procedure:
The title compound was made in a similar way as that of the compound of example 134, step a, from 3-(1-hydroxyethyl)-4-(5-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)-1H-isochromen-1-one (Intermediate B39, 411 mg, 1.069 mmol), and 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate G1, 305 mg, 1.176 mmol) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(5-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)-1H-isochromen-1-one (420 mg, 0.671 mmol, 62.8% yield) as a brown solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(Cn2ccc3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A suspension of sodium hydride (60% oil dispersion, 112 mg, 2.81 mmol) in THF (12 mL) was stirred at rt and treated with a solution of 4-bromo-1H-indole (500 mg, 2.55 mmol) in THF (3 mL). After 1-2 min, the mixture was treated with 4-fluorobenzyl bromide (0.318 mL, 2.55 mmol) and the slightly cloudy solution was stirred at rt. After 20 h, the mixture was concentrated. The residue was partitioned between EtOAc and 0.1 M hydrochloric acid, and the aqueous phase was again extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 to 50:50 hexane-EtOAc) to provide 4-bromo-1-(4-fluorobenzyl)-1H-indole as a colorless oil (461.4 mg, 85% purity, 51%) contaminated by ca. 15% by weight of 4-bromo-1,3-bis(4-fluorobenzyl)-1H-indole. 1H NMR (400 MHz, chloroform-d) δ 7.28 (1 H, dd, J=7.6, 0.8 Hz), 7.19 (1 H, d, J=8.4 Hz), 7.16 (1 H, d, J=3.3 Hz), 6.94-7.09 (5 H, m), 6.60 (1 H, dd, J=3.1, 0.9 Hz), 5.28 (2 H, s). Mass spectrum m/z 304, 306 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].O1CCCC1.[F:16][C:17]1[CH:35]=[CH:34][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1>CC1C=CC=CC=1.C(O)(=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:22])([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]2)=[CH:34][CH:35]=1
Reactant: CCOC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(OC)cc2)CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a stirred and refluxing Grignard complex previously prepared starting from 112.2 parts of 1-bromo-4-methoxybenzene, 15 parts of magnesium and 540 parts of tetrahydrofuran was added dropwise a solution of 84 parts of ethyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate in 360 parts of tetrahydrofuran. Upon completion, stirring was continued for 2 hours at reflux. After cooling to 10° C., the reaction mixture was poured onto a mixture of 300 parts of crushed ice and 40 parts of acetic acid. The whole was stirred for 5 minutes. 360 Parts of methylbenzene were added. The organic layer was separated, dried, filtered and evaporated, yielding 100 parts of ethyl 4-[(4-fluorophenyl)hydroxy-(4-methoxyphenyl)-methyl]-1-piperidinecarboxylate as an oily residue (intermediate 10).
Reaction SMILES: COC(C1C=CC(C(O)=O)=NC=1)=O.C(N)(C)C.[CH:18]([NH:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][N:25]=1)=[O:23])([CH3:20])[CH3:19]>>[CH:18]([NH:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][N:25]=1)=[O:23])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)nc1
Agent: COC(=O)c1ccc(C(=O)O)nc1
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(C(=O)O)cn1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to isopropylamine via Procedure G. Crude methyl 6-(isopropylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 227 mg of 6-(isopropylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(isopropylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N5-(4-chloro-3-(pyridin-2-yl)phenyl)-N2-isopropylpyridine-2,5-dicarboxamide. MS (Q1) 395.1 (M)+.
Reaction SMILES: [ClH:1].[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[ClH:1].[CH:13]1[C:9]2[CH2:10][CH2:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCCN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Yield: 96.1 %

Procedure:
A mixture of 3.31 g of ethyl 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinebutyrate hydrochloride, 11.7 ml of 2N sodium hydroxide aqueous solution and 35 ml of methanol was refluxed for 1 hr and concentrated. Water was added to the residue, adjusted to pH 1 with 10% hydrochloric acid. The precipitate was collected by filtlation to give 2.97 g of brown solid, which was recrystallized from a mixture of ethanol and ether to give 2.48 g of colorless needles, mp 211.5°-214.5° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([S:23](=[O:26])(=[O:25])[NH2:24])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([O:11]C)=[O:10])[CH2:2][CH2:3][CH3:4]>[OH-].[Na+]>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([S:23](=[O:26])(=[O:25])[NH2:24])[C:15]=1[O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
2.5 Grams of methyl 3-n-butylamino-4-phenoxy-5-sulfamyl-benzoate were dissolved in 50 ml of 1N NaOH and the solution was heated for 30 minutes on a steam bath. The solution was then filtered and carefully acidified. 3-n-butylamino-4-phenoxy-5-sulfamyl-benzoic acid precipitation in flakes which melted at 229°-231° C. After recrystallization from ethanol/water, the melting point was 235° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH:8]1[CH2:12][C:11](=O)[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]1=O.O.[OH-].[K+]>O1CCCC1>[NH2:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1
Reactant: NC1CC(=O)N(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC1CCN(Cc2ccccc2)C1

Procedure:
34 g (0.9 mol) of lithium aluminum hydride are initially introduced under nitrogen in 500 ml of anhydrous tetrahydrofuran, and 80.8 g (0.4 mol) of 3-amino-1-benzylpyrrolidine-2,5-dione are added dropwise to the mixture as a solution in 400 ml of tetrahydrofuran. The mixture is then refluxed for 20 hours. 34 g of water in 120 ml of tetrahydrofuran, 34 g of 10% strength potassium hydroxide solution and also 136 g of water are added dropwise in succession to the mixture. The solid is filtered off with suction, washed with THF, thoroughly boiled in 250 ml of tetrahydrofuran and again filtered off with suction. The combined filtrates are concentrated in a rotary evaporator, and the residue is distilled under reduced pressure.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](C)(=[O:29])=[O:28])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].C[Mg]Cl.C(B(CCCC)CCCC)CCC.C([O-])(=O)C.[Na+].[NH2:54]OS(O)(=O)=O>C1COCC1.C(OCC)(=O)C.O>[CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:29])(=[O:28])[NH2:54])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3S(C)(=O)=O)CC2)nn1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCCCB(CCCC)CCCC
Agent: C[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3S(N)(=O)=O)CC2)nn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.1 %

Procedure:
To an ice-cold solution of 6-[4-(2-methanesulfonylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (3-methylbutyl)amide (0.078 g, 0.17 mmol) in 5 mL of THF cooled was added methyl magnesium chloride (0.071 mL, 0.212 mmol). The resulting mixture was stirred for 15 minutes at 0° C., and then 30 minutes at ambient temperature. The reaction mixture was cooled to 0° C. again, then tributylborane (0.255 mL, 0.255 mmol) was added. The mixture was stirred at ambient temperature for 30 minutes, then heated to reflux for 18 h. After the mixture was cooled to 0° C., sodium acetate, water and hydroxylamine-o-sulfonic acid (0.067 g) were added. The mixture was stirred for 3 h, and then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried and concentrated in vacuo. The residue was purified by flash column chromatography using 20% methanol in ethyl acetate to yield the title product (0.033 g, 42% yield). 1H NMR (300 MHz, CDCl3) δ 8.58, 7.98, 7.81, 7.75-7.68, 7.64-7.58, 7.43, 7.19, 4.03-3.88, 3.78-3.59, 3.21-3.20, 3.152-3.147, 1.65-1.50, 1.46-1.35, 0.85. 13C NMR (75 MHz, CDCl3) δ 170.1, 165.5, 161.7, 146.3, 139.1, 137.3, 135.5, 131.3, 130.9, 128.8, 127.9, 114.4, 45.6, 45.2, 44.96, 42.6, 39.5, 38.8, 27.1, 22.9. MS (ES+) m/z 460.1 (M+1).
Reaction SMILES: [CH2:1]([CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](N)[CH:19]=[CH2:20]>>[CH2:20]([NH:11][C:9](=[S:10])[CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH:19]=[CH2:18]
Reactant: NC(=S)C(Cc1ccccc1)c1ccccn1
Reactant: C=CCN
Product: C=CCNC(=S)C(Cc1ccccc1)c1ccccn1

Procedure:
By the procedure of Example 7, 2-benzyl-2-(2-pyridyl)thioacetamide is reacted with allylamine to give N-allyl-2-benzyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][CH2:18][C:19]([OH:21])=[O:20]>I.C(OC(=O)C)(=O)C>[OH:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: COc1c(CCC(=O)O)cccc1Oc1ccccc1Cl
Agent: I
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCc1cccc(Oc2ccccc2Cl)c1O
Yield: 41.9 %

Procedure:
3-[2-Methoxy-3-(2-chlorophenoxy)phenyl]propionic acid (5.0 g) was dissolved in a mixture of 48% hydriodic acid (30 ml) and acetic anhydride (15 ml). The mixture was treated in a similar manner to that of Example 1-(5) and recrystallized from a mixture of benzene and n-hexane to give colorless crystals of 3-[2-hydroxy-3-(2-chlorophenoxy)phenyl]propionic acid (2.0 g). mp 90°-92° C.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:12])[O:10][CH3:11])#[N:2].[Br:13]Br>C(O)(=O)C>[Br:13][C:6]1[S:5][C:4]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:3]([C:1]#[N:2])[CH:7]=1
Reactant: COC(=O)Nc1sccc1C#N
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)Nc1sc(Br)cc1C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of compound methyl 3-cyanothiophen-2-ylcarbamate (11.5 g, 63 mmol) in acetic acid (500 mL) was added bromine (12 g, 75 mmol) at room temperature. The solution was heated at 60° C. with stifling for 1 hour and then concentrated and treated with water (500 mL). It was extracted with ethyl acetate (3×300 mL) and the combined extracts were dried over sodium sulfate and concentrated to give 14 g (89%) of methyl 5-bromo-3-cyanothiophen-2-ylcarbamate as a solid. 1H NMR 400 MHz CDCl3 δ 3.89 (s, 3H), 6.90 (s, 1H), 8.05 (s, 1H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([NH:24][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of benzenesulfonyl chloride (722 μL, 0.00566 mol), potassium carbonate (0.939 g, 0.00679 mol) in acetonitrile (15 mL, 0.29 mol) was added tert-butylamine (0.652 mL, 0.00623 mol). The resulting mixture was stirred at r.t. for 30 minutes, followed by filtration and concentration. The resulting residue was diluted with ethyl acetate, and the resulting solution was washed with water then with brine, then dried with MgSO4 followed by concentration. The crude material was purified by flash chromatography on silica gel with 40% AcOEt in hexanes to give the desired compound (1.21 g, 85% yield). MS (ESI): 236.0 (M+Na+).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[C:13]2=[O:24])=[CH:8][CH:7]=1.O.CO>C1COCC1.C(Cl)Cl>[CH3:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:14]1[CH2:15][CH2:16][N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:25])=[O:4])=[CH:7][CH:8]=2)[C:13]1=[O:24]
Reactant: COC(=O)c1ccc(N2CCN(c3cnccc3C)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccncc1N1CCN(c2ccc(C(=O)O)cc2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
LiOH (46.4 mg, 3.782 mmol) was added to a stirred solution of 4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid methyl ester (230 mg, 0.7387 mmol) in (3:2:1) THF (10 mL, water (6 mL) and MeOH (3 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was concentrated under reduced pressure, followed by the addition of ice water and neutralized with 1N HCl till a pH of about 2 was attained. The precipitate was collected and dried under reduced pressure to afford 210 mg of 4-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid (95% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.O>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH:12]=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2cc3c(C=O)c[nH]c3cc2Cl)c1
Yield: 52.5 %

Procedure:
To a solution of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (300 mg, 2 mmol) in dioxane/DMF=1/1 (4 mL) was added (3-methoxyphenyl)boronic acid (463 mg, 1.8 mmol), potassium carbonate (828 mg, 6 mmol) in water (1 mL), and Pd (dppf)Cl2 (50 mg) in a microwave vial. The sealed vial was irradiated in the microwave on a Biotage Smith Synthesizer at 110° C. for 30 min, TLC (petroleum ether/ethyl acetate=1:1) showed the reaction was complete. The solvent was removed in vacuo and the mixture was partitioned between ethyl acetate and water. The combined organics were dried over sodium sulfate, concentrated in vacuo, and purified by combi-flash to give the title compound (270 mg, 47%) as a yellow solid
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH2:20][CH:19]1[CH:24]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:25][CH:26]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:17])C1C=CC=CC=1>C(OCC)(=O)C>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH2:20][CH:19]1[CH:24]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:25][CH:26]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:17]
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCNC(=O)OCc2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
Compound 4a (14.5 g, 21.7 mmol) was dissolved in ethyl acetate (100 mL) and purged with argon. To the solution was added 10% palladium on carbon (2 g). The flask was purged with hydrogen 2 times and stirred further at room temperature under hydrogen atmosphere for overnight. The disappearance of the starting material was confirmed by the TLC. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The combined organic layer was concentrated under reduced pressure to afford compound 5 (10.56 g, 91%) as white solid. This was used as such for the next step.